Fight Aging!

Researchers here assess the effects of supplementation with the L-BAIBA metabolite combined with exercise in older mice. It modestly improves both muscle and bone, adding it to the long list of approaches that can help in some small way to resist the age-related declines in muscle mass, muscle strength, and bone mineral density. As often noted here, something better than this is required if we want to control aging rather than merely gently slow it down. Tinkering with metabolism can and does have small positive effects, which unfortunately combine in unpredictable ways, but if we want bigger and better outcomes, then we have to focus instead on repair of the cell and tissue damage that causes aging. You can't fix a malfunctioning engine by changing the oil mix, and you can't meaningfully rejuvenate a human (or a mouse) by altering metabolite intake.

Contracting skeletal muscles secrete the metabolite L-β-aminoisobutyric acid (L-BAIBA), which when supplemented in the diet can mitigate disuse-induced musculoskeletal dysfunction. However, the effects of L-BAIBA supplementation alone and combined with exercise on cardiac and musculoskeletal properties are currently unknown. We hypothesized that exercise with L-BAIBA supplementation would promote greater cardiac and musculoskeletal benefits than exercise alone. To investigate this hypothesis, we subjected 12-month-old (as a model of middle-age) male C57BL6 mice to voluntary wheel running (VWR) with L-BAIBA (100mg/kg/day) (VWR+L-BAIBA), VWR alone, L-BAIBA alone, or none (CTRL) for three months.

Soleus muscles from VWR+L-BAIBA, but not VWR, were larger, contracted more forcefully, and contained more slow-oxidative type I myofibers compared to CTRL. In extensor digitorum longus (EDL) muscle, VWR but not VWR+L-BAIBA improved fatigue resistance and caffeine-induced recovery. In bone, VWR+L-BAIBA but not VWR showed lower bone marrow adiposity, higher trabecular thickness, and connectivity, smaller bone diameter and Moment of Inertia, but higher Modulus of Elasticity than CTRL, suggesting L-BAIBA delays aging-induced periosteal expansion due to better bone material qualities.

These findings suggest a physiological interaction between exercise and L-BAIBA supplementation to improve soleus muscle and bone properties and reduce bone marrow adiposity.

Link: https://doi.org/10.18632/aging.206325

The well understood pathways by which cerebrospinal fluid drains from the brain are the glymphatic system and cribriform plate. These paths become less functional with age, for different reasons, and the consequently reduced drainage of cerebrospinal fluid allows metabolic waste to build up in the brain. This includes the misfolded and normally folded but excess amyloid-β that is associated with the development of Alzheimer's disease. Researchers here show that clearing amyloid-β from the brain via immunotherapy does not improve glymphatic fluid flow over the course of the first few months following treatment, reinforcing a view of Alzheimer's and other neurodegenerative conditions in which glymphatic dysfunction is a contributing factor to the development of the disease rather than a consequence of the disease.

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid-β peptides in the brain parenchyma, and impairment of interstitial waste clearance via the glymphatic system is suggested as one contributing factor. Recently approved disease-modifying monoclonal antibodies, such as lecanemab, are expected to slow cognitive decline by improving amyloid-β clearance. Diffusion tensor imaging along the perivascular space (DTIALPS) index has emerged as a noninvasive surrogate marker suggested to be associated with glymphatic activity. This index declines with normal aging and is significantly lower in patients with AD than in cognitively normal individuals.

The 13 participants included in this study were: (i) diagnosed with AD by neurologists; (ii) underwent brain magnetic resonance imaging (MRI) and subsequently initiated lecanemab therapy. Only participants who provided written informed consent were included. Mean DTI-ALPS index was 1.515 ± 0.152 at baseline and 1.513 ± 0.161 at 3 months, no significant difference.

The absence of early DTI-ALPS index improvement suggests that even though lecanemab treatment reduces plaque burden, the diffusion properties of perivascular spaces measured by DTI-ALPS do not change in the short term. DMT can reduce plaque burden and slow further cognitive worsening but does not restore lost function, likely reflecting the fact that neuronal damage and clearance system deficits have already been well established. Such observations, therefore, may reflect a multifactorial disease process that is not rapidly reversible during symptomatic stages, resulting in an unchanged early DTI-ALPS index.

Link: https://doi.org/10.1002/jmri.70118

Gene expression is the complex process of producing proteins from a specific gene sequence encoded in DNA. The DNA in the nucleus of a cell is constantly surrounded by the machinery of gene expression. That machinery will attempt to start the process of transcription, the first step of gene expression, for any sequence it bumps into. Recall that every part of a cell is a chemical soup of molecules moving at incredible speeds, interacting with everything that they can possibly interact with, as fast as possible, countless times every second. Control over which genes are expressed at any given time is a matter of the structure of DNA, which sequences are exposed and which are spooled around histone molecules so that they are hidden from transcriptional machinery. DNA structure is shaped by epigenetic processes, which include the addition and removal of decorations such as methyl groups to specific locations on DNA that alter its shape, modifications to the histone molecules that DNA wraps itself around, and so forth.

DNA becomes damaged constantly - again, the cell nucleus is a soup of fast-moving molecules with countless collisions and reactions taking place in every moment. DNA is protected by highly efficient repair machinery, and near every incident is fixed, even dramatic damage such as complete breakage of both strands of the double helix of DNA. A new and potentially important area of research is focused on the potential for DNA double strand break repair to produce lasting changes to DNA structure and epigenetic regulation of gene expression. This may allow researchers to explain why similar detrimental epigenetic changes occur across all cells with advancing age, driven by stochastic DNA damage that is different in every cell and largely fails to harm any sequence that is actually used by a damaged cell. Importantly, given a sufficient understanding of exactly why long-term effects result from DNA double strand break repair, researchers can focus on developing therapies to prevent this outcome.

One obvious form of therapy already known to fix these issues is partial reprogramming, exposing cells to Yamanaka factors for a period of time. But perhaps there are other approaches that do not present the same challenges that partial reprogramming presents when it comes to fixing an entire body's worth of cells. Delivery is hard, and different cell types need different degrees of Yamanaka factor exposure. If it turns out that depletion of just a few factors involved in DNA repair is the cause of epigenetic change resulting from DNA double strand break repair, perhaps restoring those targets to youthful levels will be an easier goal to achieve. But these are early days yet, and a great deal more time and funding is needed for a deeper investigation of DNA double strand breaks and their potential contribution to degenerative aging.

Repair of DNA double-strand breaks leaves heritable impairment to genome function

Eukaryotic genomes are subjected to hierarchical folding that is required to accommodate DNA wrapped around the histone scaffold (collectively called chromatin) within the three-dimensional (3D) nuclear space. Evolution harnessed the 3D arrangement of nuclear chromatin to facilitate interactions among genomic segments such as promoters and enhancers, whose proximity influences gene expression and who thus have an important role in cell fate decisions such as orderly execution of developmental programs, adaptation to a new environment, or transmission of cell identity across successive generations of dividing cells. Although beneficial in these and other physiological contexts, the 3D arrangement of the nuclear genome also enables a distinct vulnerability to environmental or metabolic assaults that can modify chromatin folding and thus derail cellular functions.

A prominent example of such stress assaults is the DNA double-strand break (DSB). Besides disrupting DNA integrity, DSBs are intrinsically coupled to massive chromatin alterations that include changes in 3D arrangement and gene silencing across megabase distances from the primary DNA lesions. Although the DSB-induced chromatin response is initially beneficial to attract genome caretakers and generate structural scaffolds for timely and efficient DNA repair, its fate after restoring the integrity of DNA sequence is unknown. This seems to be a formidable gap in understanding genome maintenance that poses important questions: Do cells restore DSB-induced chromatin folding and the associated gene expression after completion of DNA repair? If yes, is the restoration of postrepair chromatin complete and back to the predamage level? If not, do the lingering chromatin alterations cause physiological impairments that can be inherited by successive cell generations?

To answer these questions, we directed Cas9-induced DSBs to genomic loci harboring topologically sensitive protein-coding genes, as well as regulatory RNA species, to interrogate long-term consequences of DNA breakage on chromatin topology and gene activity. By combining quantitative imaging of large cell populations, DNA and RNA fluorescence in situ hybridization (FISH), and Region Capture Micro-C as readouts, we found that DSB-induced chromatin alterations do not recover to predamage level but persist as lasting changes in 3D arrangement and impaired gene expression throughout large chromatin neighborhoods that encounter, and subsequently repair, a single DSB. We show that such impairments persist through several rounds of successive cell divisions and can trigger concrete pathophysiological consequences. We term this phenomenon as chromatin fatigue and propose that it represents a hitherto unknown dimension of heritable responses to DNA breakage, with a potential to permanently alter physiology of cells that encounter DSBs through environmental or metabolic stress - but also lineages engineered for various experimental or therapeutic purposes by nuclease-based genome editing.

Finding molecules or nanoparticles that selectively target mitochondria and induce improved function is the most developed of the various strategies that might be employed to at least partially reverse the age-related loss of mitochondrial capacity thought to be important in age-related disease and dysfunction. Most of the small molecules developed to date appear to work by improving mitophagy, the processes of quality control that recycle worn and dysfunctional mitochondria, but the precise details of the mechanisms involved are incompletely understood. Mitophagy itself is incompletely understood. Continuing this trend, researchers here present a nanoparticle that is observed to improve mitochondrial function and thus cell function via improved mitophagy.

Mitophagy is crucial for the selective autophagic degradation of damaged mitochondria, helping to maintain both mitochondrial and cellular homeostasis. Here, we report a fluoroalkylated polypyridinium that specifically targets mitochondria and exhibits high activity in mitophagy induction. The polymer effectively restores mitochondrial function and alleviates the inflammatory response in foam cells by activating mitophagy, and displays inherent red fluorescence under physiological conditions, allowing for direct tracing of its biodistribution in cells and in vivo.

Besides, the polymer nanoparticle shows high serum stability due to the antifouling properties of fluoroalkyl tags. After intravenous administration, the nanoparticle reduces oxidative stress, promotes mitophagy, and decreases cellular senescence in atherosclerotic plaques, contributing to high therapeutic efficacy. This study presents an innovative and effective strategy for the treatment of atherosclerosis and other mitochondrial dysfunction-related inflammatory conditions.

Link: https://doi.org/10.1038/s41467-025-64813-0

Researchers here present a list of open problems in aging research, mined from the literature and outreach to the scientific community. This is certainly a topic on which opinions differ as to which of these areas of research are more or less important than others. An assessment of literature and community will tend to capture these differences of opinion, and ongoing debates over the best course ahead. In large part the diversity of opinions reflects the lack of a consensus measure of aging that can accurately assess the outcome of a potentially age-slowing or rejuvenating intervention. If such a measure existed, there will likely be little debate over the best path forward.

Despite advancements, the field of longevity science is at a crucial point as it continues to face numerous open problems that hinder further progress. Recent works have highlighted fundamental knowledge gaps and strong disagreements amongst scientist studying ageing. Addressing these challenges is critical for unlocking new insights and developing effective interventions to extend both lifespan and healthspan.

We now present a new list of 100 open problems in ageing science, identified and curated through a combination of community engagement and text-mining approaches. These problems span a wide range of topics, from molecular biology and comparative approaches to translational efforts and clinical applications. By outlining these 100 problems, we aim to guide and provide goals for future research and map the key areas where knowledge gaps exist.

These open problems are presented on our website (https://longevityknowledge.app), where users can interact with and find more information on each selected problem.

Link: https://doi.org/10.1007/s11357-025-01964-4

A number of approaches to inducing muscle growth or improving muscle strength have been demonstrated in laboratory animals, in early human clinical trials, and in recent years employed in medical tourism clinics. These approaches are compensatory in the context of aging, they do not address any of the underlying issues that lead to loss of muscle mass and strength per se. An adjustment of the regulation of muscle growth to favor more growth will produce larger, stronger muscles at any age, which may help to generate greater attention and use of such therapies as they are developed.

These varied approaches directly interfere in cell signaling in some way, as it is easier to adjust the levels of circulating proteins and other molecules, or their ability to interact with cell surface receptors, then it is to adjust mechanisms that operate inside cells. Inhibition of myostatin signaling and upregulation of follistatin signaling are the presently dominant approaches. The use of antibodies targeting myostatin has been assessed, but more effort is now put toward upregulation of circulating follistatin via forms of gene therapy.

In today's open access paper, researchers discuss upregulation of a different signaling protein, FGF19. This does appear to have the effect of reducing myostatin levels, but that it only increases muscle strength rather than muscle mass suggests that other mechanisms are driving the outcome. Some indication has been given in recent years that these various strategies to grow muscle or improve muscle strength may also have a positive impact on bone mineral density. Unfortunately that doesn't seem to the be the case for FGF19.

Therapeutic potential of FGF19 in combatting osteosarcopenia: effects on muscle strength and bone health in aged male mice

Osteosarcopenia, characterized by the coexistence of osteopenia/osteoporosis and sarcopenia, represents a significant health concern in geriatrics, with an increased risk of falls and fractures. The enterokine fibroblast growth factor 19 (FGF19) was recently shown to prevent muscle weakness in preclinical models. This study investigated the therapeutic potential of FGF19 in mitigating bone and muscle deterioration in aged male mice. Twenty-one-month-old C57BL/6 male mice received daily injections of human recombinant FGF19 (0.1 mg/kg) for 21 days.

Histological and functional analyses revealed a shift toward larger muscle fibers in FGF19-treated mice as well as an increased muscle strength, without affecting muscle mass. In parallel, X-ray microtomography showed that FGF19 had no overt negative impact on bone, with a range of modest, site-specific, and opposing effects. In the distal femur metaphysis FGF19, it reduced cortical thickness, but significantly increased bone cross-sectional area, with an overall increased polar moment of inertia, a geometrical parameter linked to favorable mechanical properties. It also elevated cortical bone porosity in the same region. There were no significant effects on trabecular bone or cortical bone parameters in the proximal femur side. In the L2 vertebra, cortical porosity decreased. Histomorphometry of trabecular bone and analysis of transcriptional output of selected genes in femurs revealed only minor changes in bone cellular activities and gene expression after three weeks of treatment.

In conclusion, FGF19 treatment increased muscle strength in aged male mice, without negatively impacting aging bone.

The raised blood pressure of hypertension is damaging to sensitive tissues throughout the body, but particularly the brain. Alongside many other issues in the health and function of the vascular system, hypertension increases the pace of rupture of tiny blood vessels in the brain, each such event destroying a small volume of brain tissue. Over time this adds up to degrade cognitive function and contribute to the development of outright dementia. Thus high blood pressure is harmful, and the longer the period of time in which blood pressure is elevated, the more harm is done. Here, researchers assess cumulative blood pressure over time and find a correlation between high, sustained blood pressure and a large increase in the risk of dementia.

Cumulative blood pressure (BP), which takes into account both the magnitude and duration of BP exposure, is linked to cognitive impairment. The Chinese Longitudinal Healthy Longevity Survey (CLHLS) over 16 years was divided into two consecutive sub-cohorts, namely the 2002 sub-cohort from 2002 to 2011 and the 2008 sub-cohort from 2008 to 2018. Cumulative BP exposures were calculated as the area under the curve derived from two consequence BP measurements and their corresponding time intervals.

A total of 2,142 and 1,920 cognitively healthy older adults participants from the two sub-cohorts were included in the analysis, respectively. Over a median follow-up of 6.2 years and 7.0 years, 542 and 347 older adults experienced cognitive impairment in the two sub-cohorts, respectively. Higher cumulative systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) were significantly associated with a higher risk of cognitive impairment. Compared to the lowest quartile in the two sub-cohorts, the hazard ratios for cognitive impairment risk in the highest quartile were 1.85 and 2.64 for cumulative SBP, 2.00 and 2.20 for cumulative DBP, and 1.59 and 2.10 for cumulative PP, respectively.

Link: https://doi.org/10.1186/s12877-025-06465-9

Provoking regrowth of tooth enamel by mimicking some of its structure appears to be a going concern in dental research, if judging from this paper and another similar approach using keratin. At the high level, the idea is to coat damaged enamel with material that encourages the chemical mineralization process that takes place during enamel formation. Interestingly, the specific molecular structures demonstrated here allow this process to take place even when applied to exposed dentin. We can hope that cavities and fillings will soon enough be a thing of the past.

Tooth enamel is characterised by an intricate hierarchical organization of apatite nanocrystals that bestows high stiffness, hardness, and fracture toughness. However, enamel does not possess the ability to regenerate, and achieving the artificial restoration of its microstructure and mechanical properties in clinical settings has proven challenging.

To tackle this issue, we engineer a tuneable and resilient supramolecular matrix based on elastin-like recombinamers (ELRs) that imitates the structure and function of the enamel-developing matrix. When applied as a coating on the surface of teeth exhibiting different levels of erosion, the matrix is stable and can trigger epitaxial growth of apatite nanocrystals, recreating the microarchitecture of the different anatomical regions of enamel and restoring the mechanical properties.

The study demonstrates the translational potential of our mineralising technology for treating loss of enamel in clinical settings such as the treatment of enamel erosion and dental hypersensitivity.

Link: https://doi.org/10.1038/s41467-025-64982-y

The aging of the blood vessels supplying the brain into a state of dysfunction provides an important contribution to the onset and progression of neurodegenerative conditions. There are many aspects to this vascular aging, including: loss of capillary density over time that reduces the ability of the vasculature to deliver sufficient nutrients to cells in brain tissue; the atherosclerosis that narrows and weakens major vessels with fatty deposits; the disruption of normal function of the endothelium, the inner layer of blood vessels; disruption of the normal function of the smooth muscle that controls contraction and dilation of vessels; leakage of the blood-brain barrier, the specialized cells that line blood vessels in the brain and control which molecules are allowed to pass; and so forth. Aging is a disruption of all normal functions, in one way or another.

In today's open access review, researchers take at look at the phenomenon of endothelial-to-mesenchymal transition, a feature of aging in which endothelial cells change their state and behavior to take on the characteristics of mesenchymal cells. This is detrimental to the function of surrounding tissue, which depends on cells of a specific type continuing to act as that type. As the authors note, while the causes of endothelial-to-mesenchymal transition are only partially understood, there is evidence to link its occurrence to mechanisms of aging, and particularly to the chronic inflammatory signaling that is a feature of aged tissues. There are many ways in which continual, unresolved inflammation changes cell behavior for the worse, making it an important target for future medical control over aging.

Endothelial-to-mesenchymal transition in the central nervous system: A potential therapeutic target to combat age-related vascular fragility

Age-related dysfunction of the central nervous system, including cognitive impairment and visual disorders, is a major concern for the aging population, affecting health span and quality of life. Age-related vascular dysfunction in the central nervous system includes an increase in blood-brain or blood-retina barrier permeability, an increase in vascular fragility, and impaired neurovascular coupling, contributing to cognitive impairment and vision loss. While these pathologies occur in the brain and eye with age, gaps remain in our understanding of the underlying cellular mechanisms.

During the process of endothelial-to-mesenchymal transition (EndMT), endothelial cells lose their characteristic endothelial phenotypes, which are critical for vascular function, such as barrier integrity, and transition to a mesenchymal-like phenotype. Too little is understood regarding the interplay between triggers associated with physiological aging and the process of EndMT in both non-disease and disease-related contexts in the central nervous system. This highlights a field ripe for exploration, as many age-related processes have also been shown to be triggers of EndMT. For example, many of the inflammatory factors found in the senescence-associated secretory phenotype generated by senescent cells are triggers of EndMT.

Here, we review what is known about the role of EndMT in vascular fragility in the aging brain and eye, explore the mechanistic links between endothelial cell transdifferentiation and age-associated vascular pathologies of the central nervous system, and identify potential therapeutic targets ripe for future exploration with the goal of preserving vascular function with aging by regulating EndMT.

Nicotinamide adenine dinucleotide phosphate (NADP) has a different portfolio of functions in the cell to the better known nicotinamide adenine dinucleotide (NAD) that has been a focus for parts of the research community in recent years. NADP is thought to be primarily important as a defense against oxidative stress. Here, researchers discuss the role played by insufficient levels of NADP in vascular aging, finding that it encourages greater cellular senescence in the vascular endothelium, thus promoting endothelial dysfunction as a contribution to cardiovascular disease. Thus strategies to increase NADP levels may act to usefully improve the state of the aged vasculature, better protecting it from dysfunction.

Age-related cardiovascular diseases are featured by changes in arterial function or phenotype. Moreover, microcirculation possesses a unique ability to influence the microenvironment of majority of the organs. Thus, understanding the molecular mechanisms of vascular aging is central to tackle age-related cardiovascular disease. The vascular endothelium is a single layer of cells covering the lumen of vascular vessels and plays an important role in maintaining vascular homeostasis. Numerous studies suggest that senescence of vascular endothelial cells leads to initiation and progression of cardiovascular diseases.

Nicotinamide adenine dinucleotide phosphate (NADP, oxidized form: NADP+, reduced form: NADPH) has long been recognized as a key cofactor for redox defense and reductive biosynthesis. Intracellular NADPH consumption and production in different compartments of the cell are independently regulated. While traditional enzymatic cycling assays, mass spectrometry, and chromatography have been used to monitor whole-cell NADPH pool, they require cell homogenization and cannot differentiate compartmental NADPH pools, where it regulates distinct functions. Here, we employed a highly responsive and genetically encoded NADPH sensor and revealed that cytosolic NADPH was elevated during endothelial cell senescence.

Decreased nitric oxide concentration promoted G6PD activity leading to elevated NADPH levels. G6PD overexpression significantly elevated NADPH level, inhibited glutathione oxidation and HDAC3 activity, and suppressed endothelial cell senescence and vascular aging. These results suggest that G6PD/NADPH pathway is upregulated by stimulators of vascular aging, and it plays a casual role in limiting endothelial cell aging. Furthermore, high-throughput metabolic screening of 1419 drugs approved by the Food and Drug Administration found that folic acid significantly elevated NADPH content via MTHFD1 and augmented vascular activity in naturally aged mice. These findings highlight a beneficial role of endothelial NADPH metabolism in vascular aging.

Link: https://doi.org/10.1038/s41467-025-64652-z

Thin sheets of engineered artificial tissue can be readily manufactured because they do not require a vasculature, perfusion of fluids is sufficient to support the cells. For some years now, researchers have developed the capability to manufacture thin heart tissue patches. A number of preclinical studies in various animal models have demonstrated that applying these patches to an injured heart promotes greater regeneration and restoration of function than normally takes place. Here, the technique is combined with a minimally invasive form of surgery as a proof of concept, and used in rats following heart attack to promote greater regeneration.

For years, scientists have been working on ways to replace damaged tissue with healthy heart cells derived from stem cells. Early efforts showed promise, but most required open-heart surgery - a procedure too risky for many patients already struggling with severe heart failure. Scientists have long hoped that stem cells could provide a way to rebuild what the body cannot. By reprogramming ordinary adult cells such as skin or blood cells into induced pluripotent stem cells (iPSCs), researchers can coax them into becoming replacement heart cells. But safely and effectively delivering engineered heart tissues made from these cells has remained a major challenge.

With this in mind, researchers developed a flexible, paper-thin patch made of nano- and microfibers coated with gelatin. This hybrid scaffold supports a blend of human heart muscle cells, blood vessel cells, and fibroblasts - cells that form the tissue's structural framework - to create a living, beating piece of heart tissue. Before transplantation, the tissue is infused with bioactive factors such as fibroblast growth factor 1 and CHIR99021 that encourage the growth of new blood vessels and help the cells survive once they are in place.

"The beauty of this design is that it can be folded like a piece of paper, loaded into a slender tube, and delivered precisely where it's needed through a small incision in the chest. Once in place, it unfolds and adheres naturally to the heart's surface." Testing in preclinical rat models showed that the minimally invasive method improved heart function, reduced scarring, enhanced vascular growth, and lessened inflammation compared with conventional approaches.

Link: https://newsnetwork.mayoclinic.org/discussion/mayo-clinic-researchers-identify-a-new-stem-cell-patch-to-gently-heal-damaged-hearts/

Microglia are innate immune cells resident in the brain. They are broadly similar in behavior to the macrophages found elsewhere in the body, with an added portfolio of duties relating to maintenance of the synaptic connections that link neurons to form neural networks. Researchers have provided evidence for microglia to both harm and help the aging brain, with various subpopulations of microglia either acting to cause damage and dysfunction or attempting to resist that damage and dysfunction. One of the most studied aspects of microglial aging is the increase in inflammatory signaling, as microglia react to the age-damaged environment and their own internal age-related dysfunctions with maladaptive patterns of behavior. Chronic inflammation in aged brain tissue contributes to neurodegeneration, and is driven in part by microglia.

In today's open access paper, the authors expand on recent research that points to PU.1 as a gene of interest in the regulation of microglial inflammation. A few research groups have set their sights on selective PU.1 inhibition in microglia as a potential basis for therapy, as it appears to reduce inflammation in animal studies. In this new paper, the authors report that this feature of PU.1 inhibition is actually driven by a small subpopulation of microglia that are in some way acting to regulate the behavior of other microglia. This sort of behavior is well described in the adaptive immune system - consider regulatory T cells, for example. It is interesting to see innate immune cells specializing into the regulators and the regulated in response to circumstances.

Lymphoid gene expression supports neuroprotective microglia function

Microglia, the innate immune cells of the brain, play a defining role in the progression of Alzheimer's disease (AD). The microglial response to amyloid plaques in AD can range from neuroprotective to neurotoxic. Here we show that the protective function of microglia is governed by the transcription factor PU.1, which becomes downregulated following microglial contact with amyloid plaques.

Lowering PU.1 expression in microglia reduces the severity of amyloid disease pathology in mice and is linked to the expression of immunoregulatory lymphoid receptor proteins, particularly CD28, a surface receptor that is critical for T cell activation. Microglia-specific deficiency in CD28, which is expressed by a small subset of plaque-associated low PU.1 expression microglia, promotes a broad inflammatory microglial state that is associated with increased amyloid plaque load.

Our findings indicate that low-PU.1 CD28-expressing microglia may operate as suppressive microglia that mitigate the progression of AD by reducing the severity of neuroinflammation. This role of CD28 and potentially other lymphoid co-stimulatory and co-inhibitory receptor proteins in governing microglial responses in AD points to possible immunotherapy approaches for treating the disease by promoting protective microglial functions.

Epidemiological research has consistently demonstrated a sizable difference in outcomes between those who are sedentary and those who conduct even a modest, low level of physical activity. More exercise is better, of course, but some researchers have have nonetheless focused on the degree to which small amounts of activity can be beneficial in older individuals. Here, for example, researchers show that relatively low levels of physical activity slow the progression towards outright Alzheimer's disease in patients with high levels of amyloid-β aggregation. The amyloid-β in and of itself causes only minor loss of cognitive function, but sets the stage for a later environment of inflammation and tau aggregation that causes much more severe damage to the brain and its function.

Physical inactivity is a recognized modifiable risk factor for Alzheimer's disease (AD), yet its relationship with progression of AD pathology in humans remains unclear, limiting the effective translation into prevention trials. Using pedometer-measured step counts in cognitively unimpaired older adults, we demonstrated an association between higher physical activity and slower cognitive and functional decline in individuals with elevated baseline amyloid.

Importantly, this beneficial association was not related to lower amyloid burden at baseline or longitudinally. Instead, higher physical activity was associated with slower amyloid-related inferior temporal tau accumulation, which significantly mediated the association with slower cognitive decline. Dose-response analyses further revealed a curvilinear relationship, where the associations with slower tau accumulation and cognitive decline reached a plateau at a moderate level of physical activity (5,001-7,500 steps per day), potentially offering a more approachable goal for older sedentary individuals.

Collectively, our findings support targeting physical inactivity as an intervention to modify the trajectory of preclinical AD in future prevention trials, and further suggest that preferentially enrolling sedentary individuals with elevated amyloid may maximize the likelihood of demonstrating a protective effect of physical activity on tau accumulation and cognitive and functional decline in early AD.

Link: https://doi.org/10.1038/s41591-025-03955-6

Researchers here demonstrate a novel way of delivering stem cells as a therapy for bone fractures that occur in the context of osteoporosis, by forming spheroids of stem cells combined with a bone mineral scaffolding material. The approach appears to encourage the survival of a larger fraction of transplanted cells, producing a greater regeneration of bone tissue. More usually near all of the transplanted cells die shortly after a transplantation procedure, and whatever benefits are obtained are derived from the signaling generated by the stem cells prior to that point.

Osteoporotic vertebral fractures substantially contribute to disability and often require surgical intervention. However, some challenges, such as implant failure and suboptimal bone regeneration, limit current treatments. Adipose-derived stem cells are promising for regenerative therapy because they are easily obtained, highly proliferative, and resistant to osteoporosis-related symptoms. This study aimed to evaluate the combined effects of osteogenic adipose-derived stem cell spheroids and β-tricalcium phosphate on vertebral bone regeneration in a rat osteoporotic vertebral fracture model.

Osteoporosis was induced in 33 rats (11 per group) by ovariectomy, and defects were created in the L4 and L5 vertebrae. Adipose-derived stem cells were spheroidized and mixed with β-tricalcium phosphate scaffolds. Groups included osteogenic spheroids, undifferentiated spheroids, and β-tricalcium phosphate alone. Bone regeneration was assessed using micro-CT, histology, and biomechanical testing at four and eight weeks. Further in vitro analyses were conducted.

The osteogenic spheroid group showed significantly higher bone mass, fusion score, and mechanical strength than the control group did. Histological analysis revealed enhanced new bone formation and β-tricalcium phosphate integration. Gene expression analysis revealed osteogenic marker (ALP, osteocalcin, and Runx2) and regenerative factor (BMP-7, IGF-1, HGF-1, and Oct4) upregulation, along with reduced apoptosis. Further, adipose-derived stem cell survival was confirmed at the repair site. These results indicate that adipose-derived stem cells contribute to both paracrine and direct osteogenesis.

Link: https://doi.org/10.1302/2046-3758.1410.BJR-2025-0092.R1

Stem cell therapies have existed for a few decades now, and over that time have moved from experimental use for many conditions in the medical tourism industry to a much more formulaic, controlled use for some conditions in the more regulated markets such as the US and Europe. More experimental use in medical tourism never went away, however. It became a larger industry, more varied, the body of knowledge more widespread, but the existence of a very formalized, robust set of procedures adopted by clinics and companies in more regulated markets where every therapy and its method of manufacture is reviewed in great detail (and consequently at great expense) doesn't make the earlier, less costly, less certain approach go away. Well informed patients continue to have the choice over how they proceed.

The trajectory of the stem cell therapy field is presently to replace the use of cells with the use of extracellular vesicles harvested from those cells. Extracellular vesicles are more cost-effective as a basis for therapy, as they can be manufactured centrally, frozen, shipped, and stored indefinitely with minimal loss of efficacy. In practice, as this move from cells to vesicles is at a fairly early stage in the grand scheme of things, there isn't yet all that much centralization of manufacture. There is certainly very little standardization of manufacture; it is a rerun of the early years of stem cell therapies, but for vesicles this time. This will change. As happened for stem cell therapies, there will be more regulated, more expensive extracellular vesicle therapies, manufactured more robustly, and approved by regulators to treat only some conditions. Meanwhile, the medical tourism industry will continue much as it is at the moment, only more so. Check back in a decade, and this will likely be the state of the field.

Efficacy of extracellular vesicles derived from mesenchymal stromal cells in regulating senescence: In vitro and in vivo insights

Researchers have pointed to stem cell depletion as a key mechanism contributing to cellular senescence in aging. Thus, stem cell-based therapy, especially treatment with mesenchymal stromal cells (MSCs), has become an innovative anti-aging approach. A phase I/II double-blind and placebo-controlled study showed that the application of intravenous exogenous allogenic MSCs can reverse the symptoms of frailty in elderly individuals, significantly improving quality of life, physical performance, and reducing chronic inflammation. However, using MSCs in therapeutic applications poses several challenges, including the risk of cellular rejection, tumorigenesis, and problems related to cell delivery and engraftment. These concerns have led researchers to assess alternative strategies for using MSCs for treatment while mitigating the risks related to their application. One such promising strategy involves using extracellular vesicles (EVs) derived from MSCs (MSC-EVs).

The cargo of MSC-EVs consists of various cytokines, growth factors, bioactive lipids, and regulatory microRNAs (miRNAs) that can participate in cell-to-cell communication and cell signaling and alter the metabolism of cells or tissues at short or long distances in vivo. These vesicles have the therapeutic ability of MSCs and can influence tissue response to injury, infection, and disease. Researchers showed that EVs derived from umbilical cord-derived MSCs (UC-MSCs) can delay the aging of naturally aged mice throughout the body and significantly alter the degenerative functions of various tissues and organs.

Many preclinical studies have shown that multiple sources of EVs, especially those derived from UC-MSCs, are prospective cell-free therapeutic agents for aging therapy. However, key parameters, including quality, reproducibility, and potency, determine the development of therapies based on EVs. Large-scale production of EVs faces multiple challenges, including low yield, heterogeneity, targeted delivery, storage stability, and the lack of standardized protocols to ensure quality, safety, and consistency. Current isolation techniques, such as ultracentrifugation and density gradient methods, suffer from limited yield and insufficient purity, making them inadequate for clinical-scale applications.

This study established a highly efficient technique for extracting and characterizing MSC-EVs. Additionally, we identified and implemented crucial quality control checkpoints for MSC-EVs. These measures were taken to ensure consistent yield, quality, and reproducibility of the MSC-EVs, rendering them suitable for clinical use. Next, we conducted several experiments to determine the effects of MSC-EVs on senescence in senescent cells and aged murine models. We found that MSC-EVs inhibited the aging-related secretory phenotype at the cellular level and reduced the attenuation of age-associated degenerative changes in multiple organs. Moreover, integrated metabolomics and transcriptomics analyses were performed, and the results confirmed the anti-aging mechanism of MSC-EVs.