Cerebrospinal fluid drainage is a way to remove metabolic waste from the brain. Declining flow means that this waste will build up. This includes the protein aggregates associated with neurodegenerative conditions, and probably a great many other forms of metabolic waste that individually have more subtle effects, but collectively act to provoke cell dysfunction when present at high levels. One of the more important consequences is thought to be a maladaptive inflammatory reaction in glial cells in the brain, which in turn drives the onset and progression of neurodegenerative conditions.

In today's open access paper, researchers assess measures indicative of loss of cerebrospinal fluid drainage in patients with isolated rapid eye movement (REM) sleep behaviour disorder (iRBD), which is a failure of the normal suppression of muscle activity during REM sleep. iRBD is now recognized as a very early symptom of synucleinopathies such as Parkinson's disease. Synucleinopathies are characterized by the aggregation and spread of misfolded α-synuclein through the central nervous system, and associated neuroinflammation. A failure of cerebrospinal fluid drainage can only make this worse, closing off one way to remove aggregated proteins, and increasing inflammation as a consequence.

CSF turnover dysfunction: a hidden early biomarker in iRBD?

Evidence in Alzheimer's disease and other dementias shows that changes in cerebrospinal fluid (CSF) turnover and perivascular spaces (PVS) volume are associated with disease progression through impairment of waste-clearance glymphatic pathways. Volume of CSF, PVS, and drainage structures such as venous sinus are mostly excluded in current MRI studies of premanifest synucleinopathy.

Here, we used MRI to investigate whether modifications in CSF, PVS, and venous sinus volumes occur in 18 prodromal synucleinopathy patients (namely isolated rapid-eye-movement sleep behavior disorder, iRBD) compared to 20 healthy young and 18 elderly controls. Our results demonstrated increased CSF and PVS volumes in iRBD without a matching increase in drainage venous structures, as observed in elderly controls. This suggests increased CSF and PVS fluid stasis, possibly due to impaired CSF filtration, a mechanism that could reduce glymphatic function and exacerbate the neurodegenerative process in iRBD.

Clearing out senescent cells to help stem cells work

Mesenchymal stem cell (MSC) therapies have largely underperformed in the clinic. MSCs are connective-tissue stem cells that help mostly not by becoming new tissue but by secreting repair-promoting factors. Despite strong preclinical promise, clinical MSC trials in fibrosis, inflammation, and organ failure have shown only modest benefits [2].

One of the reasons may be an unwelcoming environment full of senescent cells, which secrete a mix of inflammatory and tissue-degrading molecules called the senescence-associated secretory phenotype (SASP). Prior work suggests that SASP factors actively suppress stem cell proliferation, differentiation, and survival [3]. In a new study published in the Journal of Translational Medicine and associated with the biotech startup Immorta Bio, the authors suggest a solution: combining MSCs generated from pluripotent stem cells with the company’s proprietary senolytic agent SenoVax.

As evident from its name, SenoVax is a “senolytic vaccine” that primes the immune system against the body’s own senescent cells. Notably, Immorta describes SenoVax in two different ways. In its patent, IND, and press materials, SenoVax is presented as an autologous, personalized cellular immunotherapy: the patient’s own cells are taken via biopsy and driven into accelerated senescence, then used as an antigen source to pulse the patient’s dendritic cells generated ex vivo. The dendritic cells are then reinfused and prime T cells. This is a personalized, work-intensive, and expensive procedure. In the study, however, SenoVax is described as a simpler peptide-based vaccine: peptides derived from senescence-associated proteins and injected subcutaneously along with an immune-triggering adjuvant in the hope that resident dendritic cells will “learn the lesson” in vivo.

The combination wins every time

The researchers tested the combination in two mouse models of senescence-driven damage, asking whether the combination beats either therapy alone on inflammation, regeneration, organ function, physical performance, and survival. One model involved injecting carbon tetrachloride (CCl₄), a liver toxin, to emulate chronic liver injury and senescence-associated inflammation. The other one was based on injecting low-dose doxorubicin, a chemotherapy drug that drives cells into senescence. In each model, induced mice were split into four arms: untreated control, SenoVax alone, MSCs alone, or the combination.

The team then measured four inflammatory/SASP markers – IL-11, IL-23, IL-6, and YKL-40 – in the liver injury model. All four fell below the injured baseline in every treated arm, and the combination lowered each one the most, suggesting that both agents dampen SASP signaling and that combining them produces the largest effect. Importantly, these factors are less senescence-specific than p16, p21, or SA-β-gal, so the senolytic mechanism is rather inferred than shown. Conversely, the regeneration markers Klotho, FGF-2, VEGF, and GDF-11 rose above the injured baseline, while the liver-damage enzymes AST and ALT fell; both of these shifts pointed toward improvement. In each case, the combination moved furthest, supporting the idea that clearing SASP takes the brakes off regeneration.

To show the pattern isn’t specific to chemical liver injury, the researchers then repeated the SASP and the regenerative markers panels in the doxorubicin-induced “accelerated aging” model. The results were similar: most positive with the combination.

To test physical function in the “accelerated aging” model, the team used the “T-climbing” test, which times how long a mouse takes to climb down a vertical pole – a standard motor-coordination and strength assay. The combination improved climbing performance by roughly 65%. However, this claim, made in the Discussion session, is not supported by the correspondent figure, which only contains bars for single interventions, not for the combination. Numbers for monotherapies do not appear in the paper.

Large lifespan effects – but short lifespans

In the capstone experiment, which tested survival, mice received doxorubicin until death or a humane endpoint. The combination again gave the best results: about 50% of the animals were alive at Day 35 and 20% at Day 40, versus complete mortality by Day 30 in untreated doxorubicin controls. Monotherapies extended median survival only modestly, to about Day 35.

While the accompanying press release touts a 73% increase in mean survival and ~84% extension of median lifespan compared with untreated controls in validated murine aging models, the extremely short lifespan puts it more into the “acute toxin-related damage” territory, as opposed to accelerated aging, much less natural aging.

Despite the several drawbacks and quirks, the study lends certain support to the intriguing concept behind Immorta Bio: using senolytics to create an auspicious niche for MSCs to work their magic. Hopefully, the company will keep developing this concept further.

Literature

[1] Ichim, T. E., Markov, N., Lopes, G., Pascual, K. A., Evans, A., Reznik, R., … & Reznik, B. N. (2026). Synergistic senolytic–regenerative therapy significantly extends healthspan and lifespan Journal of Translational Medicine, 24(1), 745.

[2] Levy, O., Kuai, R., Siren, E. M., Bhere, D., Milton, Y., Nissar, N., … & Karp, J. M. (2020). Shattering barriers toward clinically meaningful MSC therapies. Science advances, 6(30), eaba6884.

[3] Moiseeva, V., Cisneros, A., Sica, V., Deryagin, O., Lai, Y., Jung, S., … & Muñoz-Cánoves, P. (2023). Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration. Nature, 613(7942), 169-178.

Immune aging may contribute to Alzheimer's disease. Bacillus Calmette-Guérin (BCG), a vaccine known to induce trained immunity, has been linked to reduced Alzheimer's risk in prior studies. However, whether trained immunity can be observed in the human central nervous system remains unclear. We conducted two related one-year, open-label clinical trials in adults aged 55 years or older (n = 12 without Alzheimer's-related pathology; n = 11 with Alzheimer's-related pathology) recruited at a single center. Participants received two intradermal BCG vaccinations one month apart.

We show that BCG induces persistent, trained immunity-like changes in immune cells in cerebrospinal fluid, including enhanced innate responsiveness and associated transcriptional programs. These responses differ from blood, suggesting compartment-specific immune imprinting. In participants without Alzheimer's-related changes, these immune shifts are accompanied by decreased amyloid-β levels in cerebrospinal fluid and increased levels in blood. BCG was well tolerated, with no unexpected safety signals observed. This approach may represent an early neurodegenerative intervention strategy, although larger controlled studies are needed to confirm these observations.

Link: https://doi.org/10.1038/s43856-026-01691-7

Currently, the primary causes of death following myocardial infarction include sudden cardiac death, malignant arrhythmias, and acute heart failure, all resulting from myocardial necrosis caused by coronary artery occlusion. Cellular senescence refers to the permanent arrest of cell proliferation in response to stress stimuli; it serves as a crucial tumor defense mechanism and is closely associated with tissue aging and chronic inflammation. The senescence-associated secretory phenotype (SASP) is one of the most characteristic features of senescent cells. Cardiac cells develop a SASP and secrete SASP factors in response to stimuli such as oxidative stress, DNA damage, and hypoxia, playing a key role in immune regulation and tissue repair following myocardial infarction.

The SASP exhibits marked spatiotemporal heterogeneity following myocardial infarction: during the acute phase, it contributes to inflammatory amplification and immune cell recruitment; during the subacute phase, it is involved in inflammation resolution, matrix remodeling, and scar formation; and during the chronic phase, it promotes chronic inflammation, paracrine senescence, pathological fibrosis, and cardiac dysfunction. Spatially, the SASP influences scar stabilization in the infarct zone, inflammation-electrophysiological coupling in the border zone, and compensatory remodeling in the distal region. The sustained expression of the SASP is a major driver of adverse ventricular remodeling and excessive fibrosis following myocardial infarction.

Therefore, targeting senescent cells and persistent, pathological SASP represents a highly promising therapeutic strategy in the field of cardiovascular regenerative medicine. This review will discuss senescence in different cell types following myocardial infarction, the spatiotemporal heterogeneity of the immune response mediated by the SASP after myocardial infarction, and the immune cells regulated by the SASP.

Link: https://doi.org/10.3389/fimmu.2026.1850084

A question of entropy

The cascading failure of bodily systems, leading to the loss of organ function, sits downstream of fundamental damage to genomics and epigenomics. However, how much of this damage is due to random, outside sources, such as unavoidable radiation, has been repeatedly questioned. Depending on the clock used, the stochastic portion of epigenomic damage ranges anywhere from two-thirds to nine-tenths [1], with the rest being attributed to deterministic processes.

The most well-known and well-established source of this sort of damage is radiation, which is impossible to completely avoid under ordinary conditions. Even if a sample or organism is kept safe from such well-known damage sources as ultraviolet radiation, fundamental particles known as muons, which originate from cosmic ray collisions with the atmosphere, will inevitably strike.

Where the muons aren’t

To prevent these particles from disrupting sensitive experiments, physics researchers have made use of deep underground laboratories (DULs), which take advantage of the fact that far fewer muons get through a substantial barrier of solid rock. This perspective paper holds that the same technique can and should be used for fundamental aging research in order to determine what happens when tissues are grown in an environment insulated from muon radiation.

Some work has already been done in this area, and the results were surprising. A population of Drosophila fruit flies grown in a DUL was found to have its natural repair mechanisms severely impaired without regular use [2].

This paper proposes an experiment with a different aim: to determine how much age-related epigenetic damage is caused by muon radiation. Specifically, the authors wish to use the Laboratorio Subterráneo de Canfranc (LSC) in Spain, which is the second-largest in Europe and one of only 14 DULs that exist around the world.

In such an experiment, the LSC would be used with one set of cells, while an above-ground lab would be used with the same type of cells grown in otherwise identical conditions to serve as a control group. Of course, as the authors note, this cannot possibly eliminate all random sources of damage; internal enzymes and oxidative stress would still exist, along with other chemistry-related issues and internal radiation, such as from imperfectly stable atoms of carbon and potassium. However, the purpose is simply to remove one source in order to determine its effects on the clock. While they do not expect its contribution to be large, they note that “this framework enables us to quantitatively test the muon-depletion hypothesis instead of presuming its mechanism.”

Many variables to measure

The authors also note that epigenetic clocks measure more than just genomic damage and that muon exposure may be having effects on both the epigenome and the genome, which must both be measured to gauge the effects of muon depletion. They intend to measure a great many factors of epigenetic aging, including repair signaling, senescence, inflammation, and cellular division. Similarly, they intend to measure radiation in all its forms, including radiation derived from objects around the samples, in order to have a background value to compare the effects of muon flux against.

Two competing hypotheses are entertained in this paper. The first is that epigenetic clocks will have more stability outside the effects of muon radiation and that variance will be decreased. However, the second is that, as the fruit fly experiments suggested, a certain level of background radiation is required for maintenance. Additionally, under this hypothesis, deviant, metastable cell lineages that would normally be obliterated by background muon radiation would proliferate. The results of an epigenetic clock under these conditions would be “increasingly governed by residual internal biases and long-lived states rather than by a simple narrowing of diffusion around an unchanged programmed drift”.

This is a perspective paper that recommends a direction of research, so these experiments have yet to be carried out. If they are, they could teach the research community valuable information about the relationship between background muon radiation and epigenetic aging. It would also be particularly valuable for astronauts, who are constantly beset by cosmic radiation, and anyone seriously considering long-term occupation of the Moon or Mars.

Literature

[1] Tong, H., Dwaraka, V. B., Chen, Q., Luo, Q., Lasky-Su, J. A., Smith, R., & Teschendorff, A. E. (2024). Quantifying the stochastic component of epigenetic aging. Nature Aging, 4(6), 886-901.

[2] Morciano, P., Iorio, R., Iovino, D., Cipressa, F., Esposito, G., Porrazzo, A., … & Cenci, G. (2018). Effects of reduced natural background radiation on Drosophila melanogaster growth and development as revealed by the FLYINGLOW program. Journal of cellular physiology, 233(1), 23-29.

Sadly, exactly because dasatinib and quercetin are cheap compounds, there is very little incentive for anyone to fund the sizable expense of running large clinical trials to first establish optimal dosing, and secondly confirm that this treatment is as good for aged humans as it is for aged mice. Those trials that have taken place were funded by academic institutions, were small, exploratory, and the results were promising. Only larger trials can move from promising to "yes, this works," however. Meanwhile, any older person willing to put in the effort can run their own study of one, and see how a range of biomarkers look before and after treatment. The human trials suggest that side-effects for a short course of treatment are minimal compared to potential benefits.

Multi-omics profiling reveals systemic rejuvenation of the aged kidney through senolytic therapy

Cellular senescence is a key driver of kidney aging, leading to functional decline and increased susceptibility to chronic kidney disease. While the senolytic combination of dasatinib and quercetin (D + Q) has shown promise in mitigating age-related pathologies, its long-term effects and underlying multi-level systemic mechanisms in the aging kidney remain poorly defined. Here, we systematically evaluated the long-term effects of D + Q in naturally aged mice using multi-omics approaches. Beginning at 12 months of age, mice assigned to the treatment arm received biweekly oral gavage of the D + Q cocktail for a total duration of 8 months.

We show that D + Q treatment reduces senescence markers (p16, p21, SA-β-gal), restores the anti-aging protein Klotho, and attenuates renal fibrosis and inflammation. Proteomic profiling reveals that D + Q enhances apoptotic clearance of senescent cells and promotes proliferative and regenerative pathways. Moreover, D + Q reactivates PPARα signaling, improves fatty acid oxidation, and reduces lipid accumulation in aged kidneys. Single-cell transcriptomics further demonstrates that D + Q reverses transcriptional aging signatures across multiple renal cell types and remodels cell-type-specific pathways associated with metabolism, inflammation, and fibrosis. Cell-cell communication analysis reveals that D + Q normalizes the hyperconnected intercellular network in aged kidneys, particularly by modulating inflammation-related signaling.

Our findings offer a comprehensive, systems-level understanding of how senolytic therapy restores renal homeostasis, emphasizing its potential as a multifaceted intervention to combat kidney aging.