Fight Aging!

Cells become senescent constantly throughout life, usually upon reaching the Hayflick limit to replication, but also in response to injury, high levels of cell stress, or potentially cancerous damage. Senescent cells cease to replicate, grow in size, and secrete pro-inflammatory signals to attract the attention of the immune system. In youth, the immune system clears senescent cells rapidly, but this becomes less efficient with advancing age for a range of reasons yet to be fully explored. Senescent cells appear to alter their biochemistry in ways that inhibit immune clearance, but the immune system as a whole also becomes less effective at all of its tasks. Senescent cells linger, accumulate, and disrupt tissue structure and function with their inflammatory signaling.

The vascular system is vital to health, and many of its issues are known to start with dysfunction in the inner lining of vessels, the vascular endothelium. Inflamed regions of endothelial tissue, populated by growing numbers of senescent endothelial cells, are an early feature in the development of the fatty, obstructive plaques of atherosclerosis, disruption of the blood-brain barrier allowing leakage into the brain, dysfunctional smooth muscle that degrades the ability of vessels to contract and dilate appropriately, and forth.

In today's open access paper, researchers outline a possible target for reduction of the burden of cellular senescence in aged blood vessels. MTR4 expression appears to reduce the pace at which vascular endothelial cells become senescent, but unfortunately declines with age. Enhancing expression is shown to extend life in short-lived nematode worms, suggesting that trying a lifespan study in mice is worth the effort. The vascular endothelium is a challenging target for gene therapies, however, because there is so very much of it. Even though the endothelium is just about the first destination for any suitably engineered vector that is injected intravenously, it would be challenging to deliver enough vector to cover the entire endothelium without an excessive amount spilling over to end up in liver tissue and cause issues there.

MTR4: A Conserved Youth Factor for Vascular Endothelium

Vascular endothelial cells (VECs) form the inner lining of blood vessels and act as a critical interface between the circulation and surrounding tissues. Beyond their role as a physical barrier, VECs dynamically regulate vascular tone, permeability, inflammation, and hemostasis, thereby maintaining multi-organ homeostasis and modulating disease pathogenesis. Chronically exposed to hemodynamic and metabolic stress, VECs are among the first cell types to acquire age-related damage. Senescent VECs undergo irreversible cell cycle arrest and acquire a pro-inflammatory senescence-associated secretory phenotype (SASP), which propagates local and systemic chronic inflammation. Endothelial dysfunction is now recognized as a central driver of major age-related disorders.

Here, we identify MTR4, an evolutionarily conserved RNA helicase and nuclear RNA exosome cofactor, as a novel regulator of VEC senescence. MTR4 protein declines markedly in senescent human umbilical vein endothelial cells (HUVECs) and aged mouse aortas, independent of general cell cycle exit. Mechanistically, senescence-induced upregulation of the E3 ubiquitin ligase synoviolin 1 (SYVN1) promotes K638-linked ubiquitination and proteasomal degradation of MTR4. MTR4 depletion drives proliferating HUVECs into premature senescence, whereas its overexpression restores a youthful phenotype in senescent cells by binding BUB3 to stabilize BUB3 and sustain BUBR1 expression.

In mice, endothelial Mtr4 knockdown promotes vascular dysfunction and multi-organ aging, while endothelium-specific Mtr4 overexpression alleviates these phenotypes. In C. elegans, mtr-4 overexpression dramatically extends lifespan, comparable to classic longevity models and surpassing most single-gene interventions, while its knockdown accelerates aging. Our findings establish MTR4 as a critical guardian of endothelial homeostasis and organismal aging, with strong translational potential for mitigating age-related vascular dysfunction.

Education, intelligence, socioeconomic status, and healthy longevity are all correlated with one another in human populations. No concrete determination of the mechanisms that make this the case has yet been established, but there is no shortage of hypothesizing on the topic. Does education produce an effect through the greater socioeconomic status that it tends to produce, or is there, for example, some physical benefit arising from a greater use of the brain during developmental years that lasts for long enough to affect neurodegeneration in late life? Or it is that more intelligent people tend to be more educated, and thus intelligence is the factor that one needs to look at for causation? And so forth. Here, researches present results that argue more for a contribution of physical effects in the brain than for other possibilities.

Lower educational attainment has been identified as a major risk factor for Alzheimer's disease and related dementias (ADRD). However, little is known about whether and how much of this association reflects a causal effect from education to ADRD. Part of the challenge in distinguishing correlation from causation is that third factors, such as childhood circumstances, socioeconomic background, and genetics, may confound the relationship between education and ADRD. Also, there may be individual characteristics, such as self-control, that drive both behavioral risk factors and educational attainment.

We overcome these challenges by combining a natural experiment with dementia data constructed from administrative health records for a large cohort. In 1972, England, Scotland, and Wales increased the minimum age at which students could drop out of school from 15 to 16 years of age. The reform affected only students born after September 1, 1957, generating a discontinuity in the relationship between education and date of birth. We exploit this discontinuity to estimate the causal effect of education on dementia incidence.

We found that this additional schooling induced by a natural experiment in the United Kingdom in the early 1970s subsequently reduced the cumulative incidence of ADRD in affected cohorts by approximately 0.88%. These results suggest that ADRD incidence can be modified by social policy, a welcome finding given the expected exponential growth in cases of dementia and their large costs. Encouragingly, we also found that the school reform mitigated the genetic risk of developing ADRD - rejecting the common perception that the influence of genetics on diseases such as ADRD cannot be altered by environmental interventions.

Link: https://doi.org/10.1073/pnas.2529506123

Despite a number of approved devices and some widely used protocols (that are not very consistent from device to device and provider to provider), few electromagnetic therapies have demonstrated consistent benefits. Some research groups are focused on applying electromagnetic fields to the brain, specifically ultrashort wave fields that may act to reduce inflammation. Here, researchers note that short wave electromagnetic therapy improves the drainage of cerebrospinal fluid from the brain into the glymphatic system. This drainage declines with age for a range of different reasons, and this contributes to neurodegeneration by encouraging protein aggregates and other metabolic waste to accumulate in brain tissue. One of the reasons why drainage declines is that the water channel AQP-4 becomes mislocalized in astrocyte cells. AQP-4 needs to be in the extended endfeet structures of astrocytes, which wrap around the perivascular spaces used to transport fluid away from the brain, and in aged tissues AQP-4 is not correctly localized in large enough amounts for efficient passage of fluid. The electromagnetic therapy appears to function by improving AQP-4 localization.

The glymphatic system clears cerebral waste, yet strategies to enhance its function remain elusive. Here, we show that 40.68 MHz ultrashort wave (USW) rapidly enhances glymphatic bulk flow in healthy mice within 10 minutes. USW potentiates both glymphatic influx and efflux, concomitant with increased Delta wave neuronal synchronization, as confirmed by local field potentials and electroencephalograms. Chemogenetic silencing confirms that USW-driven glymphatic enhancement depends on neuronal activity, while pharmacological blockade of aquaporin-4 (AQP4) abolishes the effects, revealing dual reliance on neural dynamics and astrocytic water channels.

Mechanistically, USW-induced Delta oscillations promote AQP4 polarization, coupling synchronized firing to perivascular AQP4 redistribution. Moreover, USW ameliorates traumatic brain injury-induced cerebral edema and improves cognitive deficits in Alzheimer's model mice by restoring glymphatic function. Our findings establish USW as a non-invasive neuromodulatory strategy for enhancing glymphatic clearance, offering therapeutic potential for neurological disorders characterized by glymphatic dysfunction.

Link: https://doi.org/10.1126/sciadv.aeh8870

Lysosomes are structures within cells packed full of enzymes capable of breaking down proteins and structures into raw materials; they serve as recycling centers. Lysosomes are the final destination of damaged or unwanted proteins and structures flagged for destruction by the cellular maintenance processes of autophagy. Lysosomes are known to become dysfunctional with age, for reasons that are not fully explored. Some of it is a matter of changes in the expression of relevant genes, some of it is a matter of the accumulation of persistent metabolic waste that lysosomes cannot effectively break down. Given enough of that waste, lysosomes become bloated and inefficient. If a cell cannot effectively recycle, it becomes dysfunctional, inflammatory, and eventually dies. The more that this happens, the more that it contributes to degenerative aging.

Lysosomal dysfunction didn't make it into the Hallmarks of Aging as a headline category of its own. Arguably it should have. The earlier Strategies for Engineered Negligible Senescence (SENS) proposals included lysosomal dysfunction as a part of the problem of the aggregation of persistent metabolic waste inside cells, and did not focus all that much on harmful epigenetic change, save as it exists as a maladaptive reaction to other forms of molecular damage.

In today's open access paper, researchers report on novel findings in lysosomal aging, and show that it is possible to build a sufficiently complex signature of lysosomal aging from these findings to enable the creation of an aging clock. That one can build a decent aging clock from this data doesn't definitively indicate that this is an important cause of degenerative aging, however. That has to be separately determined the old-fashioned way. As is usually the case, the fastest path to demonstrating relevance as a contributing cause of aging is to find a way to reverse the specific observed changes in isolation, and then observe the outcome. Unfortunately one has to establish a path to therapy, then see whether or not it is viable, and not the other way around.

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic, and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Researchers now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine, and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis.

The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine, and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders, and vulnerability to late-onset neurodegeneration.

Researchers here propose that greater efforts should be devoted to considering the variety of G-protein coupled receptors (GPCRs) as a regulatory network in the matter of aging and age-related disease. Aging produces sweeping changes in protein levels, gene expression, protein function and interactions, and one can thus make similar arguments for many different classes of molecule found in cells. The question is always whether one can justify intervention in a given mechanism on the basis of its importance to aging: where does it sit in the interacting network of cause and consequence? Is it causing a great deal of downstream harm, or is it more of an end stage consequence? How close is it to root causes of aging? This is a lot harder to answer than whether or not a mechanism has a role at all, but it is the crux of the matter, determining whether targeting that mechanism is a good choice or not.

G protein-coupled receptors (GPCRs) are arguably the most important class of signal transducers discovered to date. GPCRs are heptahelical transmembrane proteins that mediate responses to, among others, hormones, neurotransmitters, steroids, and immune modulators, many of which undergo dysregulation with age. GPCRs efficiently modulate a wide variety of signaling processes that underpin nearly all the mechanisms responsible for chronic age-related disease. Given their vital physiological role, dysfunction of GPCR signaling networks may represent a potential driver of aging pathophysiology. For example, age-related alterations in GPCR signaling contribute to chronic, low-grade inflammation (inflammaging), as seen in the increased activity of chemokine and cytokine receptors that results in immune system dysfunction. Additionally, GPCRs involved in metabolic regulation, such as adrenergic and insulin-sensitizing receptors, become less responsive with age, exacerbating metabolic disorders and insulin resistance. Mitochondrial dysfunction, another profound hallmark of aging, is also influenced by GPCR signaling through pathways that regulate oxidative stress and cellular energy homeostasis.

Therefore, GPCRs represent promising new therapeutic targets for mitigating - at both tissue-specific and systemic levels - age-associated diseases, which could work toward extending a person's healthspan. We posit that, while many diseases possess a specific genomic basis in their later stages, they may share a common feature in their genesis: the loss of cellular homeostasis. In this article, we evaluate the "GPCR-ome" as a central, "mega-trophic" regulator of human healthspan. We begin by examining the structural and functional vulnerabilities across major GPCR classes that render them susceptible to age-dependent decline. We then detail how these receptors functionally integrate with the fundamental hallmarks of aging (e.g., inflammaging, mitochondrial failure, and cellular senescence) to drive multisystemic disease. Finally, we propose a transformative therapeutic framework to transition from treating individual symptoms to targeting aging itself as a manageable, tunable process.

Link: https://doi.org/10.3389/fsci.2026.1891819

Researchers here provide a demonstration that a form of liver cancer can emerge from change in the epigenetic control over gene expression in the absence of mutation of nuclear DNA, rather than from mutation of nuclear DNA. It is an interesting open question as to the degree to which aging predisposes to cancer via a growing burden of mutation versus a growing burden of epigenetic change that alters expression of oncogenes. The answer will likely be very different on a tissue by tissue and cancer by cancer basis; biology is complex at every level.

Large-scale genome sequencing analyses have identified driver gene mutations (DGMs) in most cancers as well as their associated tumorigenic mechanisms. However, a small fraction of cancers are not positive for these canonical DGMs, leaving the mechanisms underpinning their formation a mystery. We hypothesized that canonical DGM-negative cancers might be driven by activation of the transcriptional coactivator YAP1 that led to the induction of epigenetic changes.

To test this theory, we established a mouse mosaic model of hepatocellular carcinoma (HCC) in which we induced YAP1-TEAD activation in a few hepatocytes. Whole-exome sequencing did not identify canonical DGMs in HCCs, but bisulfite sequencing revealed widespread DNA demethylation leading to the transcriptional activation of multiple oncogenes. Knockdown of the DNA demethylation-promoting gene, Tet1, attenuated HCC formation in these mice. Single-cell spatial transcriptomics identified a Tet1-high subpopulation of HCC cells that interacted with other hepatic cell types.

Our mechanistic mouse data align with the observation that YAP1-TEAD-TET1-associated signatures were also elevated in hepatocytes from patients with Fontan-associated liver disease (FALD), a condition associated with the development of HCCs with lower frequencies of canonical DGMs. Our study suggests that the YAP1-TEAD-TET1 axis promotes canonical DGM-negative HCC development, and provides new insights into the molecular processes involved.

Link: https://doi.org/10.1038/s42003-026-10882-w

Stem cell therapies involve a stage of expansion of cells in culture prior to injecting them into the patient. The research community has realized that both the state of the original source cells and small variations in the subsequent cell culture environment can result in large differences in the quality of the transplanted cells. For example, how many of the cells in the culture have become senescent, and are thus now generating pro-inflammatory signals. There are other possible variations in cell state that could contribute negatively to outcomes, diminishing any benefits resulting from the therapy, however. Differences in cell state and behavior may be the cause of much of the well-known and undesirable variability of outcomes in stem cell therapy.

Some clinics may have started to at least attempt to use senolytic treatments to reduce the number of senescent cells in stem cell cultures, but this is by no means yet a standard. Today's open access paper discusses this issue, expanding the consideration from senescent cells to other problematic changes in cell state that may negatively impact outcomes for patients. They present this as a quality issue, discoveries to be added to the consensus on what constitutes Good Manufacturing Practice (GMP) for stem cell therapies provided within more regulated regions of the world. Medical tourism of course remains a black box in this as in many other matters.

Proteotoxic stress in stem cell therapies: The overlooked roles of senescence, EV cargo, and SOD1

The rapid clinical expansion of therapies based on stem cells and cell-free extracellular vesicles (EVs) has outpaced the development of rigorous quality control standards. Current Good Manufacturing Practice (GMP) standards evaluate identity, viability, sterility, and genetic stability, but do not routinely assess protein homeostasis in donor cells. Cellular senescence, which frequently emerges during ex vivo expansion, impairs protein quality control and yields an EV secretome enriched with proteotoxic cargo. In neural stem cells (NSCs), oxidized superoxide dismutase 1 (SOD1) accumulates during senescence and is packaged into EVs that propagate neuronal toxicity and secondary senescence in recipient cells.

While established primarily in NSCs, analogous proteostatic decline across other stem cell types warrants targeted validation in mesenchymal stromal cell (MSC) and induced pluripotent stem cell (iPSC)-derived products. Donor cell proteostatic fitness is a plausible determinant of therapeutic outcome. Evaluating senescence burden and EV proteomic integrity should therefore become a standard critical quality attribute within cell and EV manufacturing pipelines. Practical steps toward this goal include the careful selection of cell sources, the establishment of quantitative senescence thresholds, and proteomic profiling of EV cargo. Targeted cargo sanitization strategies, such as selective clearance of misfolded SOD1, shows promise for pre-transplant conditioning, although clinical feasibility, scalability, and off-target effects require further study.

Peripheral nerves are capable of regeneration to restore connections across gaps caused by injury, but the larger the gap the less likelihood of a successful outcome. The medical community has developed approaches that help by laying guides along the path that regrowth must take, often composed of donor nerve tissue, which may be taken from elsewhere in the patient, but these are far from optimal. There is considerable research interest in the development of entirely artificial nerve regrowth guides that have a low cost and high rate of success in stimulating the necessary regeneration for a complete restoration of function. The paper here is an example of this sort of research and development, focused on bioprinting an implantable path for nerve regrowth.

Conventional cell-laden electro-direct writing (CEDW) technology faces challenges in terms of balancing printability, mechanical integrity, and biocompatibility. As a result, its application in neural tissue engineering remains limited. To overcome this challenge, this study develops a temperature-regulated cell-laden electro-direct writing (TCEDW) technology that achieves stage-specific rheological modulation through precise cylinder temperature control, thereby decoupling printability from biocompatibility and enabling high-resolution (36.05 µm) cell printing.

Using Schwann cell-laden alginate/gelatin methacryloyl/polyethylene oxide (alginate/GelMA/PEO) bioinks, TCEDW constructs were fabricated with both improved structural fidelity and preserved cell viability. In vitro co-culture of Schwann cells and PC12 cells demonstrated that TCEDW microfilaments significantly promoted neurite alignment and maturation by providing synergistic topographical and biochemical cues.

Gene expression analysis revealed that TCEDW scaffolds activated axon guidance and cGMP-PKG signaling pathways while suppressing proliferation programs to promote PC12 neuronal differentiation. Furthermore, a hybrid electro-assisted bioprinting approach integrating melt electro-writing, electro-spinning, and TCEDW was employed to fabricate three-layer composite nerve guidance conduits (NGCs). In vivo investigations demonstrated that the composite NGC platform promoted nerve fiber regrowth, Schwann cell migration, myelination, and functional recovery.

Link: https://doi.org/10.1088/2631-7990/aea8a3

Many forms of cell stress provoke much the same response of increased maintenance and damage repair activities, such as increased autophagy. A mild level or intermittent stress can result in overall benefit to cell and tissue function, and when applied over time to an organism this can modestly slow aging. How the cell regulates this response to stress and the fine details of the response to stress vary between different forms of stress, however. Thus developing a therapy to mimic, for example, the response to the low nutrient stress of calorie restriction, may be quite a different exercise to mimicking the response to cold, or heat, or toxin exposure. For illustration, researchers here dig into some of the regulatory mechanisms involved in the beneficial response to cold stress in nematode worms, and one can see the differences from what is known of calorie restriction in the same species.

Moderately cold temperatures extend lifespan and promote health across species, yet the molecular mechanisms underlying these benefits remain unclear. Here we define a metabolite-driven, multi-tissue signalling system that links cold temperature to enhanced longevity and proteostasis in Caenorhabditis elegans. Cold temperature upregulates the biopterin-synthesis enzyme CAT-4 (GCH1 in humans), increasing production of dihydrobiopterin (BH2), a transportable reservoir for the bioactive cofactor tetrahydrobiopterin (BH4).

BH2 is produced in muscle and transported to distal tissues, including the intestine and neurons, where it is converted into BH4 by the salvage enzyme DHFR-1. BH4 functions as an essential cofactor for phenylalanine hydroxylase PAH-1, promoting tyrosine synthesis and extending lifespan. This BH2-BH4 axis also prevents disease-related protein aggregation and subsequent neuronal dysfunction during ageing. Importantly, increasing BH2 synthesis specifically in muscle is sufficient to promote longevity and suppress pathological protein aggregation in distal tissues, even at normal or elevated temperatures.

In human cells, BH2 or tyrosine supplementation reduces aggregation of polyQ-expanded proteins associated with Huntington's disease, as well as mutant variants of TDP-43 and FUS that cause amyotrophic lateral sclerosis. Together, these findings identify BH2 as a cold-induced metabolite of which the synthesis, intertissue transport and conversion into bioactive BH4 preserve organism-wide proteostasis and extend lifespan.

Link: https://doi.org/10.1038/s41586-026-11152-9

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