Fight Aging!

One of the many factors impeding the pace of research into age-related neurodegeneration is that it is relatively challenging to obtain human brain tissue from any sizable living population for study. Post-mortem tissue is more accessible, albeit burdened by the usual regulation, but this represents only a slice of the population, largely those with the most advanced burden of damage and dysfunction. By necessity, researchers wanting to investigate earlier stages of degeneration, or healthy brains, are steered towards patients who must undergo forms of brain surgery, and there are always questions as to the degree to which those patients are reflective of the broader population.

In today's open access paper, researchers work with brain tissue derived from epilepsy patients who underwent brain surgery in an attempt to reduce the severity of their condition. Their argument is that this population can provide insight into features of cognitive aging, even though that cognitive aging is accelerated in epileptic patients versus non-epileptic individuals. The study is of interest for the reported correlation between a population of supporting cells in the brain and the severity of cognitive decline. The paper has little to say about the exact mechanisms involved: that is for others to follow up on given the direction provided here.

An age-related decline in human fluid intelligence corresponds with immature astroglia prevalence

Therapeutic development for cognitive decline has been steered by the interpretation that it predominantly results from compromised neuronal function, yet neuron-focused strategies have so far yielded only modest benefits. With the advent of cell type-directed combination therapies targeting both neurons and glia identifying specific cellular drivers of discrete cognitive deficits can guide the design of more effective treatment strategies. Rodent studies have recognized that astroglial cells, traditionally viewed as mere supportive cells to neurons, are active regulators of learning and memory. Meanwhile, various studies indicate that dysfunctional astrocytes contribute to the decline of rodent cognitive functions.

Cognitive decline is a comorbidity that occurs progressively in epilepsy patients. People with epilepsy demonstrate accelerated brain aging and cognitive decline is especially pronounced in older individuals. Mesial Temporal Lobe Epilepsy (MTLE) is the most common form of adult epilepsy, and patients who do not respond to medications undergo surgical removal of epileptic hippocampal tissue as treatment. Since these patients have detailed presurgical cognitive assessment, this platform provides a unique ante-mortem window into understanding the altered cellular features that are associated with human cognitive decline.

Our previous research in MTLE patients revealed the persistent presence of a pathological Dcx+ immature astroglial cell in the epileptic hippocampus that was undetectable in control postmortem tissue. The number of Dcx+ immature astroglial cells in MTLE hippocampus trended toward an increase with age; however, the significance of this phenotype and its association with cognitive decline was not investigated. In this study, we first identified cognitive functions that strongly undergo an age-associated decline in epilepsy patients. We then assessed the significance of an age-associated increase in Dcx+ immature astroglia and how it is associated with various cognitive functions. Our study identified an association between aging, a decline in fluid intelligence and an increase of immature astroglia in epilepsy patients. These findings highlight immature astroglia as an epilepsy-associated cellular feature corresponding to age-related cognitive decline and provides a basis for future mechanistic and translational studies.

Researchers are engaged in finding alternative ways to induce the desirable epigenetic rejuvenation produced by exposing cells to the Yamanaka factors, without the risk of losing cell state to dedifferentiation and the creation of induced pluripotent stem cells that could give rise to tumors. Yamanaka factors are a challenging basis for many forms of therapy because it would be somewhere between difficult and impossible to reconcile the different requirements for dose and timing for different cell populations in a tissue. Here, screening leads researchers to a splicing factor that is capable of producing some degree of epigenetic rejuvenation in cells and extended healthy life in mice. Splicing factors are of interest because each influences the expression of many different genes, potentially thousands of genes, and thus represent centralized points of control over cell state and behavior. This result will likely encourage a range of existing programs aimed at better understanding what can be achieved by manipulation of splicing factor activity.

The therapeutic use of Yamanaka factors is causing concern for some researchers because their overexpression also raises the risk of cancer formation. Researchers have therefore been hunting other factors for rejuvenating aging tissues in safer and more controllable ways. However, "in reprogramming, there is a fundamental tradeoff between rejuvenation and cell identity; achieving one without losing the other requires walking a fine line."

In this study, researchers designed a machine learning algorithm trained on gene expression (transcriptomic) profiles across multiple aging processes in human skin fibroblast cells spanning a wide age range. This predictor accurately pinpointed the "transcriptomic age" of skin cells obtained from several donors. Leveraging this age predictor as a scorable readout then enabled the team to screen a focused collection of genes that were predicted to affect aging processes in one way or another. The goal was to identify candidates that, when over-expressed, could shift the originally assigned aging score of old fibroblast cell lines to a more youthful score.

The top-scoring gene, encoding an RNA processing factor known as SRSF1, was indeed able to reduce features that corresponded to several hallmarks of aging, such as a biological process where damaged cells stop dividing but do not die (cellular senescence), disruptions in the normal balance and turnover of proteins (proteostatic stress), and chronic low-grade inflammation (also dubbed "inflammaging"). Importantly, the rejuvenated fibroblasts maintained their identity: they kept their specific spindle-shaped morphology, continued the expression of genes that encode typical fibroblast functions and didn't induce the pluripotency programs that Yamanaka factors turn on. Importantly, when delivered to aged mice, where it primarily accumulated in the liver, SRSF1 reduced the animals' rate of aging and extended their lifespan by 14%, highlighting SRSF1 as a "geroprotective" target.

Link: https://wyss.harvard.edu/news/reversing-age-by-reprogramming-gene-expression-networks/

Extracellular vesicles secreted by cells are divided into types by size, in the absence of greater knowledge that would allow functional classification. Exosomes are one of these size classes, and a popular choice as a basis for therapies intended to replace the transplantation of stem cells. Stem cell therapies produce benefits via the signaling generated by transplanted cells, a sizeable fraction of that signaling is carried in extracellular vesicles, and it is logistically much easier to harvest, store, and use exosomes than it is to use cells in therapy. As researchers here note, exosomes are not universally beneficial. Like all cell communications, context matters, and stem cell derived exosomes can produce potential harms, such as promotion of cancerous growth or undesirable immunomodulation that dampens the response to infection.

Exosomes are nanosized extracellular vesicles (30-150 nm) with a bilayer lipid membrane that encapsulates proteins, lipids, and nucleic acids, first identified in the 1960s and expanded in application from disease diagnostics to targeted therapeutics. They are intercellular communicators with roles in physiological regulation and pathological progression, which have a large applications in gene therapy, drug delivery, tissue regeneration, and disease diagnostics. Their unique biological properties have attracted considerable attention for applications in regenerative medicine, targeted drug delivery, gene therapy, and disease diagnosis.

This review highlights the dual biological nature of exosomes by discussing their beneficial 'Elixir' and detrimental 'Trojan Horse' functions. Exosomes activate signaling pathways such as Wnt/β-catenin and PI3K/Akt, deliver anti-aging molecules, and promote angiogenesis, owing to their properties such as biocompatibility, ability to cross the blood-brain barrier, and use as vectors for selective cargo delivery. Conversely, the same mechanisms that promote regeneration can also lead to undesired outcomes like tumor progression, drug resistance, immune responses suppression, and pathogenic factors spread underscore their "Trojan horse" potential. The exosome's dual nature can presents challenges.

Link: https://doi.org/10.1016/j.biopha.2026.119957

The gut microbiome is made up of thousands of distinct microbial species, interacting with one another to process food and generate a broad range of metabolite molecules that are varying degrees of necessary, helpful, and harmful to the tissues of the body. The balance of these microbial populations changes with age in detrimental ways; microbes that provoke chronic inflammation grow in number at the expense of microbes that manufacture beneficial metabolites. In recent years, researchers have mapped the microbiome in human populations, finding correlations with age-related diseases and specific microbial metabolites that contribute to specific forms of age-related dysfunction. We might expect near every common age-related disease to have many different meaningful connections to aspects of the composition of the gut microbiome and how that composition changes with age.

In today's open access paper, researchers discuss what is known of the ways in which the aging of the gut microbiome contributes to the characteristic age-related loss of bone mineral density, leading to osteoporosis. The extracellular matrix of bone is continually remodeled throughout life, created by osteoblast cells and broken down by osteoclast cells. The proximate cause of osteoporosis is a growing imbalance between these two cell populations that favors osteoclasts. Why this imbalance happens, which of the many known contributing mechanisms are more versus less important than the others, and whether all of the important mechanisms are in fact known, is a topic of ongoing debate and research. Here, researchers focus on inflammatory effects resulting from the influence of the aging gut microbiome upon the immune system, which in turn disrupts the balance to favor destruction of bone extracellular matrix.

Research progress on the mechanisms by which gut microbiota dysbiosis remodels the bone marrow neuroimmune microenvironment to drive age-related osteoporosis

Age-related osteoporosis has traditionally been attributed to impaired bone formation, excessive bone resorption, senescence of bone marrow mesenchymal stem/stromal cells (BMSCs), and deterioration of the bone marrow microenvironment. However, these local alterations do not fully explain the progressive, systemic, and heterogeneous nature of age-related bone loss. The bone marrow is not only a site of bone remodeling but also a critical niche for hematopoietic stem cell maintenance and for the generation, differentiation, and functional regulation of immune cells. Aging is accompanied by profound remodeling of the immune system. T cells, B cells, macrophages, and dendritic cells undergo age-related changes in phenotype and function. Together, immunosenescence and inflammaging disrupt the RANKL/OPG axis, increase exposure to pro-inflammatory cytokines, and enhance osteoclastogenic signaling. Consequently, bone homeostasis gradually shifts from protective immunoregulation toward a resorption-dominant state.

Gut microbiota dysbiosis has recently emerged as an important upstream regulator of bone homeostasis. During aging, alterations in microbial composition and metabolism, together with impaired intestinal barrier integrity, may promote the systemic dissemination of gut-derived inflammatory signals. These signals may reach the bone marrow and contribute to remodeling of its immune microenvironment. In addition, gut microbiota and their metabolites may influence autonomic nervous system activity through vagal and sympathetic pathways. Through these routes, intestinal signals may modulate the activation state of bone marrow immune cells and the immune networks that regulate bone remodeling. Although gut microbiota dysbiosis, inflammaging, and neural regulation have each been implicated in disordered bone metabolism, their interactions in age-related osteoporosis remain incompletely understood. In particular, the mechanistic links among gut microbiota dysbiosis, neuroimmune dysregulation, remodeling of the bone marrow immune microenvironment, and impaired bone remodeling have not been systematically clarified.

Therefore, this review summarizes the pathological basis of age-related osteoporosis, focusing on how aging-associated gut microbiota dysbiosis, intestinal barrier dysfunction, and gut-derived inflammatory signals reshape the bone marrow immune microenvironment. We also discuss the potential roles of impaired vagal anti-inflammatory signaling and abnormal sympathetic outflow in promoting osteoimmune imbalance within the bone marrow. By positioning the bone marrow neuroimmune microenvironment as a key intersection between gut-derived signals, neural regulation, and osteoimmune remodeling, this review provides an immunological framework for understanding disease mechanisms and for developing risk-stratification strategies and precision interventions in age-related osteoporosis.

Senescent cells accumulate with age to drive the onset and progression of age-related disease and loss of function. Over the past decade, a broad range of research and development efforts have emerged to attempt to address this cause of aging. Senostatic therapies reduce the pace at which senescent cells are created. Senolytic therapies selectively destroy senescent cells. Senomorphic therapies suppress aspects of the harmful behavior of senescent cells, principally the pro-inflammatory signaling that contributes to the chronic inflammation of aging and is disruptive to tissue structure and function. Researchers here describe the discovery of a senomorphic microRNA in the context of an attempt to reduce the burden of senescent cells generated by cancer therapy. Many forms of cancer treatment leave the patient with increased numbers of senescent cells, and this greater burden of dysfunction is thought to be an important contributing cause of increased mortality and disease risk in cancer survivors.

Senomorphic microRNAs (miRNAs) are a class of small regulatory RNAs that selectively suppress the senescence-associated secretory phenotype (SASP) without eliminating senescent cells, thereby offering a targeted approach to counteract the pro-tumorigenic consequences of therapy-induced senescence (TIS). Despite their therapeutic potential, senomorphic miRNAs in luminal breast cancer remain poorly characterized. Here, we performed small RNA sequencing to profile miRNA expression changes in a doxorubicin-induced TIS model using the luminal breast cancer line MCF7. We identified miR-3155b as a previously uncharacterized miRNA significantly downregulated during TIS.

Functional studies revealed that miR-3155b overexpression suppressed the mRNA and protein levels of multiple SASP factors, including IL6, IL8 (CXCL8), MMP13, TNF, IL1B, and IFNB1, whereas its knockdown enhanced their expression. Critically, these effects occurred without affecting core senescence phenotypes such as proliferation arrest, SA-β-gal activity, or DNA damage foci formation. This senomorphic function was further confirmed in an ionizing radiation (IR)-induced TIS model and in T47D luminal breast cancer cells. miR-3155b was confirmed to target the CXCL8 mRNA by luciferase reporter assays, and RNA pull-down assays indicated that miR-3155b physically associates with IFNB1, IL6, TNF, and MMP13 mRNAs.

Collectively, our findings identify miR-3155b as a senomorphic miRNA in Luminal A breast cancer TIS and provide a potential target for optimizing chemoradiotherapy strategies aimed at mitigating SASP-driven adverse effects.

Link: https://doi.org/10.3389/fcell.2026.1868137

Researchers here relate an interesting story: they designed and synthesized a small peptide that is intended to interfere with an interaction between amyloid-β and zinc ions, with the aim of suppressing a necessary part of the process of amyloid-β aggregation. This amyloid-β aggregation, proceeding slowly over years, is thought to be the causative mechanism in Alzheimer's disease. The researchers then discovered that this peptide already exists in the body, and is in fact reduced in level in Alzheimer's patients.

A hallmark of Alzheimer's disease (AD) is extra-neuronal protein aggregates formed mainly by the amyloid-β peptide (Aβ), that are deposited inside the brain as amyloid plaques. The formation of amyloid plaques requires participation of zinc ions. The 11-Glu-Val-His-His-14 region of Aβ is critical for interaction between Aβ and zinc ions. The engineered peptide Ac-His-Ala-Glu-Glu-NH2 (HAEE) acts as competitive inhibitor of such interactions and suppresses formation of Aβ aggregates in animal models of AD.

We sought to develop a reliable method for studying the behavior of the synthetic HAEE peptide in the human blood in preparation for clinical trials of this peptide as a potential anti-amyloid drug for AD. The analytical method to monitor HAEE concentration in blood plasma combines separation by high-performance liquid chromatography and registration on a mass detector of the parent quasi-molecular ion and fragment ions. We discover that HAEE peptide represents a normal endogenous component of human blood plasma. Moreover, the HAEE level has been significantly reduced in patients with a clinical diagnosis of AD (n = 200) as compared with the control participants with no clinical diagnosis of cognitive impairment (n = 150). Deficiency of endogenous HAEE may be considered as a potential blood-based biomarker in the diagnosis of AD, while exogenous synthetic HAEE may serve as a drug in AD-modifying therapy.

Link: https://doi.org/10.1093/pnasnexus/pgag320

Microglia are innate immune cells of the brain, similar in behavior to tissue resident macrophages elsewhere in the body, but with an additional portfolio of duties relating to maintenance of neural networks. Like macrophages, microglia can adopt packages of behavior, and switch between them depending on environment cues; pro-inflammatory M1 focused on defense against pathogens versus anti-inflammatory M2 focused on tissue maintenance, for example. With age, the microglial population becomes more inflammatory, contributing to chronic inflammation of brain tissue and consequent disruption of normal function that contributes to the onset and progression of neurodegenerative conditions. Some of this inflammatory behavior is a consequence of an increased burden of cellular senescence in microglia and other supporting cells of the brain, but not all of it. Regardless, microglial dysfunction is a topic of increasing interest for researchers aiming to produce novel therapies to address the aging of the brain.

An active area of exploration is the contribution of lipid metabolism dysfunction to the inflammatory behavior of microglia in the aging brain. Of particular interest is the point that variants of APOE are well demonstrated to alter the risk of Alzheimer's disease, this protein is deeply involved in lipid metabolism, and evidence suggests it contributes to microglial inflammation. A further point is that excess cholesterol in cells can cause mitochondrial dysfunction, and the aging brain (and particularly in neurodegenerative conditions) exhibits both of these features. Finding specific dysfunctions in lipid metabolism and then attempting to address them with novel therapies seems a promising area of exploration in neurodegenerative research. Today's open access paper discusses evidence for the involvement of lysosomal aging in dysfunctional lipid metabolism in microglia, another possible starting point for a search for novel treatments.

Dysfunction of lipid metabolism and lysosomal capacity: at the core of microglial aging?

The metabolism of lipids is emerging as an essential regulator of microglial homeostatic activity and the ability to adapt their functional state to environmental changes across the lifespan. Microglial lipids serve structural roles in membrane maintenance and remodeling and act as signaling mediators in key regulatory pathways, including energy production and inflammatory mediator release. Beyond their intrinsic lipid needs, microglia phagocytose lipid-rich substrates (i.e., myelin fragments, cell debris, and synaptic elements) and generate intracellular lipid cargo through housekeeping autophagic processes. Intracellular lipid droplets (LD), which store excess lipids, are emerging as essential regulators of microglial metabolic programming and functional capacity. To maintain lipid balance and prevent lipotoxicity, microglia possess a complex feedback-regulated system for lipid uptake, processing, recycling, storage and export of excess lipids. Lysosomes, the cellular degradative and signaling hubs, lie at the center of these key lipid-handling pathways, both organizing lipid turnover and being modulated by the lipid status. This bi-directional interplay underlying microglial metabolic programming is coordinated by a variety of lipid- and nutrient-sensing molecular players, notably involving mechanistic target of rapamycin complex 1 (mTORC1) or triggering receptor expressed on myeloid cells 2 (TREM2).

Aging drives maladaptive microglial functions contributing to inflammation and neurotoxicity in age-associated disorders. Dysfunctional lipid handling and lysosomal processing have been connected to this detrimental polarization, highlighting the relevance of this pathway for therapeutic targeting. While significant advances have been made in the study of microglial lipid metabolism in contexts of aging-related diseases, our understanding of its changes over the course of physiological aging remains lacking, which creates a critical knowledge gap. Several single-cell analyses further indicate that microglial aging occurs in a central nervous system region-dependent manner, raising fundamental questions: (1) is this regional heterogeneity associated with distinct microglial lipid signatures and/or lysosomal capacities; (2) do these putative baseline differences play a role in susceptibility to and extent of aging-related microglial dysfunction; and (3) is microglial lipid shift inherent and/or driven by environmental challenges? On a broader level, how these metabolic and functional aging microglial changes are translated into higher cognitive processes, and what role they play in their aging-associated decline and disease susceptibility, represents a crucial area for investigation.

Despite the only small benefits shown to Alzheimer's patients following clearance of amyloid-β aggregates in the aging brain, the consensus remains that a slow accumulation of amyloid-β aggregates over years is the inciting form of dysfunction that gives rise to the later tau aggregation, neuroinflammation, and cell death in Alzheimer's disease. Removal of amyloid-β may be preventative in the earliest stages of the condition, but this is a hypothesis still undergoing assessment. Amyloid-β in the brain has been shown to be in dynamic equilibrium with amyloid-β outside the brain, and this has led to clinical trials in which amyloid-β is removed from blood, causing a greater amount of amyloid-β to exit the brain. Here, researchers discuss this holistic view of amyloid-β distribution throughout body and brain, and whether current efforts are too focused on only the burden of amyloid-β aggregates in the brain.

Alzheimer's disease (AD) represents one of the most prevalent neurodegenerative disorders without approved disease-modifying therapies. A major contributing factor is that, for decades, drug development has focused almost exclusively on repairing or removing lesions within the brain itself. Yet a growing body of work now points to AD as a systemic disorder, rooted in a breakdown of whole-body Aβ homeostasis. Nevertheless cerebral Aβ transport and peripheral Aβ clearance are commonly investigated as independent processes, and the coordinated interplay remains insufficiently characterized. This review bridges the current research gap by systematically elaborating the full trafficking cascade of brain-derived Aβ from intracerebral drainage to peripheral elimination.

Four major intracranial clearance pathways are comprehensively summarized, including the blood-brain barrier, blood-cerebrospinal fluid barrier, arachnoid granulation venous outflow, and meningeal lymphatic/glymphatic system. The peripheral clearance processes of circulating Aβ in the blood, liver, kidney, and gastrointestinal tract are further illustrated. A broad spectrum of emerging therapeutic strategies targeting Aβ transport and clearance is also reviewed, including specific pathway modulators, microglia regulators, Aβ aggregation inhibitors, natural multi-target compounds, ultrasound-mediated blood-brain barrier opening, and exosome-based intervention approaches.

When we compare the relative contributions of central versus peripheral clearance, comparative analysis of central and peripheral Aβ clearance indicates that the liver appears to dominate the peripheral elimination of Aβ, yet the real driver of cerebral Aβ deposition is not the failure of any single route, but rather the loss of synergy among multiple pathways. This mechanistic framework explains why purely brain-centric therapeutics are unlikely to correct a systemic Aβ imbalance. Instead, future translational efforts should give higher priority to combination regimens that simultaneously facilitate intracerebral drainage and bolster peripheral organ clearance. This review further discusses current hurdles and emerging opportunities in systemic AD drug discovery, with the aim of offering a unified conceptual framework-one that providing a unified conceptual framework for understanding AD pathogenesis and facilitating the exploration of novel therapeutic paradigms.

Link: https://doi.org/10.3389/fragi.2026.1921485

Recovery and transplantation of organs following vitrification using cryoprotectant is an important step along the road to the future technological capability of whole body vitrification and recovery - and recovery of those individuals already preserved at low temperature by the cryonics industry. It is particularly important because it is a highly desirable capability for the organ transplant industry, and thus a way to bring significant funding and credibility to the endeavor of cryonics, the preservation of people for future revival. Scaling up vitrification and rewarming to human sized organs has been a major challenge on several fronts, such as effective perfusion of cryoprotectant in large tissues, performance of the cryoprotectant, consistent warming of deeper tissue in a large vitrified mass, and so forth. It is much easier to vitrify and reward small tissue samples than large ones. Here researchers report success in pig kidneys, albeit using an approach to rewarming that requires preparation of the organs prior to vitrification, and thus cannot be applied to tissues and people preserved prior to its introduction. Nonetheless, it is an important step forward.

Vitrification and nanowarming have enabled long-term preservation and transplantation of rodent kidneys but have not been demonstrated at the scale of clinically relevant organs. Here we show that vitrification and electromagnetic nanowarming enable long-term cryogenic storage and functional recovery of human-scale porcine kidneys. Kidneys 100-fold larger than previously nanowarmed kidneys were successfully recovered after storage at -150 °C for up to one year. A new cryoprotectant formulation and multithermic perfusion strategy enabled ice-free vitrification at cooling rates achievable in large kidneys, while controlled cooling with annealing and staged volumetric nanowarming limited thermal stress and enabled rapid rewarming without cracking.

Nanowarming was developed to overcome the limitations of surface-based rewarming. Silica-coated iron oxide nanoparticles distributed through the vasculature before vitrification generate heat when exposed to an alternating electromagnetic field, enabling rapid volumetric rewarming throughout the organ.

Rewarmed kidneys demonstrated vascular, metabolic, and excretory function during normothermic perfusion, with limited histological injury, and reperfused homogeneously and produced urine immediately after transplantation. Functional recovery approached static cold storage outcomes across several measures and was similar to that of kidneys exposed to cryoprotectant alone, suggesting minimal additional functional injury from vitrification, cryogenic storage, and nanowarming. These findings overcome major scale and storage-duration barriers to organ cryopreservation and establish a path toward organ banking on timescales far beyond those of conventional preservation.

Link: https://doi.org/10.64898/2026.10.07.756990

The vascular system is prone to calcification with advancing age. Cells in the vasculature inappropriately take on the features and behavior of the osteoblast cells responsible for building bone extracellular matrix. These errant vascular cells deposit calcium phosphate structures into vascular tissue, stiffening it. Calcification proceeds in parallel with atherosclerosis, the thickening of artery walls and generation of fatty plaques that obstruct vessels and ultimately rupture to cause a heart attack or stroke, but is an independent process that would cause dysfunction and mortality even if the causative mechanisms of atherosclerosis were eliminated.

Stiffening of vascular walls, however it occurs, whether by this process, other forms of damage and change in the extracellular matrix, or loss of responsiveness to cues for contraction and dilation in vascular smooth muscle, induces hypertension, among other issues. Perhaps more importantly, calcification of structures in the heart, such as the aortic valves, is ultimately fatal.

Present therapeutic options for calcification are limited. For example, a form of chelation using EDTA has been assessed in clinical trials, is readily available in clinics, but produces only modest benefits at best. Thus it is interesting to keep an eye on developments in this space. Today's open access paper describes a micropeptide therapy that can inhibit calcification processes, slowing vascular calcification meaningful in animal models. Slowing is a start, but effective reversal of age-related tissue calcification remains a unfulfilled goal.

PKM2 AP: a micropeptide inhibits vascular calcification via molecular glue-mediated ubiquitination of PKM2

Vascular calcification (VC) is not merely a passive mineralization process, rather, it is an active pathological event that is propelled by the osteogenic phenotypic transition of vascular smooth muscle cells (VSMCs). This transition is characterized by aberrant deposition of hydroxyapatite crystals within the vascular wall, leading to loss of vascular elasticity and increased risk of cardiovascular events. Despite advancements in clinical management strategies for VC, such as intensified dialysis regimens and phosphate binder therapies, current treatments remain insufficient to halt calcification progression, resulting in limited long-term prognostic improvement.

VSMCs undergo phenotypic switching from contractile to synthetic or inflammatory states under pathological stimulation, a critical initiating event in VC. Notably, this phenotypic transition is accompanied by marked metabolic reprogramming, characterized by a shift from oxidative phosphorylation to aerobic glycolysis, leading to lactate accumulation. Emerging evidence suggests that lactate not only induces synthetic phenotypic switching in VSMCs but also promotes vascular calcification through dual mechanisms: activating NR4A1-mediated mitochondrial fission and BNIP3-dependent mitophagy. Pyruvate kinase M2 (PKM2), a key rate-limiting enzyme in glycolysis, catalyzes the irreversible conversion of phosphoenolpyruvate to pyruvate, directly regulating lactate biosynthesis. Strikingly, recent studies demonstrate that PKM2 inhibition preserves VSMC contractile phenotype and improves vascular homeostasis, suggesting its pivotal role in calcification-associated metabolic regulation.

In this study, we identified a 40-amino acid micropeptide, termed PKM2-associated micropeptide (PKM2 AP), which was highly expressed in patients with chronic kidney disease-related vascular calcification. PKM2 AP localized to both mitochondrial and cytoplasmic compartments and exhibited functional interactions with PKM2. Functional experiments demonstrated that overexpression of PKM2 AP both in vitro and in vivo attenuated the progression of vascular calcification. Mechanistically, PKM2 AP functioned as a molecular glue-like factor that facilitated the recruitment of the E3 ubiquitin ligase STUB1 to PKM2, thereby promoting PKM2 ubiquitination and degradation, ultimately suppressing aerobic glycolysis and lactate production in human aortic vascular smooth muscle cells (HAVSMCs). In vivo administration of PKM2 AP alleviates vascular calcification phenotypes in mouse models.

Researchers here identify the gene PLA2G2F as a regulator of compensatory responses to some of the damage and dysfunction of aging. The researchers were primarily investigating a population of neurons found in the hippocampus, involved in memory function, but find that the gene is relevant in supporting cells of the brain also, such as microglia. Expression of PLA2G2F increases with age, and artificially increasing expression over natural levels produces greater protection. PLA2G2F appears to be involved in maintenance of normal lipid metabolism. Evidence suggests that dysfunctions in lipid metabolism occur in the aging brain, and cause harm via provoking greater inflammatory behavior in a number of supporting cell populations.

Cognitive reserve theory posits that compensatory mechanisms during aging stave off cognitive decline and lower risk for Alzheimer's disease. Here, in a screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors in mice, we identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging and is associated with cognitive resilience in humans. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes, including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation, lipid droplet accumulation, and hippocampal-dependent memory loss.

Conversely, boosting Pla2g2f in DGCs during aging is sufficient to prevent these pathophysiological alterations in hippocampal-cortical circuits, protect memory, and prophylactically modify trajectory of cognitive decline. Mutagenesis of the catalytic site of PLA2G2F prevented lipid droplet mobilization and reduction of reactive gliosis and inflammatory microglia. Neuronal PLA2G2F mediates intercellular signaling to decrease lipid droplet and cholesterol ester load in human induced pluripotent stem cell-derived microglia. Our findings implicate PLA2G2F as a compensatory neuroprotective broadcast signal that maintains lipid homeostasis to counteract aging-associated cognitive decline.

Link: https://doi.org/10.1038/s41593-026-02465-z

Of the common variants of the APOE gene, APOEε4 presents the greatest risk of Alzheimer's disease. APOE is involved in lipid metabolism, and APOEε4 is associated with lipid-related contributions to inflammation in microglia, suggesting a primarily inflammatory mechanism for the increased risk of neurodegeneration. Here, researchers find that APOEε4 also interferes in the ability of oligodendrocyte cells to maintain the myelin structures that sheath the axons that connect neurons into neural networks, again via lipid-related mechanisms. This myelin sheathing is required for effective communication between neurons. Myelin maintenance does falter to some degree in normal aging, and the consequent loss of myelin is thought to contribute to dysfunction in the aging brain. It is reasonable to hypothesize that greater myelin loss driven by APOEε4 is a factor in accelerated neurodegeneration.

A new study shows that APOE4 leads to a suppression of Wnt signaling in the oligodendrocyte cells that provide neurons with a fatty insulation, called myelin. When Wnt signaling is deficient, the cells accumulate droplets of lipids rather than deploying fats to properly myelinate the neurons' axon branches. When the researchers restored Wnt signaling in APOE4-carrying oligodendrocytes, myelination rebounded, both in human cell cultures and in mice modeling Alzheimer's.

Researchers discovered Wnt's key role via multiple methods including a screen in which they used CRISPR gene editing to systematically knock out each protein-coding gene in the genome, one by one, in cultures of human APOE4-carrying oligodendrocytes. The screen showed that when genes promoting Wnt activity in oligodendrocytes were lacking, lipid droplets accumulated, and that when genes suppressing Wnt were lacking, lipid droplets were, too. Further analysis revealed how Wnt signaling became depressed in cultured APOE4 oligodendrocytes. Two proteins, beta-catenin and GSK3b, each compete to regulate Wnt-beta-catenin promotes it and GSK3b suppresses it. The team found that in APOE4 oligodendrocytes compared to APOE3 ones, there was reduced beta-catenin expression and excessive GSK3b expression.

The team then tested interventions that manipulate GSK3b activity. In human APOE3 oligodendrocyte cultures, they showed that increasing GSK3b with a chemical called Dif3 increased lipid droplets. In APOE4 oligodendrocytes, they showed that inhibiting GSK3b with a chemical called CHIR99021 reduced droplets. In more complex "organoid" cultures combining APOE4 oligodendrocytes with neurons, they found that inhibiting GSK3b increased myelination and promoted the growth of neural axons. The tests suggested that GSK3b inhibition could be a proof-of-concept therapeutic strategy for restoring Wnt signaling and myelination.

Link: https://picower.mit.edu/news/how-biggest-alzheimers-risk-gene-disrupts-process-insulating-neurons

Mitochondria are the power plants of the cell, creating the chemical energy store molecule adenosine triphosphate used to power cellular processes. Mitochondrial function declines with age, and the research community is engaged in a variety of approaches that might at least modestly reduce this loss. The supplement urolithin A is known to improve mitochondrial function, though, and as is the case for other approaches, how exactly urolithin A accomplishes this outcome is not fully understood. Most of the ways to modestly improve mitochondrial function, ranging from exercise and calorie restriction through to NAD+ upregulation via vitamin B3 derivatives and MitoQ, may primarily function through improvements to autophagy targeted at mitochondria, improving overall mitochondrial function via improved clearance of damaged and dysfunctional mitochondria. This is by no means a definitive answer, but the supporting evidence is suggestive.

In today's open access paper, researchers show that topical application of urolithin A improves the function of aged skin. It is interesting to compare this with a small study of topical application of low dose rapamycin, another approach to improve autophagy. Increased autophagy (and accompanied improvement in mitochondrial function) has in the past been shown to reduce the pace at which cells become senescent in aged tissues. This allows the immune system to catch up in its task of clearing senescent cells, and thus reduce the harmful burden of senescent cells that contributes to dysfunction in aged tissues. Cellular senescence is known to be important in the aging of skin, and increased autophagy over time is an approach to reducing this contribution to degenerative aging.

Topical application of urolithin A activates mitophagy and enhances mitochondrial function to promote skin longevity

The most common visual signs of aging skin are the appearance of wrinkles, skin thinning, hyperpigmentation, sagginess, and dryness. This derives from a combination of biological changes, including a decline in the quantity and quality of structural components of the skin, such as collagen and elastin, as well as dysfunctions in cellular bioenergetics. Indeed, most of the energy to support skin cell health is derived from mitochondria, making mitochondrial dysfunction a key hallmark of skin aging. The aging process impacts immune cells in the skin. This reduces the ability of the skin to cope with excessive inflammation and significantly contributes to the emergence of photoaging. Finally, cellular senescence is emerging as a key additional hallmark that affects skin health as we age, which can be counteracted by removal of the senescent cells (i.e., senolytic effect) or blunting of their detrimental secretome (i.e., senomorphic effect).

Urolithin A (UA) is a promising molecule to explore for its impact on skin longevity, considering its origins as a postbiotic of the gut microbiome that has been shown to both improve mitochondrial health and reduce age-associated inflammation, i.e., inflammaging, when administered orally. UA increases mitophagy, the process of recycling faulty mitochondria, and enhances biomarkers associated with improved mitochondrial function in several models of aging and age-associated conditions. In humans, oral supplementation of UA was shown to be safe, improve mitochondrial function, and increase muscle strength, endurance, and immune decline in clinical studies in middle-aged and elderly subjects. Topical application of UA represents a compelling approach to support skin health and extend skin longevity through its combined effect on multiple hallmarks of cellular aging.

UA was evaluated for its effects on skin health in human skin models and when applied topically to healthy subjects in randomized clinical studies. UA tested in 2D and 3D reconstructed human skin and ex vivo human skin explants showed enhanced mitochondrial respiration, activated mitophagy markers, reduced inflammatory mediators and senescence-associated markers, and increased proteins involved in extracellular matrix structure and epidermal differentiation. In randomized, placebo-controlled clinical studies, UA reduced periorbital wrinkle depth after 8 weeks and attenuated UVB-induced erythema. Skin transcriptomics supported increased extracellular matrix and epidermal development programs together with decreased inflammatory and senescence-associated signaling.

Why, mechanistically, is female reproductive aging so accelerated in relation to the rest of the aging process? Researchers here point to a role for a progressive loss of ribosomes in oocytes. Cells contain many ribosomes, vital components of the cell where messenger RNA is translated into protein, and usually synthesize more as needed. Oocytes do not tend to synthesize new ribosomes, however, one of many differences in behavior intended to retain a much higher standard of cell quality during the reproductive lifespan. Female germline cells are among the most protected of all cell types, and have to be in order to maintain a sufficiently low level of reproductive failure for evolutionary success. Here, it is suggested that this ribosomal approach to increased cell quality produces the trade-off of a shorter cell life span and an earlier end to reproductive life span, as ribosomes are not replaced as they fail, and new oocytes are not created in adult life. In support of this view, researchers find that artificially reducing ribosome count in oocytes recapitulates the features of reproductive aging.

Protein synthesis declines with age across many tissues, but whether this decline actively contributes to physiological aging remains unclear. Oocytes may be particularly vulnerable because they rely on ribosomes synthesized during growth and maintained for prolonged periods without continual replacement. Here we show that declining translational capacity is a causal component of oocyte aging. An unbiased genetic screen identified ribosome dosage as a major determinant of oocyte longevity, and experimentally reducing ribosome abundance was sufficient to accelerate the loss of developmental competence and prematurely recapitulate meiotic defects that arise during natural aging, while also producing defects in early embryonic development.

Ribosomes isolated from aged Drosophila oocytes exhibit ∼50% lower translational activity despite only a modest reduction in ribosome abundance and preserved gross structure and composition, with both ribosomal subunits contributing to this functional decline. Protein synthesis also declines markedly in aged metaphase-I mouse oocytes. Together, these findings identify long-lived translational machinery as an intrinsic vulnerability of the oocyte and establish declining ribosome function as a mechanistic contributor to reproductive aging.

Link: https://doi.org/10.64898/2026.09.29.755503

Aging clocks can be produced from large databases of near any form of biological data that changes with age via the use of machine learning techniques that identify weighted combinations of measures that correlate strongly with chronological age, remaining life expectancy, mortality risk, and so forth. The true goal of developing clock technology is to find a way to rapidly assess the quality of any new potential therapy to slow or reverse aspects of aging, and thus greatly accelerate research and development, focusing attention on the best possible approaches. Unfortunately no clock can be trusted to perform accurately in the face of a new approach to treat aging. A clock could underestimate, overestimate, or be unaffected by biological changes that do have meaningful effects on aging. It is unknowable in advance how this will play out, and the only way to determine what will happen is to first calibrate the clock against the therapy using lengthy studies, which defeats the point of the exercise. Nonetheless, researchers are engaged in producing as much data as possible on the way in which clocks behave, in an attempt to at least try to predict the degree of trust one should have in a giving clock assessing a given therapy.

Epigenetic clocks have emerged as potential biomarkers of aging due to their association with morbidity and mortality. They have recently gained traction as outcome measurements for anti-aging interventions. However, as the number of new epigenetic clocks continues to grow, different clocks may not agree on the effect of an intervention. This raises the question of when researchers can trust epigenetic clock results. In this study, we find that when extending previously published single-clock intervention studies to include additional clock models, no additional clocks reach statistical significance.

We then analyze clock behavior across positive control datasets (age-accelerating events) to propose three criteria that increase confidence in a result: (1) reliable principle component based clocks respond, (2) mortality-trained or pace-of-aging clocks respond, and (3) multiple clocks respond in the same direction. To explain why genuine effects would appear across multiple clocks, we perform a simulation study to demonstrate how reliable clocks are more sensitive to true effects, and use longitudinal control datasets to show that reliable clock changes are correlated with each other. We then show examples of interventions that do satisfy these criteria.

These findings provide a framework for interpreting epigenetic clock results in anti-aging intervention studies, and suggest that some previously published single-clock findings may warrant reexamination.

Link: https://doi.org/10.1111/acel.70756