LongeCityNews Last Updated: 16 March 2026 - 11:25 PM

On the matter of cellular senescence as a contributing cause of degenerative aging, there is a school of thought whose members argue that at least some senescent cells are doing something useful by existing, despite their problematic behavior. Therefore therapeutic approaches should focus on prevention of senescence (senostatics) or reducing the harmful senescence-associated secretory phenotype (SASP) (senomorphics) rather than on outright destruction of senescent cells (senolytics). Within the array of possible ways to reduce the pace at which cells become senescence, sabotaging the ability of senescent cells to encourage their neighbors to also become senescent has been little explored, so it is interesting to note recent work on this topic.

Today's open access paper represents is an early step on the path to finding ways to block bystander senescence. It is likely that the relevant interactions differ by cell type and tissue, making it a more challenging exercise than would otherwise be the case. Here, the focus is on the brain, and the researchers outline potential target interactions that might be blocked to reduce the spread of cellular senescence in an aged brain. As an approach to therapy, this does have the look of an intervention that could increase risk of cancer, however. The ability of the senescent state to spread from cell to cell is one of the ways in which early cancers are suppressed before they can become an issue. But at the end of the day, the only practical way to assess hypothetical benefits versus hypothetical risks is to build a therapy and test it in animal studies.

Characterizing the SASP-Dependent Paracrine Spreading of Senescence Between Human Brain Cell Types

One of the defining phenotypes of a senescent cell is the senescence-associated secretory phenotype (SASP), which can propagate senescence in neighboring cells both in vitro and in vivo. Importantly, this paracrine spreading of senescence can act in a cell non-autonomous manner, influencing neighboring cell populations and contributing to immune cell recruitment. As cellular senescence has recently been linked to both age-related neurodegenerative phenotypes and local inflammation and is more clearly defined across brain cell types in a cell-type-dependent manner, an urgent question remains regarding how a cell-type-specific paracrine spreading of senescence occurs in the brain.

Here, we sought to unravel the relationship between key brain cell types (astrocytes, endothelial cells, microglia, oligodendrocytes, and neurons) in the context of a paracrine spreading of senescence via the SASP. We utilized our previously established in vitro DNA damage-induced human brain cell line senescence model and conditioned media experiments to profile the cell-type-dependent SASP, characterize the directionality of a paracrine spreading of senescence between the relevant cell types, identify key SASP ligands and receptors that mediate the cell-type-specific spread, and target these factors using various inhibitors in an attempt to prevent the paracrine spreading of senescence.

We demonstrate that a cell-type-specific SASP profile of each brain cell type drives differential induction of secondary senescence, where some cell types can induce senescence in themselves as well as in other cell types, while other cell types are only capable of receiving secondary senescence induction, but cannot spread. Importantly, we identified both cell-type-specific and common SASP ligands and receptors, which we successfully targeted to prevent the induction of secondary senescence depending on the cell types communicating with one another. Taken together, this work gives key insights into the mechanisms of paracrine spreading of senescence between brain cell types in vitro and offers potential therapeutic targets to prevent this spreading, which may in turn help to alleviate age-related tissue decline and inflammaging.

Researchers publishing in Aging Cell have discovered that the nuclei of the cells that line injured arteries quickly become misshapen and that this leads to accelerated cellular senescence. Delivering zinc to these cells partially alleviates this dysmorphism.

Two seemingly unrelated concepts

This paper begins with a discussion of two different concepts that, on the surface, appear to be unrelated. First, the researchers discuss vascular damage, particularly in the context of surgeries; even minimally invasive procedures that involve cutting, scraping, or burning arteries must cause some level of damage. This includes such procedures as catheter implantation as a treatment for heart disease [1] and the resection of cancerous tumors [2].

The paper then pivots towards the shapes of the nuclei within cells. Misshapen nuclei are a biomarker of cellular senescence [3]. Dysfunction of the lamina, which maintains the nucleus’ shape, is linked to DNA damage [4]. Mutations of the Lamin A gene are well-known to be key in accelerated aging (progeria), and the accumulation of its immature and nonfunctional precursor, prelamin A, has been linked to vascular aging [5].

This work bridges those two concepts, demonstrating that vascular aging is directly linked to physical injury.

The muscle cells of injured arteries have misshapen nuclei

The researchers first examined the arteries of 18 human donors. Some of them had underwent percutaneous transluminal angioplasty (PTA), a procedure that damages the femoral arteries by necessity, before later having their femoral arteries removed for unrelated reasons. A control group had their femoral arteries removed without ever receiving PTA.

The nuclei of the vascular smooth muscle cells (VSMCs) in the control group’s arteries were cigar-shaped, but the nuclei of the VSMCs in the PTA group’s arteries were visibly dysmorphic, with inconsistent shapes and common irregularities. A similar experiment that involved using balloons to damage the carotid arteries of rats yielded similar results; the nuclei of the rats’ VSMCs in the area became significantly misshapen. This altered morphology was found to occur immediately after injury.

This altered morphology was directly linked to aging. In the human samples, injured arteries were found to be more likely to express the senescence biomarker SA-β-gal, while in rat samples, SA-β-gal was directly linked to a loss of nuclear solidity, demonstrating that these injuries lead to cellular senescence.

These researchers had previously found that the release of platelet-derived microvesicles (pMVs) after injuries leads to vascular dysfunction [6]. Here, the researchers demonstrated that administering pMVs directly to vascular tissues leads to the nuclear dysmorphism found in naturally injured arteries. This was found to be due to an accumulation of prelamin A; cells with more accumulation of prelamin A were found to be more dysmorphic.

Similarly, using CRISPR to modify cells into not being able to properly process prelamin A, by depriving them of the enzyme Zmpste24, led to the same dysmorphism. As expected, mice that were engineered not to produce this key enzyme experienced accelerated vascular aging.

Zinc is the key

The mineral zinc is a key part of the function of Zmpste24, and administering zinc alongside pMVs was found to nearly negate their negative effects. On the other hand, administering TPEN, which chelates zinc away from cells, was found to cause similar nuclear dysmorphism as pMVs. Experimenting with Zmpste24-deficient cells determined that this enzyme was indeed responsible for preventing the dysmorphism.

In injured VSMCs, there is a downregulation of ZIP4, a protein responsible for bringing zinc into these cells. These effects were also recapitulated with the direct administration of pMVs.

The researchers then performed another experiment on rats. In addition to a control group, some of the rats were fed a zinc-rich diet, while others were given ZIF-8, a nanoparticle that encloses zinc within platelet membranes. These rats were then subjected to vascular injury. The rats fed a high-zinc diet were found to express slightly less prelamin A, and the ZIF-8-treated rats were found to express even less, although the injury’s effects were not completely mitigated. A further examination of the treated rats did not find any side effects caused by ZIF-8.

The researchers report that their “findings reveal that the pMVs/ZIP4/zinc/prelamin A axis constitutes a novel signaling pathway regulating nuclear dysmorphism and vascular aging.” If these findings can be corroborated, it is reasonable to suggest that zinc supplementation, or the use of ZIF-8 nanoparticles, should be included as part of the surgical process in order to prevent accelerated aging of the associated vasculature.

Literature

[1] Calabro, P., Gragnano, F., Niccoli, G., Marcucci, R., Zimarino, M., Spaccarotella, C., … & Working Group of Interventional Cardiology and the Working Group of Thrombosis of the Italian Society of Cardiology. (2021). Antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. Circulation, 144(16), 1323-1343.

[2] Eom, B. W., Yoon, H. M., Kim, Y. W., Min, J. S., An, J. Y., Hur, H., … & Ryu, K. W. (2024). Quality of life and nutritional outcomes of stomach-preserving surgery for early gastric cancer: a secondary analysis of the SENORITA randomized clinical trial. JAMA surgery, 159(8), 900-908.

[3] Heckenbach, I., Mkrtchyan, G. V., Ezra, M. B., Bakula, D., Madsen, J. S., Nielsen, M. H., … & Scheibye-Knudsen, M. (2022). Nuclear morphology is a deep learning biomarker of cellular senescence. Nature Aging, 2(8), 742-755.

[4] Pérez-Hernández, M., van Opbergen, C. J., Bagwan, N., Vissing, C. R., Marrón-Liñares, G. M., Zhang, M., … & Lundby, A. (2022). Loss of nuclear envelope integrity and increased oxidant production cause DNA damage in adult hearts deficient in PKP2: a molecular substrate of ARVC. Circulation, 146(11), 851-867.

[5] Revêchon, G., Witasp, A., Viceconte, N., Helgadottir, H. T., Machtel, P., Stefani, F., … & Eriksson, M. (2025). Recurrent somatic mutation and progerin expression in early vascular aging of chronic kidney disease. Nature Aging, 5(6), 1046-1062.

[6] Bao, H., Li, Z. T., Xu, L. H., Su, T. Y., Han, Y., Bao, M., … & Qi, Y. X. (2021). Platelet-derived extracellular vesicles increase Col8a1 secretion and vascular stiffness in intimal injury. Frontiers in cell and developmental biology, 9, 641763.

Researchers here provide data on the correlations between (a) secreted proteins circulating in blood that are distinct to senescent cells of various types, and (b) a number of different age-related conditions. Some cell types are better than others when it comes to the strength of correlation between the burden of senescence as assessed by circulating proteins and status of given age-related condition. This process of mapping the landscape of senescence and aging sets the stage for the development of better assays that can inform patients as to the risk resulting from the burden of senescence, and later the degree of improvement produced by therapies capable of reducing the burden of senescent cells.

Senescence is characterized in part by proteomic expression changes, including the secretion of pro-inflammatory cytokines and other proteins, which become amplified during sustained senescence and in large part drive its deleterious effect in a chronic, age-related context. These senescence-associated proteins (SAPs) have since proven to be heterogeneous by cell type and senescence-inducing stimulus.

One promising technique in assessing individual senescence burden is through the quantification of SAPs in circulating plasma. The plasma senescence burden has previously demonstrated compelling clinical associations, including with age, frailty, and mortality. In recent years, a group of senescence-targeting compounds collectively known as senotherapeutics has been investigated for their limited and context dependent senescence-attenuating effects. Senotherapeutic drugs have demonstrated an ability to lower circulating SAPs in human trials, and to partially alleviate some aging phenotypes.

A remarkable recent finding is that beyond general clinical traits such as age and mortality, organ-specific proteins can be tracked in circulation and used to model organ age and organ-specific clinical traits. Considering the previously demonstrated clinical relevance of circulating canonical senescence signatures, examining cell type-specific senescence signatures in circulation could similarly shed light on the unique clinical relevance of organ-specific senescence.

In this study, senescence signatures from the Senescence Catalog (SenCat), including 14 human cell types such as peripheral blood mononuclear cells, renal epithelial cells, vascular smooth muscle cells, among others, are examined for their clinical relevance in circulation in two longitudinal studies: 1,275 participants of the Baltimore Longitudinal Study of Aging (BLSA) and 997 participants of the Invecchiare in Chianti (InCHIANTI) study. Notably, pooled senescence proteins outperformed non-senescence proteins in predicting many clinical parameters such as age and hypertension, and in many instances cell type senescence signatures mapped most strongly to their corresponding health domain. Importantly, the immune cell senescence signature is associated with future onset of several diseases such as diabetes.

Link: https://doi.org/10.64898/2026.02.06.26345739

Senescent cells accumulate in tissues with age to promote degenerative aging. Senescent cells cause harm via the signals that they send to other cells, the senescence-associated secretory phenotype (SASP). The SASP is by no means fully understood, and while it clearly contains many pro-inflammatory and pro-growth signals, it probably has many other effects as well. Here, researchers provide evidence for one specific SASP signal molecule to interfere in the benefits of exercise. Clearance of senescent cells should therefore produce an enhanced response to exercise in old individuals, in addition to the other benefits already demonstrated in a sizeable number of animal studies.

Adaptation to physiological stress is fundamental to health but varies widely among individuals. In humans, this heterogeneity is evident in markedly different gains in fitness in response to identical exercise training. The molecular determinants of this variable "trainability" remain poorly understood. Here we identify insulin-like growth factor binding protein-7 (IGFBP7), a senescence-associated secreted protein, as a circulating constraint on exercise adaptation.

Plasma proteomics in older adults enrolled in a randomized exercise trial revealed that IGFBP7 levels inversely predicted fitness gains after one year of high-intensity interval training despite similar baseline fitness. In mice, genetic deletion of IGFBP7 markedly amplified training-induced gains in exercise capacity across distinct training protocols, whereas somatic overexpression abolished this advantage. In the UK Biobank, lower IGFBP7 levels were associated with reduced mortality and multiple incident age-related diseases, mirroring the breadth of ties between fitness and healthspan.

Together, these findings identify circulating IGFBP7 as a molecular brake on physiological plasticity in response to exercise, linking training responsiveness, aging biology, and health outcomes.

Link: https://doi.org/10.64898/2026.02.09.26345899