LongeCityNews Last Updated: 08 January 2026 - 04:22 PM

Cystathionine γ-lyase (CSE) levels are reduced with age, and researchers here show that removing CSE entirely in mice reproduces aspects of brain aging. That isn't enough to prove that the smaller reductions that take place with age do in fact make a meaningful contribution to neurodegeneration, but it is sufficient to justify greater attention and further research into to the mechanisms involved. The researchers chose to focus on CSE because it is involved in the production of hydrogen sulfide (H2S) in the brain. You may recall that the ability of increased H2S to be somewhat protective in the context of aging, such as via effects on inflammation and autophagy, has grown as a topic of interest in recent years. It is hard to effectively deliver H2S to the brain, however, as both normal and beneficial levels are very low; it is arguably better to try to adjust the operation of the biochemistry responsible for producing H2S instead.

Once considered to function predominantly in the peripheral systems, cystathionine γ-lyase (CSE) is emerging as a key player in neuroprotection. Prior studies had considered cystathionine β-synthase (CBS) to be the principal enzyme governing H2S signaling in the brain. In this study, through an integrated approach combining genetic, proteomic, biochemical, and behavioral studies, we demonstrate that CSE is crucial for maintaining brain homeostasis and that loss of CSE is sufficient to trigger cognitive deficits.

CSE, the enzyme responsible for neuronal cysteine and hydrogen sulfide production, is dysregulated in aging and neurodegenerative diseases including Alzheimer's disease and Huntington's disease, both marked by cognitive decline in addition to motor deficits. To determine whether CSE loss directly causes cognitive decline, we genetically ablated CSE in mice. This loss was sufficient to induce oxidative damage, compromise blood-brain barrier integrity, impair neurogenesis and neurotrophin signaling, and elicit cognitive deficits. Global proteomic analysis further revealed molecular alterations that contribute to impaired neurogenesis.

Our findings establish CSE as an essential guardian of homeostatic brain health and identify it as a potential therapeutic target for neurodegenerative disorders.

Link: https://doi.org/10.1073/pnas.2528478122

Treatment immediately following stroke is not the most obvious path to take for the clinical development of therapies intended to improve drainage of cerebrospinal fluid via the glymphatic system, but nonetheless that is the approach taken by the research program noted here. A range of compelling evidence points to age-related impairment of the drainage of cerebrospinal fluid from the brain as an important issue, but is largely focused on the slow development of neurodegenerative conditions as a result of the buildup of metabolic waste in the brain. The immediate aftermath of a stroke is a very different scenario, amenable to different approaches to improvement of drainage channels, such as the non-invasive devices proposed here that would probably be infeasible for long-term use.

The "brain-draining lymphatics" are a set of drainage pathways that clear waste from the brain, with dysfunction of this "clean-up and drainage network" linked to Alzheimer's disease and other neurological and neurodegenerative diseases (NNDs). Researchers found that improving brain-draining lymphatic function can boost recovery following ischemic stroke and are now developing non-invasive devices that help the neck's lymphatic vessels pump more effectively, improving the clearance of excess fluid and harmful waste from the brain right after stroke has occurred - at a time when every second counts.

The researchers are also using advanced imaging techniques to study the brains of 140 participants. Initial studies have found that women have less lymphatic vessel coverage in the brain's outer layer compared to men, potentially leading to less efficient waste drainage and explaining why women are at higher risk or have worse outcomes for many NNDs, including stroke and Alzheimer's disease. "The brain was considered to be devoid of a lymphatic system. It wasn't until 2015 that two separate teams discovered that lymphatics in the brain's outer layer transport fluid and waste products from the brain to lymphatic vessels in the neck. We now know that this system plays a crucial role in keeping the brain healthy. By boosting this natural clean-up system, we hope to change how ischemic stroke and other NNDs are treated."

Link: https://www.monash.edu/news/articles/scientists-unlock-brains-natural-clean-up-system-to-develop-new-treatments-for-stroke-and-other-neurological-diseases

The overt manifestations of the aging of hair follicles, going gray and losing hair, often appear to bother people to a greater degree than the impending failure of their internal organs. In principle a sufficient understanding of the mechanisms of aging should lead to ways to avoid both outcomes. Rejuvenation therapies that repair the cell and tissue damage of aging should do as much for hair as for any other part of the body. Under the hood, however, there is still the matter of the ferocious complexity of cellular biochemistry and its changes with age. A hair follicle is not like a muscle fiber or a glomular unit of the kidney or a portion of a neural network in the brain. These are all made of cells, but completely different in the details of their responses to the damage that is characteristic of aging.

As illustrated by the fact that effective therapies to address hair aging do not yet exist, the research community does not fully understand the ways in which the processes of hair growth and coloration run awry with age. Hair growth is quite complex. It is not a continuous process, but one that proceeds in phases of communication between cells of various types that make up a hair follicle. Different cells do different things at different times and in different locations in the follicle - and this can all be impaired in any number of ways. In response to this sort of challenge, the research community settles into a mode of gathering ever more detailed data, in search of patterns that might lead towards greater understanding and points of intervention.

Single-cell RNA sequencing profiles age-related transcriptional landscapes in human hair follicle cells

Hair loss and graying, the earliest visible signs of skin aging, are driven by the functional decline of hair follicle stem cells and their niches. To elucidate the transcriptional mechanisms involved in scalp aging, we conducted a comprehensive analysis of human scalp samples using single-cell RNA sequencing and spatial transcriptomic technologies. Our study profiled the transcriptomes of 57,181 cells from scalp samples obtained from four young, six middle-aged, and one elderly individual. The integrated bioinformatic pipeline included cell clustering, spatial deconvolution, pseudotime trajectory, as well as cell-type specific gene expression, and intercellular communication analysis. An additional 92 volunteers were included, comprising 90 (37 young, 27 middle-aged, and 26 elderly) for trichoscopic examination, one young individual for senescence-associated β-galactosidase (SA-β-gal) staining, and one elderly individual for both MKI67 immunofluorescence and SA-β-gal staining.

This approach led to several key findings: we identified three subtypes of mitotic keratinocytes that localized in the interfollicular epidermis (IFE), outer root sheath (ORS), and hair matrix, with pseudotime trajectory further confirming their transitional stage. Furthermore, in middle-aged scalps, we observed activated activator protein 1 (AP-1) transcription factor complex in keratinocytes, upregulated DCT gene in melanocytes, and decreased bone morphogenetic protein (BMP) and noncanonical wingless/integrated (ncWNT) signaling in dermal papilla (DP)-keratinocytes cross-talk.

In the age-associated analysis of single-cell transcriptomics, AP-1 activation emerged as a hallmark of middle-aged hair follicle and epidermal cells, consistent with its known role in chromatin remodeling and senescence-associated transcriptional reprogramming. The downstream targets of AP-1 - such as MYC, SOCS3, DUSP1, NR4A1, and NFKBIA - form an intricate regulatory network that influences cell cycle progression, inflammatory responses, and stem cell depletion. This coordinated regulation reflects a dynamic cellular strategy in aging skin - balancing stem cell activation and stress adaptation while restraining excessive proliferative and inflammatory signaling to maintain tissue homeostasis. In addition, DCT was upregulated in melanocytes in the middle-age group, suggesting overactive melanin synthesis caused by inflammaging. Future studies leveraging in vivo and in vitro human hair follicle models are essential to elucidate the causal role of this AP-1-centered network and to evaluate whether targeting AP-1 or its downstream pathways could delay stem cell depletion and offer novel therapeutic avenues for age-related hair loss and graying.

A recent study investigated biomarkers that can help monitor trajectories of Alzheimer’s disease-related molecular processes, such as neuronal cell death, and how patients respond to treatments. The authors reported that using biomarkers enabled them to gain insights into the molecular processes that contribute to improved cognition following human recombinant granulocyte macrophage colony-stimulating factor (GM-CSF, sargramostim) treatment [1].

Measuring the damage

Alzheimer’s disease is accompanied by neuronal loss and increased inflammation [2, 3]. However, to monitor those processes, whether for diagnostic purposes or to aid in the development of Alzheimer’s disease therapies, easy-to-measure blood biomarkers are indispensable.

The authors of this study investigated such biomarkers. They focused on three proteins: ubiquitin C-terminal hydrolase-L1 (UCH-L1) for neuronal cell loss, neurofilament light (NfL) for neuron and axon damage, and glial fibrillary acidic protein (GFAP) for astrogliosis (an abnormally high number of astrocytes in response to neuronal destruction) and inflammation.

Changes in the healthy population

The researchers assessed the levels of UCH-L1, NfL, and GFAB in 317 healthy participants aged 2 to 85. Plasma UCH-L1 and NfL concentrations grew exponentially from ages 2 to 85. However, there were some differences between the two markers. For UCH-L1, the rate of exponential increase in females is faster than in males. For NfL, the estimated change per year is greater than that of UCH-L1, and the rate of exponential increase in females is slower than in males (opposite to that of UCH-L1).

Such an exponential age-dependent increase in neuronal damage markers suggests that brain aging is a lifelong process; however, its effects are evident in older age, “as the accumulated neuronal damage overcomes neurogenesis, functional redundancy, and resiliency in some individuals but not all.”

GFAP showed a different type of relationship with age. GFAP levels remain relatively constant up to 25, and around 40, they start to rise exponentially. As with previous markers, there are sex-specific differences, with females showing higher GFAP plasma levels across all ages.

It appears that plasma biomarkers of neuronal damage, UCH-L1 and NfL, increase earlier in life than the astrogliosis marker (GFAP), suggesting that astrogliosis and inflammation are responses to age-related neuronal damage.

Alzheimer’s disease trajectories

Once the trajectories of plasma markers of neurodegeneration (UCH-L1 and NfL) and of astrogliosis and inflammation (GFAP) in healthy individuals throughout their lifespan were established, the researchers compared them with those observed in 36 people with Alzheimer’s disease and 32 patients with mild cognitive impairment.

Patients diagnosed with mild cognitive impairment or mild-to-moderate Alzheimer’s disease had higher levels of NfL and GFAP compared to healthy controls of the same age. The same was true for UCH-L1 levels in plasma from participants with mild cognitive impairment, but in patients with mild-to-moderate Alzheimer’s disease, UCH-L1 levels in plasma were comparable to those of healthy participants of the same age.

Efficacy

The biomarkers investigated in this study can provide a better understanding of the mechanisms and trajectories of brain aging and help assess the efficacy of interventions aimed at slowing brain aging and neurodegenerative diseases.

The researchers used their previous study to evaluate the usefulness of those biomarkers in testing the efficacy of Alzheimer’s disease treatment, specifically using the immune-system-modulating cytokine GM-CSF, a long-approved drug that has also been investigated in the treatment of many other neurological injuries and diseases, including age-related cognitive decline, Down syndrome, stroke, traumatic brain injury, and Parkinson’s disease [4-8].

Treatment of a mouse model of Alzheimer’s disease with GM-CSF “reverses cognitive decline and the rate of neuron death after just a few weeks of treatment,” said the study’s senior author, Professor Huntington Potter, PhD, director of the University of Colorado Alzheimer’s and Cognition Center at CU Anschutz. The benefits of GM-CSF extend beyond Alzheimer’s disease and also benefit normal brain aging, as it improves impaired cognition and reduces neuronal function in aged wild-type mice [9].

The benefits are not limited to mice. These researchers conducted a phase 2, double-blind, randomized, placebo-controlled trial of human recombinant GM-CSF (sargramostim) in people suffering from mild-to-moderate Alzheimer’s disease [10]. “This drug improved one measure of cognition and reduced a blood measure of neuron death in people with AD in a relatively short period of time in its first clinical trial,” Potter said.

However, one of the most significant improvements was observed in the plasma UCH-L1 concentrations. “When people with AD were given sargramostim in the clinical trial, their blood levels of the UCH-L1 measure of neuronal cell death dropped by 40% – in our study, this was similar to levels seen in early life,” Potter said. “We were very surprised.”

Given the high sensitivity of UCH-L1 to sargramostim/GM-CSF, this biomarker might be a good candidate for assessing the efficacy of many Alzheimer’s disease treatments, including lifestyle changes.

NfL and GFAP were not reduced. The most likely reason is the very short treatment period (only 3 weeks) and the short plasma half-life of UCH-L1 relative to NfL and GFAP.

Understanding the mechanism

An aged rat model of Alzheimer’s disease helped to understand the mechanism behind GM-CSF treatment’s effects on caspase-3, a marker of cellular death by apoptosis. The number of caspase-3-positive cells is increased in humans and animal models with Alzheimer’s disease, and this was also evident in the aged Alzheimer’s disease rats used in this experiment, specifically in hippocampal neurons. GM-CSF treatment significantly reduced those numbers to levels comparable to those of wild-type untreated animals, suggesting that GM-CSF reduces neuronal cell death. Assessment of GFAP staining showed that GM-CSF treatment also reverses astrogliosis in some hippocampal regions of the Alzheimer’s disease rat model.

Those results suggest that the beneficial effects of GM-CSF treatment on cognition and various biomarkers are “likely due to a reduction in the number of apoptotic neurons in the brain.” The authors also add that since the GM-CSF can stimulate some of the immune cells, it can also contribute to “removal of damaged, apoptotic, and senescent neurons, thus allowing the remaining neurons to function more effectively.”

Informative biomarkers

Potter summarized, “These findings suggest that the exponentially higher levels of these markers with age, likely accelerated by neuroinflammation, may underlie the contribution of aging to cognitive decline and AD and that sargramostim treatment may halt this trajectory.”

Additionally, using those markers, the researchers can identify people with mild cognitive impairment, suggesting they may be used to predict future Alzheimer’s disease. However, variability in marker levels indicates that other players also influence the risk of developing the disease, and factors such as genetics or lifestyle can shape the trajectory of cognitive decline.

Literature

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[2] Risacher, S. L., Anderson, W. H., Charil, A., Castelluccio, P. F., Shcherbinin, S., Saykin, A. J., Schwarz, A. J., & Alzheimer’s Disease Neuroimaging Initiative (2017). Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline. Neurology, 89(21), 2176–2186.

[3] Hyman, B. T., Van Hoesen, G. W., Damasio, A. R., & Barnes, C. L. (1984). Alzheimer’s disease: cell-specific pathology isolates the hippocampal formation. Science (New York, N.Y.), 225(4667), 1168–1170.

[4] Kim, N. K., Choi, B. H., Huang, X., Snyder, B. J., Bukhari, S., Kong, T. H., Park, H., Park, H. C., Park, S. R., & Ha, Y. (2009). Granulocyte-macrophage colony-stimulating factor promotes survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced murine Parkinson’s disease model. The European journal of neuroscience, 29(5), 891–900.

[5] Kelso, M. L., Elliott, B. R., Haverland, N. A., Mosley, R. L., & Gendelman, H. E. (2015). Granulocyte-macrophage colony stimulating factor exerts protective and immunomodulatory effects in cortical trauma. Journal of neuroimmunology, 278, 162–173.

[6] Kong, T., Choi, J. K., Park, H., Choi, B. H., Snyder, B. J., Bukhari, S., Kim, N. K., Huang, X., Park, S. R., Park, H. C., & Ha, Y. (2009). Reduction in programmed cell death and improvement in functional outcome of transient focal cerebral ischemia after administration of granulocyte-macrophage colony-stimulating factor in rats. Laboratory investigation. Journal of neurosurgery, 111(1), 155–163.

[7] Schneider, U. C., Schilling, L., Schroeck, H., Nebe, C. T., Vajkoczy, P., & Woitzik, J. (2007). Granulocyte-macrophage colony-stimulating factor-induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion. Stroke, 38(4), 1320–1328.

[8] Olson, K. E., Abdelmoaty, M. M., Namminga, K. L., Lu, Y., Obaro, H., Santamaria, P., Mosley, R. L., & Gendelman, H. E. (2023). An open-label multiyear study of sargramostim-treated Parkinson’s disease patients examining drug safety, tolerability, and immune biomarkers from limited case numbers. Translational neurodegeneration, 12(1), 26.

[9] Boyd, T. D., Bennett, S. P., Mori, T., Governatori, N., Runfeldt, M., Norden, M., Padmanabhan, J., Neame, P., Wefes, I., Sanchez-Ramos, J., Arendash, G. W., & Potter, H. (2010). GM-CSF upregulated in rheumatoid arthritis reverses cognitive impairment and amyloidosis in Alzheimer mice. Journal of Alzheimer’s disease : JAD, 21(2), 507–518.

[10] Potter, H., Woodcock, J. H., Boyd, T. D., Coughlan, C. M., O’Shaughnessy, J. R., Borges, M. T., Thaker, A. A., Raj, B. A., Adamszuk, K., Scott, D., Adame, V., Anton, P., Chial, H. J., Gray, H., Daniels, J., Stocker, M. E., & Sillau, S. H. (2021). Safety and efficacy of sargramostim (GM-CSF) in the treatment of Alzheimer’s disease. Alzheimer’s & dementia (New York, N. Y.), 7(1), e12158.