LongeCityNews Last Updated: 01 April 2026 - 10:28 AM

Astrocytes make up a sizable population of supporting and structural cells in the brain, with a broad portfolio of activities that are collectively necessary for the normal operation of brain metabolism and neural activity. Like all cell populations, astrocytes are negatively impacted by the accumulating damage and dysfunction of aging, both internal to cells and in the tissue microenvironment. An area of focus for the research community is how aging provokes an ever increasing number of astrocytes into (1) a reactive, inflammatory state that harms brain tissue, but also (2) into a senescent state, which is also a source of inflammatory signaling that becomes detrimental to tissue structure and function when sustained over the long term. Reactivity and senescence may overlap in their contribution to neurodegeneration, and in root causes, but they are distinct issues.

Today's open access paper reviews what is known of reactivity and senescence in astrocytes, connecting these states to the bigger picture of how loss of cognitive function and onset of neurodegenerative disease emerges from aging. The present understanding of astrocyte biochemistry is, as for all cell types, incomplete. The goal of medicine is ever more precise control over cell state and cell activities, and this drives the scientific endeavor towards assembling an ever more complete understanding of cellular biochemistry. That is a very long term trajectory, however, with an end goal far out of sight of the present day to day work. In the short term, research is a matter of trying to find single genes, single proteins, single interactions in the cell that act as points of control for aspects of behavior, and thus might lead to novel therapies. Medicine remains at a very crude level of cellular control, as illustrated by our struggles with age-related disease.

Astrocyte States in Brain Aging and Neurodegeneration: At the Crossroads of Senescence and Reactivity

Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles in metabolic support, synapse regulation, proteostasis, neuroinflammation, and blood-brain barrier maintenance. Aging is accompanied by broad transcriptional and functional remodeling in astrocytes, leading to the emergence of distinct cellular states that cannot be defined by classical morphological criteria alone.

This review discusses how aging modifies astrocyte identities toward reactive and senescence-like states. We summarize core features of astrocyte senescence, including altered secretory signaling, impaired neuronal support, and changes in mitochondrial and proteostatic pathways, while integrating recent single-cell and regionally transcriptomic studies that delineate multiple reactive states associated with aging and pathological contexts. We further address evidence that reactivity and senescence are not mutually exclusive endpoints, but may coexist, arise sequentially, or partially overlap depending on timing, brain region, biological sex, and pathological insults. Finally, we define key open questions and experimental priorities required to establish the temporal and causal relationships among astrocyte states.

We argue that resolving these issues is essential for advancing therapeutic strategies that specifically target defined astrocyte phenotypes, rather than nonspecifically suppressing astrocyte activity, in aging and neurodegenerative diseases. In this view, both astrocyte reactivity and senescence represent components of a broader spectrum of astrocyte states, encompassing different degrees of inflammatory signaling, metabolic adjustments, proteostatic imbalance and alteration of homeostatic functions across aging trajectories and disease contexts. Notably, although astrocyte states are becoming increasingly well defined, additional layers of complexity are only beginning to be appreciated.

Importantly, reactive and senescent astrocytes should not be regarded as mutually exclusive identities. Instead, they may coexist within the same tissue, arise sequentially, or partially overlap depending on local conditions and disease stage. This perspective helps reconcile the heterogeneity observed across experimental models and human studies, suggesting that susceptibility to neurodegenerative disease depends not only on the presence of astrocyte dysfunction, but also on how specific astrocyte states interact with neuronal circuits, other glial cells, immune responses, and systemic factors. Moving forward, approaches that combine spatially resolved transcriptomics, longitudinal analyses and functional analyses of defined astrocyte populations will be essential to clarify the temporal and regional dynamics of these states.

Arming NK and T cells with metabolite-sensing receptors enhances their ability to infiltrate tumors and improves cancer outcomes in mice in a new study [1].

How to get immune cells into the tumor?

One of the central challenges in cancer immunotherapy is getting the right immune cells to the right place. Natural killer (NK) cells and cytotoxic T cells can recognize and destroy cancer cells, but even when artificially enhanced, such as by being armed with chimeric antigen receptors (CARs), these cells often fail to rein in solid tumors [2].

One reason is that the immune cells have trouble getting in, since solid tumors are surrounded by a hostile microenvironment that creates physical and biochemical barriers to immune cell entry. Tumors also actively suppress the signaling pathways used by immune cells to home on their targets [3]. In a new study from Stanford University, published in Nature Immunology, the researchers attempted to address this “targeting problem.”

Targeting metabolites

First, they ran an unbiased gain-of-function search for which receptors, if artificially switched on in killer cells, would cause those cells to migrate into tumors. The search targeted 256 candidate genes derived from two separate datasets. NK cells expressing any of eight receptors – GPR183, GPR84, GPR34, GPR18, LPAR2, FPR3, C5AR1, and CXCR2 – were consistently found at higher rates inside tumors than in reference tissues across all breast cancer models. Six of these also appeared in the ovarian cancer screen. A larger follow-up screen of over 5,500 genes in the ovarian cancer model again returned GPR183 and GPR84 as top hits.

Notably, only one chemokine receptor (CXCR2) appeared as a hit. Chemokines are signaling proteins that are often suppressed by cancer cells in an attempt to fool the immune system, which might be a reason why only one of them made it to the top-hit list. GPRs, on the other hand, are a large group of metabolite-sensing receptors. Tumor metabolism is usually very different than that of healthy tissues. The top-hit receptors reacted to those “metabolic idiosyncrasies,” causing the NK cells to home on their sources.

To specifically test directed migration toward a chemical gradient (chemotaxis) and infiltration, the authors ran two ingenious in vitro screens using cancer breast cancer cells and three-dimensional spheroids – miniature tumor-like structures. All GPRs were among the top 10 hits, confirming that NK cells expressing these receptors actively migrate toward factors secreted by cancer cells and effectively infiltrate spheroids. GPR183 was consistently at the top.

GPR signaling was also found to alter gene expression. GPR183 activation caused dramatic transcriptional remodeling, but only in the presence of its ligand. This ligand dependence means that GPR183 functions as a conditional switch, only altering cell behavior when the ligand is present – such as in a tumor environment.

Improved survival in breast cancer

Next, the authors tested whether the improved infiltration actually translates to better therapeutic outcomes. Mice bearing subcutaneous triple-negative breast cancer xenografts received weekly intravenous injections of either control NK cells or GPR183-overexpressing NK-92 cells. The latter significantly delayed tumor growth compared to both untreated mice and control NK cells.

To test the combination of tumor targeting (via CAR) and migration enhancement (via GPR183), the authors built a CAR targeting a surface antigen broadly expressed on breast cancer cells. GPR183-overexpressing CAR NK cells produced much better control of tumor growth than control CAR NK cells and significantly improved survival. The team achieved similar results with T cells from different human donors.All prior in vivo experiments used immunocompromised NSG mice, which lack functional mouse immune cells. This means that any interference – beneficial or harmful – from the host’s own immune system was absent.

To address this, the authors moved to a fully immunocompetent mouse model of breast cancer. The mouse homolog Gpr183 was introduced into mouse T cells, and these cells significantly delayed tumor growth and prolonged survival compared to control T cells. 7 out of 10 mice achieved complete responses (tumor elimination), compared to only 3 out of 10 in the control group.

“We found that when we equip immune cells with receptors that sense metabolites released by cancer cells, they can sense the tumor, migrate toward it, infiltrate it and control tumor growth, which markedly enhances the survival of mice with human breast and ovarian cancers,” said Livnat Jerby, Ph.D., assistant professor of genetics and the senior author of the paper.

“Surprisingly, we didn’t see many chemokine receptors among the winners,” she added. “What came up were receptors that recognize bioactive, chemoattracting metabolites that have not been studied nearly as much in the context of cell engineering and tumor immunology. To the best of our knowledge, no one has tried to use cancer metabolism, a hallmark of drug resistance and aggressive tumor growth, to attract cancer-killing immune cells to the tumor, but our study uncovered the potential of this approach, and the results are quite promising.”

Literature

[1] Kim, Y. M., Tsai, M. K., Sun, C., Laveroni, O., Akana, R. V., Frombach, K., & Jerby, L. (2026). Engineering NK and T cells with metabolite-sensing receptors to target solid tumors. Nature Immunology, 1-14.

[2] Marofi, F., Motavalli, R., Safonov, V. A., Thangavelu, L., Yumashev, A. V., Alexander, M., … & Khiavi, F. M. (2021). CAR T cells in solid tumors: challenges and opportunities Stem cell research & therapy, 12(1), 81.

[3] Joyce, J. A., & Fearon, D. T. (2015). T cell exclusion, immune privilege, and the tumor microenvironment. Science, 348(6230), 74-80.

The reduced intake of protein is what triggers many of the beneficial changes in cell behavior that result from calorie restriction. One of the many outcomes of calorie restriction is that some white fat tissue transitions to become beige fat via an increase the number of brown fat cells present in the tissue. Brown fat cells are involved in thermogenesis and, on balance, a greater proportion of brown fat in the body leads to incrementally better metabolic health and modestly slowed aging. Interestingly, activity in specific microbial species of the gut microbiome is necessary for the browning of white fat to take place in response to reduced protein intake, suggesting possible paths to the production of novel therapies that induce fat browning.

Interactions between diet and the gut microbiota are fundamental to metabolic health, shaping energy balance and disease susceptibility. However, the underlying mechanisms by which dietary and microbial factors converge to regulate host physiology remain unclear. Here we show that protein availability profoundly modulates the functional landscape of the gut microbiota and promotes remodelling of white adipose tissue (WAT). Specifically, low-protein diets (LPDs) robustly induce signature genes of browning in WAT to a similar extent to that seen in response to classical stimuli, such as cold exposure or β-adrenergic receptor activation.

LPD-mediated browning was markedly diminished in germ-free mice, and this defect was rescued by colonization with defined bacterial consortia made up of strains that were isolated and down-selected from the faeces of either LPD-fed mice or healthy human volunteers with 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)-confirmed brown- or beige-fat activity. Microbiota-induced browning was mediated both by bile acids driving the activation of the farnesoid X receptor (FXR) in adipose progenitor cells, and by nrfA-encoding commensal-derived ammonia driving the expression of fibroblast growth factor 21 (FGF21) in hepatocytes. The bile acid-FXR and ammonia-FGF21 axes both have non-redundant, essential roles in promoting WAT browning.

These findings highlight a mechanistic link between diet, gut microbial metabolism and adipose tissue remodelling, uncovering microbiota-dependent pathways by which the host responds to dietary cues.

Link: https://doi.org/10.1038/s41586-026-10205-3

Any sufficiently complex set of data that changes with age can be used to produce an aging clock, given a database of measures from people of various ages. Machine learning is applied to discover algorithmic combinations of that data that predict age. This is thought to produce outcomes that reflect biological age; a person with a predicted age higher than chronological age has a greater burden of damage and dysfunction. No clock is fully understood, in the sense that it is unknown at the time of creation as to how exactly the clock will react to a higher or lower burden of any one specific form of cell and tissue damage or consequent dysfunction in aging. This makes clocks hard to use in the way that we would like to use them, to speed up the process of evaluating potential rejuvenation therapies by providing a rapid, low cost measure of the efficacy of a given treatment.

Biological age reflects the current state of the body, considering the aspects of lifestyle, environment, and hereditary component. Currently there is no universal formula for determining it, but there are markers that can be used to calculate it. This study aims to develop and compare two models for calculating biological age based on laboratory blood tests and composition of gut microbiota.

The biochemical model of biological age uses 7 indicators and is gender-specific (general - cystatin-C, IGF-1, DHEAS, only for females - homocysteine, urea, glucose, zonulin, only for males - HbA1c, NT-proBNP, free testosterone, hs-CRP). The microbial model requires the input of percentages of 45 bacterial species as indicators of the gut microbiota. Both methods demonstrate high predictive accuracy (mean absolute error ~ 6 years, R-squared > 0.8) and the degree of agreement of assessments both with each other and with PhenoAge (correlation > 0.89).

Among the selected 45 gut bacterial species, 16 were positively associated with age. Of these, 3 species (Muribaculum intestinale, Ruminococcus albus, Ruminococcus champanellensis) can be considered "beneficial," as they are involved in acetate production, carbohydrate fermentation, and support overall microbiota and metabolic health. However, 5 other species (Catabacter hongkongensis, Clostridium saudiense, Desulfovibrio desulfuricans, Holdemanella biformis, Howardella ureilytica) are potentially pathogenic and may cause infections or contribute to inflammatory bowel disease (IBS) involving an immune component. The remaining 8 positively associated species can be classified as neutral, as they produce acetate, butyrate, and propionate, and modulate metabolic pathways.

The majority of microorganisms (29 species) exhibited a negative correlation with age, meaning their abundance decreases in older age. Among these, 7 species (Anaerobutyricum hallii, Butyricicoccus pullicaecorum, Clostridium leptum, Coprococcus comes, Eubacterium rectale, Fusicatenibacter saccharivorans, Lachnospiraceae bacterium Choco86) can be considered beneficial. They are responsible for synthesizing or fermenting various substances, support barrier function, exert anti-inflammatory effects, and reduce the risk of metabolic disorders. Conversely, only 5 species (Blautia obeum, Blautia producta, Dialister invisus, Enterocloster bolteae, Sutterella wadsworthensis) are potentially pathogenic, potentially contributing to obesity, IBS, and negatively impacting mental health. Most of the remaining age-negatively correlated species can be classified as neutral; they produce and ferment substances but under certain conditions may cause gastrointestinal disorders and metabolic disturbances.

The bacterial species used in the model collectively reflect an age-related decline in protective and metabolic functions, an increase in pro-inflammatory potential, and a disruption and impoverishment of metabolic networks.

Link: https://doi.org/10.18632/aging.206360