Fight Aging!

One of the most interesting areas of research into aging at the moment is the question of whether detrimental epigenetic changes that occur in cells throughout the body with age, altering cell behavior for the worse, are caused by the operation of DNA repair processes in response to stochastic damage to nuclear DNA. The concept and animal study evidence are recent enough that it should be considered speculative, and any of the details published to date subject to revision.

If true, however, this relationship in which DNA repair causes epigenetic aging would neatly resolve a range of challenges in the understanding of the role of nuclear DNA damage in aging. For example that mutational damage to nuclear DNA doesn't appear to cause enough harm to cell function to explain the major changes that occur with age. Most nuclear DNA damage occurs in somatic cells with few cell divisions remaining, limiting the spread of the mutation, and occurs in gene sequences that don't much matter or are not even used.

Somatic mosiacism, the spread of mutations over time from stem cell populations out into the tissues they support via the vector of daughter somatic cells, can somewhat salvage this situation by amplifying a tiny number of mutations into widespread existence. However, present investigations of the role of clonal hematopoiesis of indeterminate potential, the name given to somatic mosaicism in hematopoietic cells and the immune system, suggest that it isn't harmful enough to explain very much of aging. It raises risks, it isn't driving degeneration.

Today's open access paper is a recent exploration of epigenetic change induced by DNA damage, employing a mouse model generated a few years ago. Here, this model is crossbred with an Alzheimer's disease model in order to look at relevance to that condition. Cynically, one should assume that this choice of direction in research is driven as much by the funding incentives as the reasonable scientific rationale for the relevance of a mechanism of aging to any specific age-related condition, as work on Alzheimer's disease represents a sizable fraction of all public funding for aging research. Still, all significant new work on this issue of DNA repair and epigenetic change is welcome.

DNA Break-Induced Epigenetic Alterations Promote Plaque Formation and Behavioral Deficits in an Alzheimer's Disease Mouse Model

The dramatic increase in human longevity over recent decades has contributed to a rising prevalence of age-related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD). While accumulating evidence implicates DNA damage and epigenetic alterations in the pathogenesis of AD, their precise mechanistic role remains unclear. To address this, we developed a novel mouse model, DICE (Dementia from Inducible Changes to the Epigenome), by crossing the APP/PSEN1 (APP/PS1) transgenic AD model with the ICE (Inducible Changes to the Epigenome) model, which allows for the controlled induction of double-strand DNA breaks (DSBs) to stimulate aging-related epigenetic drift.

We hypothesized that DNA damage induced epigenetic alterations could influence the onset and progression of AD pathology. After experiencing DNA damage for four weeks, DICE mice, together with control, ICE, and APP/PS1 mice, were allowed to recover for six weeks before undergoing a battery of behavioral assessments including the open-field test, light/dark preference test, elevated plus maze, Y-maze, Barnes maze, social interaction, acoustic startle, and pre-pulse inhibition (PPI). Molecular and histological analyses were then performed to assess amyloid-β pathology and neuroinflammatory markers.

Our findings reveal that DNA damage-induced epigenetic changes significantly affect cognitive behavior and alters amyloid-β plaque morphology and neuroinflammation as early as six months of age. These results provide the first direct evidence that DNA damage can modulate amyloid pathology in a genetically susceptible AD model. Future studies will be aimed at investigating DNA damage-induced epigenetic remodeling across additional models of AD and neurodegeneration to further elucidate its role in brain aging and disease progression.

Butyrate is one of the better known metabolites generated by microbial populations within the gut microbiome, a product of the fermentation of dietary fiber. Butyrate has been shown to produce beneficial effects in a range of tissues, such as via increased BDNF signaling to improve brain and muscle health. Production of butyrate declines with age, a consequence of harmful shifts in the composition of the gut microbiome that take place with age. Here, researchers show that butyrate is senomorphic, in that is reduces the number of cells entering a senescent state. This sort of effect is thought to be beneficial over time, as it allows the normal mechanisms of senescent cell clearance, impaired with age but still operating, to catch up and reduce the age-related burden of senescence.

Advancing age is accompanied by an accumulation of senescent T cells that secrete pro-inflammatory senescence-associated secretory phenotype (SASP) molecules. Gut-microbiota-derived signals are increasingly recognised as immunomodulators. In the current study, we demonstrated that ageing and the accumulation of senescent T cells are accompanied by a reduction in microbial-derived short-chain fatty acids (SCFAs).

Culturing aged T cells in the presence of butyrate suppresses the induction of a senescence phenotype and inhibits the secretion of pro-inflammatory SASP factors, such as IL6 and IL8. Administration of faecal supernatants from young mice rich in butyrate prevented in vivo accumulation of senescent spleen cells in aged mice. The molecular pathways governing butyrate's senomorphic potential include a reduced expression of DNA damage markers, lower mitochondrial reactive oxygen species (ROS) accumulation, and downregulation of mTOR activation, which negatively regulates the transcription factor NFκB.

Our findings establish butyrate as a potent senomorphic agent and provide the evidence base for future microbiome restitution intervention trials using butyrate supplements for combating T cell senescence, ultimately reducing inflammation and combating age-related pathologies to extend lifelong health.

Link: https://doi.org/10.1111/acel.70257

Scar tissue is formed by excess deposition of extracellular matrix molecules such as collagen. It obstructs complete healing. In aged tissues, fibrosis is a form of inappropriate scarring and consequent loss of function produced by the disruption of normal tissue maintenance. Researchers here provide evidence for scarring following injury to be driven by a subpopulation of monocytes and macrophages, types of myeloid immune cell. The pro-fibrotic behavior of these cells is triggered by mechanical cues. Mechanosensing is a complex set of regulatory pathways by which cells react to the mechanical properties of the surrounding environment, such as degree of tissue stiffness or mechanical stresses placed upon the tissue. These regulatory pathways can be manipulated via drugs and genetic engineering, just like others, and this opens the door to a novel approach to reducing scar formation following injury.

In response to injury, a variety of different cells are recruited to sites of injury to facilitate healing. Recent studies have examined the importance of the heterogeneity of tissue resident fibroblasts and mechanical signalling pathways in healing and fibrosis. However, tissue repair and the inflammatory response also involves blood cells that are recruited from the circulation.

Here we identify mechanoresponsive myeloid subpopulations present in scar and unwounded skin. We then modulate these subpopulations by manipulating mechanical strain in vivo and in vitro and find that specifically targeting myeloid mechanical signalling is sufficient to reduce the pro-fibrotic myeloid subpopulations and restore the native, anti-inflammatory subpopulations.

In addition, myeloid-specific mechanotransduction ablation also downregulates downstream pro-fibrotic fibroblast transcriptional profiles, reducing scar formation. As inflammatory cells circulate and home to injury sites during the initial healing phases in all organs, focusing on mechanoresponsive myeloid subpopulations may generate additional directions for systemic immunomodulatory therapies to target fibrosis and other diseases across other internal organ systems.

Link: https://doi.org/10.1038/s41551-025-01479-5

On the one hand there is a modest amount of evidence for GLP-1 receptor agonist drugs to produce beneficial effects on an aged metabolism that are unconnected to weight loss. On the other hand, when Big Pharma has a very successful drug, it will attempt to use that drug for every condition it can that is associated with a sizable market, whether or not the expected effects are marginal. So it isn't necessarily indicative of support for these non-weight-loss mechanisms that leads the clinical trial of a weight loss drug for patients with Alzheimer's disease. Cynically, it is that Alzheimer's is an enormous market.

The present state of regulation makes it more cost-effective for companies to push existing drugs into new marginal uses than it is to develop new drugs that are actually effective for that new use. At times, it seems that the entire world cares nothing for how well a drug, a supplement, any intervention actually works at its given task. Effect sizes are boring, a dead letter. Drugs that do relatively little and only marginally slow progression of a condition are marketed aggressively and have huge sales. Big Pharma is far from the only culprit in this matter, of course. Just look at the supplement industry.

That a weight loss drug produces weight loss but at the same time fails to slow Alzheimer's disease might be taken as another data point to illustrate that the relationship between obesity and Alzheimer's disease is very different in character to, say, the robust and very direct relationship between obesity and type 2 diabetes. Yes, being overweight appears to be a risk factor that plays into Alzheimer's disease, but it isn't as strong a relationship, indicating a great deal more complexity and variation from individual to individual in the mechanisms involved.

Novo Nordisk A/S: Evoke phase 3 trials did not demonstrate a statistically significant reduction in Alzheimer's disease progression

Novo Nordisk today announced the top-line results from the 2-year primary analysis of evoke and evoke+ phase 3 trials in early-stage symptomatic Alzheimer's disease. The two trials were randomised, double-blinded, enrolled a total of 3,808 adults and evaluated the efficacy and safety of oral semaglutide compared to placebo on top of standard of care. The decision to pursue an Alzheimer's disease indication with semaglutide was based on real-world evidence studies, pre-clinical models as well as post-hoc analyses from diabetes and obesity trials.

The evoke and evoke+ trials did not confirm superiority of semaglutide versus placebo in the reduction of progression of Alzheimer's disease, as measured by the change in Clinical Dementia Rating - Sum of Boxes (CDR-SB) score compared to baseline. While treatment with semaglutide resulted in improvement of Alzheimer's disease-related biomarkers in both trials, this did not translate into a delay of disease progression.

The chemistry of molecules in solution is dynamic and complex, such as the spontaneous liquid-liquid phase separation in which a solution divides into regions of greater and lesser concentrations to form droplets. This process is important in the formation of protein aggregates involved in neurodegenerative disease. Here, researchers show that the α-synuclein that misfolds and aggregates to cause Parkinson's disease does not undergo liquid-liquid phase separation on its own, but rather is dragged into the liquid-liquid phase separation and droplet formation of another protein, UBQLN2. This suggests possible novel targets to interfere in this chemistry.

Some neurodegenerative disease-associated proteins form liquid droplets via liquid-liquid phase separation (LLPS). Over time, these droplets transition from a highly labile liquid state to a hydrogel state, and eventually to a solid-like condensate, via self-interaction and oligomerization of the proteins within, thereby leading to the formation of amyloid fibrils. Recently, α-synuclein (α-syn) has been reported to be one such protein. However, the precise molecular events involved in the early stages of α-syn aggregation remain controversial.

In this study, we show that α-syn aggregation is promoted by droplets formed by ubiquilin-2 (UBQLN2), rather than by α-syn LLPS itself. During the liquid-gel/solid transition of UBQLN2 droplets, α-syn within the droplets transforms into pathogenic fibrils both in vitro and in cells. Immunohistochemistry of brain sections from sporadic Parkinson's disease patients revealed UBQLN2 in substantia nigra Lewy bodies, implicating UBQLN2 in α-syn aggregation in vivo. Furthermore, the small molecule 1,2,3,6-tetra-O-benzoyl-muco-inositol (SO286) inhibited both UBQLN2 self-association and its interaction with α-syn by binding to the STI1 domain, thereby suppressing α-syn aggregation.

These findings demonstrate that UBQLN2 droplets catalyze α-syn fibrillization and suggest that small molecules targeting fibril-catalyzing proteins such as UBQLN2 may represent a promising therapeutic approach for neurodegenerative diseases.

Link: https://doi.org/10.1038/s44318-025-00591-1

Brown fat, or adipose tissue, is responsible for generating heat to maintain body temperature. Research has shown its presence and activity to be beneficial in the context of aging, in that the presence of more brown adipose improves long-term health. However, like all tissues, brown adipose tissue becomes dysfunctional with age. Here, researchers investigate what appears to be an important mechanisms in this process, in which brown fat adipocyte cells and macrophage cells of the innate immune system interact in ways that provoke inflammation and dysfunction.

Loss of brown adipose tissue (BAT) activity observed during ageing, obesity, and living at thermoneutrality is associated with lipid accumulation, fibrosis, and tissue inflammation in BAT. The mechanisms that promote this degenerative process of BAT remain largely enigmatic. Here, we show that an imbalance between sympathetic activation and mitochondrial energy handling causes BAT degeneration, which leads to impaired energy expenditure and systemic metabolic disturbances.

Mechanistically, we demonstrate that brown adipocytes secrete adenosine triphosphate (ATP) in response to imbalanced thermogenic activation, which activates the P2X4 and P2X7 receptors of BAT-resident macrophages. Notably, mice lacking activity of these purinergic receptors in myeloid cells are protected against BAT inflammation, thermogenic dysfunction, and systemic metabolic disturbances under conditions of imbalanced BAT activation, thermoneutrality, or overnutrition. These results highlight the relevance of extracellular ATP released by brown adipocytes as a paracrine signal for myeloid cells to initiate BAT degeneration.

Link: https://doi.org/10.1038/s44319-025-00642-y

Stem cells exist in order to minimize the number of cells capable of unrestricted replication; most cells in the body are limited in the number of times that they can divide. This limit serves to reduce the risk of cancer - and other severe disruptions that could result from unlimited replication of a malfunctioning cell - to an acceptably low level to enable evolutionary success. Stem cells provide a supply of daughter somatic cells to replace those that are lost over time, due to limited somatic cell replication. In actuality, stem cells spend much of their time in a state of quiescence, without replicating. This is necessary to preserve their function and minimize damage over the course of a lifetime. When forced into excessive activity, stem cells risk a state of exhaustion, becoming dysfunctional and displaying harmful alterations in behavior.

Hematopoietic stem cells reside in the bone marrow and are responsible for generating immune cells and red blood cells. The dysfunctions that arise with aging in this cell population, such as a growing bias towards the production of myeloid cells at the expense of lymphoid cells, appear similar to the dysfunctions that arise when hematopoietic stem cells are forced into exhaustion by excessive replication. In today's open access paper, researchers explore the relevance to hematopoietic stem cell aging of IL-10 signaling intended to bring an end to an acute episode of inflammation, such as in response to an infection that is now defeated. Hematopoietic stem cells must be ever ready to produce large numbers of immune cells to help defend the body, but at the same time they must also return to quiescence when that danger is passed. The chronic inflammation of aging may well sabotage this balance, driving ever greater dysfunction in the production of immune cells.

Impaired IL-10 Receptor Signaling Leads to Inflammation Induced Exhaustion in Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) are maintained in quiescence, which protects this pool from the damaging effects of excessive proliferation. Quiescence is tightly regulated by intrinsic programs, including FoxO3a, p53, and cyclin-dependent kinase inhibitors, and by extrinsic cues such as TGF-beta and Notch. Under homeostatic conditions, HSCs remain largely dormant but can rapidly activate in response to inflammatory stimuli, such as infection, to support emergency hematopoiesis. A timely return to quiescence after activation is essential to prevent stem cell exhaustion, which occurs if cycling persists.

Many hallmarks of stem cell exhaustion, including impaired regenerative capacity, expansion of phenotypic HSCs with reduced function, increased inflammatory signaling, and a shift toward myeloid-biased differentiation, mirror features of aged hematopoiesis. Aging is associated with chronic, low-grade inflammation that stresses the HSC pool, driving both functional decline and selective pressure for clones that resist inflammation-induced exhaustion.

Although much is known about maintaining HSC quiescence under steady-state conditions, the signals that govern the return to quiescence after inflammatory activation remain poorly defined. In other cell types IL-10 is an anti-inflammatory cytokine that restrains excessive immune activation by suppressing responses downstream of Toll-like receptor (TLR) stimulation. We identify IL-10 receptor (IL-10R) signaling as critical for returning HSCs to quiescence. IL-10R blockade prolongs HSC cycling and sustains activated transcriptional programs after acute inflammation. With chronic exposure, blockade increases cumulative divisions and accelerates aging hallmarks, including myeloid bias, loss of polarity, and functional defects, under conditions that do not otherwise exhaust HSCs when IL-10R signaling is intact. Our findings identify IL-10R signaling as a key coordinator of post inflammatory return to quiescence and suggest that modulating this axis could preserve HSCs and shape clonal hematopoiesis.

Age-related loss of function in hematopoietic stem cells resident in the bone marrow is an important component of immune system aging, and thus important to aging as a whole. There is a tendency to think of cells only in terms of chemistry, but some of that chemistry is linked to structure, mechanical forces, and the physical properties of surrounding tissues. Researchers here find that RhoA, a key protein in a cell's response to mechanical stimulus, is important in loss of function in aged hematopoietic stem cells. It is something of an open question as to how much of this importance is driven by changes in the mechanical properties of surrounding tissues versus epigenetic changes inside the cell that affect its structure, but RhoA inhibition clearly restores some degree of lost hematopoietic function regardless of the precise details.

Biomechanical alterations contribute to the decreased regenerative capacity of hematopoietic stem cells (HSCs) upon aging. Mechanical forces trigger multiple signaling pathways that converge in the activation of RhoA, which is a small RhoGTPase that can cycle between an active (RhoA-GTP) and an inactive (RhoA-GDP) status. RhoA is a key regulator of mechanotransduction regardless of whether the activating mechanical stimulus is cell extrinsic, as occurs in cells responding to alterations of substrate stiffness, or cell intrinsic, such as, for example, when the cell nucleus acts as a mechanosensor of genomic changes.

Here we show that murine HSCs respond to increased nuclear envelope (NE) tension by inducing NE translocation of P-cPLA2, which cell-intrinsically activates RhoA. Aged HSCs experience physiologically higher intrinsic NE tension, but reducing RhoA activity lowers NE tension in aged HSCs. Feature image analysis of HSC nuclei reveals that chromatin remodeling is associated with RhoA inhibition, including restoration of youthful levels of the heterochromatin marker H3K9me2 and a decrease in chromatin accessibility and transcription at retrotransposons.

Finally, we demonstrate that RhoA inhibition upregulates Klf4 expression and transcriptional activity, improving aged HSC regenerative capacity and lymphoid/myeloid skewing in vivo. Together, our data outline an intrinsic RhoA-dependent mechanosignaling axis, which can be pharmacologically targeted to restore aged stem cell function.

Link: https://doi.org/10.1038/s43587-025-01014-w

It is well established that excess visceral fat is harmful to health. The primary mechanism is likely that this tissue provokes chronic inflammation in a variety of ways, from increased cellular senescence to mimicking the signaling produced by infected cells. It is also well established that muscle tissue is protective in later life, however here the underlying mechanisms are less well understood. Muscle tissue is just as metabolically active as visceral fat, and generates a variety of signal molecules that alter the behavior of cells throughout the body, particularly following exercise. Cataloging these signals and their effects is an active area of ongoing research.

Researchers have found that a specific body profile - higher muscle mass combined with a lower visceral fat to muscle ratio - tracks with a younger brain age. Brain age is the computational estimation of chronological age from a structural MRI scan of the brain. Muscle mass, as tracked by body MRI, can be a surrogate marker for various interventions to reduce frailty and improve brain health, and brain age predicted by structural brain images can lend insight to Alzheimer's disease risk factors, such as muscle loss.

For the ongoing study, 1,164 healthy individuals (52% women) were examined with whole-body MRI. The mean chronological age of the participants was 55.17 years. The researchers combined MRI imaging with T1-weighted sequences, a technique that produces images where fat appears bright and fluid appears dark. This allows for optimal imaging of muscle, fat and brain tissue. A machine learning algorithm was used to quantify total normalized muscle volume, visceral fat (hidden belly fat), subcutaneous fat (fat under the skin) and brain age.

The researchers found that a higher visceral fat to muscle ratio was associated with higher brain age, while subcutaneous fat showed no significant association with brain age. Building muscle and reducing visceral fat are actionable goals. Whole-body MRI and brain-age estimates provide objective endpoints to design and monitor interventions, including programs or therapies under study that lower visceral fat while preserving muscle.

Link: https://www.rsna.org/media/press/2025/2614

Lysosomes are a vital component in the recycling systems of the cell, organelles that break down harmful or unwanted molecules in order to provide raw materials for manufacture of new molecules. As is the case for all cell components, lysosomes become dysfunctional with age. The buildup of persistent metabolic waste, such as lipofuscin, that cells struggle to break down is implicated in age-related lysosomal dysfunction in long-lived cells, such as neurons. Sweeping epigenetic and transcriptomic changes that alter the production of proteins occur with age in all cells, and it is likely that a subset of these changes contributes meaningfully to impaired lysosomal function.

Today's open access paper is interesting not just for the connection between specific forms of lysosomal dysfunction and hematopoietic stem cell aging, and thus the aging of the immune system, but also because the researchers involved found that a vacuolar ATPase inhibitor can reverse this dysfunction. Vacuolar ATPases are responsible for acidifying lysosomes, among other activities, and the specific issue identified in aged hematopoietic stem cells is that their lysosomes are overly acidic. When lysosomes cease to function efficiently, as appears to happen in this circumstance, the whole cell suffers because harmful molecules are not cleared and recycled in good time. As the researchers point out, this includes mislocalized DNA from mitochondria that can trigger inflammatory pathways. Restoring lysosomal function in aged cells reduces inflammatory signaling and improves cell health.

Scientists Reverse Aging in Blood Stem Cells by Targeting Lysosomal Dysfunction

Lysosomes are specialized structures that act as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. Lysosomes accumulate and degrade waste, and eventually recycle it to be reused in biosynthetic processes. Lysosomes can also store nutrients to be released when needed. Lysosomes are recognized as pivotal for regulating metabolism in the cell, both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).

As people age, hematopoietic stem cells (HSCs) become defective and lose their ability to renew and repair the blood system, decreasing the body's ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.

Researchers discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells' metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function. The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out "inflammation" signals that can cause damage in the body.

Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells

Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging - beyond their passive mediation of autophagy - is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.

As you might be aware, the genetic differences present in Down syndrome patients produce a dramatic acceleration of amyloid-β aggregation, tau aggregation, and the other pathologies of Alzheimer's disease. Researchers here describe the discovery of a variant in the gene CSF2RB in a subset of Down syndrome patients that resist loss of cognitive function, and show that it improves the function of microglia. Microglia are innate immune cells resident in the brain. Increased inflammation and dysfunction in this cell population is strongly implicated in neurodegenerative conditions such as Alzheimer's disease. When equipped with the variant CSF2RB, microglia are less inflammatory and more capable when exposed to Alzheimer's-related protein aggregates - which may be enough to explain the resilience of patients with this gene variant.

Alzheimer's disease causes progressive cognitive decline, yet some individuals remain resilient despite developing hallmark pathology. A subset of people with Down syndrome (DS), the most common genetic cause of Alzheimer's disease, demonstrates such resilience. Given the elevated risk of hematopoietic mutations in DS, we hypothesize that certain variants may confer microglial resilience.

Here, we introduce a myeloid DS-linked CSF2RB A455D mutation into human pluripotent stem cell-derived microglia from both donors with DS and healthy donors and study their function in 4 to 10-month-old chimeric mice. We find that this mutation suppresses type I interferon signaling in response to tau pathology, reducing inflammation while enhancing phagocytosis, thereby ameliorating microglial senescence.

Thus CSF2RB A455D-expressing microglia form a unique protective subpopulation and preserve neuronal functions. Importantly, they replace diseased wild-type microglia after tau exposure. These findings provide proof of concept that engineered human microglia can enhance resilience against tauopathy, opening avenues for microglial replacement therapies.

Link: https://doi.org/10.1038/s41593-025-02117-8

Researchers here point out that inflammatory bowel disease can produce intestinal dysfunction that is in ways similar to the intestinal dysfunction that occurs in aging, but the underlying mechanisms are quite different. It is a good example of the way in which forms of cell and tissue damage can produce dysfunction that appears superficially similar to aging, even when the damage is not the same as occurs during aging. This is true for DNA repair deficiencies that lead to excessive DNA damage, far more than occurs with aging, for example, or for the excessive accumulation of broken lamin A in progeria that doesn't occur to a large degree in normal aging.

Inflammatory bowel disease (IBD) and physiological gut aging present with overlapping clinical features, including impaired barrier functioning, decreased nutrient absorption, and intestinal frailty. Emerging evidence indicates that even young IBD patients can exhibit gut phenotypes akin to those seen with aging. However, the two processes differ substantially in their underlying mechanisms.

Gut aging is characterized by low-grade, chronic inflammation, and gradual cellular senescence, whereas IBD involves persistent immune activation, cyclical tissue damage, and accelerated degenerative changes. This review systematically contrasts physiological gut aging and IBD-associated accelerated gut aging across several dimensions: cellular senescence and programmed cell death, immune cell remodeling, alterations in gut microbiota, changes in mesenteric adipose tissue, and the evolving role of the appendix.

By integrating current advances in basic and translational research, this article highlights both the shared and distinct pathways driving gut dysfunction in aging and IBD, and underscores the importance of early recognition and targeted intervention for premature gut aging in clinical practice.

Link: https://doi.org/10.5582/bst.2025.01279

One of the ways in which transplanted stem cells aid native cells in the short period of time before they die is by transferring mitochondria. This happens in much the same way as the cells also transfer signals via extracellular vesicles. A mitochondrion and a vesicle are both membrane-wrapped packages of molecules, albeit that the former is much more complex and functional. Mitochondria are important to cell function, as they generate the chemical energy store molecule adenosine triphosphate (ATP) required to power the cell.

Unfortunately, loss of mitochondrial function occurs with age, and is thought to be an important component of degenerative aging. The roots of age-related mitochondrial dysfunction are complex, involving damage to mitochondrial DNA, epigenetic changes that alter the expression of important mitochondrial genes, failure of the quality control mechanisms of mitophagy, and so forth. Transferring in new, youthful mitochondria harvested from cell cultures has been shown to help, and a few companies are working on the manufacturing techniques needed to make this form of therapy a reality. What if existing stem cell therapies could be made more effective as a vector for the provision of new mitochondria, however? That question is explored in today's open access paper, a followup to work published last year.

Nanomaterial-induced mitochondrial biogenesis enhances intercellular mitochondrial transfer efficiency

Intercellular mitochondrial transfer has emerged as a fundamental biological process whereby cells exchange mitochondria to mitigate stress and promote tissue repair, an extension of mitochondrial movement and cellular communication. Occurring in a wide variety of cells, this innate mechanism has the potential to be co-opted to support local energy demands where existing mitochondrial networks struggle. Mesenchymal stem cells (MSCs) display a particular propensity for initiating mitochondrial transfer to nearby cells; their mitochondria enhance cellular respiration, induce cell reprogramming, and repair metabolic function in recipient cells. Due to their lower energy demands, MSCs are favored for mitochondrial transfer to diseased cells with high bioenergetic needs. Their immune privilege, availability from various sources, and ease of use render MSCs ideal donor cells for delivering healthy mitochondria.

However, despite growing recognition of the therapeutic potential of mitochondrial transfer, its widespread adoption is hindered by limited rates of mitochondrial translocation. Existing methods to enhance transfer rates-such as overexpressing mechanistic proteins like the motor protein Miro1 and gap junction Cx43, or engineered techniques like MitoCeption and MitoPunch, are cumbersome and labor-intensive. Consequently, despite advances in understanding intercellular mitochondrial transfer, current therapeutic strategies often fall short due to limited efficacy and challenges in delivery, underscoring the need for new approaches.

To address these limitations, we have developed a biomaterial-based therapeutic strategy employing molybdenum disulfide (MoS2) nanoflowers with atomic-scale modifications to transform human mesenchymal stem cells (hMSCs) into mitochondrial biofactories. The increased mitochondrial content within MSCs enhances their capacity for intercellular mitochondrial transfer via tunneling nanotubes (TNTs). Utilizing nanomaterial platforms allows us to bypass limitations in transfer rates and eliminates the need for complex genetic interventions or extensive use of systemically administered drugs targeting mitochondrial function. This method capitalizes on the natural propensity of MSCs to transfer mitochondria, amplifying this capability through available mitochondrial mass. Our findings underscore the potential of nanomaterial-enhanced intercellular mitochondrial transfer as a viable therapeutic option for treating a wide range of mitochondrial dysfunctions.

In studies in mice, it is much easier to show a slowing of atherosclerotic plaque growth over time than it is to show regression of existing plaque. Only a tiny number of approaches have shown any robust ability to regress obstructive plaque in the arteries once it has formed. Thus one should suspect that any new approach presented with data to show a slowing of plaque growth may not actually have the capacity to regress plaque - otherwise the researchers would have presented that much more desirable outcome instead.

Here, researchers turn the well established approach of engineering T cells to have chimeric antigen receptors to the problem of oxidized LDL particles. LDL particles carry cholesterol from the liver out into the body, and when they become oxidized they cause additional stress to cells and accelerate the development of plaque by worsening an already toxic plaque environment in blood vessel walls. Engineering T cells to target and clear oxidized LDL particles is clearly beneficial, producing a sizable slowing of plaque growth. This reinforces other lines of research indicating that oxidized LDL is an important mechanism in these mouse models.

CAR T cell therapy has revolutionized treatment for blood cancers. It works by engineering a patient's own T cells in the lab and training them to recognize a marker found on cancer cells, creating an immune response that destroys the cancer. Scientists have been exploring the potential of this powerful technology to treat other diseases. Researchers have now engineered a CAR regulatory T cell (Treg) that targets oxidized LDL (OxLDL), the main inflammation-stoking form of LDL cholesterol that drives plaque buildup in atherosclerosis.

Initial lab-dish tests with human cells confirmed that the anti-OxLDL CAR Tregs suppress inflammation in response to OxLDL, greatly reducing the buildup of the cells that are a central feature of atherosclerotic plaques. The team then engineered a mouse version of the anti-OxLDL CAR-Treg and tested it in mice that were genetically predisposed to high cholesterol and atherosclerosis. After about twelve weeks of treatment, the treated mice's hearts and aortas showed a roughly 70 percent lower atherosclerotic plaque burden compared to control mice - indicating a clear preventive effect of the CAR-Tregs. Despite this effect, there was no disruption of general immune function in the treated mice.

Link: https://www.eurekalert.org/news-releases/1106906

The amino acid arginine has been shown to act as a chaperone, or improve the ability of existing chaperone molecules to reduce aggregation of misfolded proteins such as the amyloid-β associated with the development of Alzheimer's disease. Researchers here supplement the diets of mice with sizable doses of arginine in order to produce effects on amyloid-β aggregation; the equivalent dose in humans would be something like 1 gram per kilogram of body weight, daily. One caveat is that the mouse model of Alzheimer's used here is relevant to familial early onset Alzheimer's rather than the much more common sporadic late onset form of the condition. Nonetheless, it is an interesting study.

Although amyloid β (Aβ)-targeting antibody therapies for Alzheimer's disease (AD) have recently been developed, their clinical efficacy remains limited, and issues such as high cost and adverse effects have been raised. Therefore, there is an urgent need for the establishment of safe and cost-effective therapeutic approaches that inhibit Aβ aggregation or prevent its accumulation in the brain.

In this study, we report that arginine, a clinically approved and safe chemical chaperone, suppresses Aβ aggregation both in vitro and in vivo. We demonstrated using an in vitro assay that arginine inhibits the aggregation formation of the Aβ42 peptide in a concentration-dependent manner. In a Drosophila model of AD expressing the Aβ42 peptide with an Arctic mutation E22G, the oral administration of arginine dose-dependently reduced Aβ42 accumulation and rescued Aβ42-mediated toxicity. In an AppNL-G-F knockin mouse model harboring human APP familial mutations, the oral administration of arginine suppressed Aβ plaque deposition and reduced the level of insoluble Aβ42 in the brain. The arginine-treated AppNL-G-F knockin mice also showed the improvement of behavioral abnormalities and the reduced expression of the neuroinflammation-associated cytokine genes.

These results indicate that the oral administration of arginine not only reduced Aβ deposition, but also ameliorated Aβ-mediated neurological phenotypes in animal models of AD. These findings identify arginine as a safe and cost-effective drug candidate that suppresses Aβ aggregation, and highlight its repositioning potential for rapid clinical translation for AD treatment. Arginine is also potentially applicable to a wide range of neurodegenerative diseases caused by protein misfolding and aggregation.

Link: https://doi.org/10.1016/j.neuint.2025.106082