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21 November 2025 - 08:38 AM
Injected Oxytocin Slows Cognitive Decline in Aged Mice 20 November 2025 - 07:22 PM
Circulating oxytocin levels are known to decline with age, and a number of research groups have focused on upregulation of oxytocin as an approach to treating aging. A couple of papers published a few months ago are indicative of the animal studies presently taking place, the first focused on increased longevity in mice achieved via the combined reduction of TGF-β and increase in oxytocin, and the second evaluating intranasal delivery of oxytoxin as a route to improve function in the aging brain.
Today's paper reports on another example of oxytocin delivery in aged mice. These researchers are also focused on the brain, but in this case the oxytocin is delivered via intraperitoneal injection. As with most peptide or protein therapies, the effects are limited in scope as the delivered molecules have a short half-life. Repeated treatments are required, often daily, as is the case here. Given further progress towards the clinic, however, we might expect that the community of developers presently assessing gene therapies to safely transform a small number of cells into long-lasting factories that produce a desired circulating molecule (such as klotho or follistatin) will add oxytocin to their list.
Brain aging is characterized by progressive structural and functional deterioration, leading to cognitive decline and impaired social functioning. A key factor in this process is the age-related decline in adult neurogenesis, particularly in the hippocampal dentate gyrus, which is linked to deficits in learning, memory, and increased social anxiety. Oxytocin, a neuropeptide synthesized in the hypothalamus, regulates social behavior, cognition, and emotion by acting on brain regions including the hippocampus. Importantly, oxytocin levels decrease with age, potentially contributing to cognitive impairment.
Here, we examined whether chronic intraperitoneal oxytocin administration could attenuate cognitive decline in aged mice. Twelve-month-old mice received oxytocin injections (0.5 mg/kg) five times weekly for 13 weeks. Behavioral testing at 12 weeks of treatment using the object-place recognition task showed enhanced spatial learning and recognition memory in oxytocin-treated mice compared with saline controls. Immunohistochemistry revealed significantly increased doublecortin (DCX)-positive cells in the hippocampus, indicating enhanced neurogenesis. Furthermore, oxytocin treatment upregulated the expression of glutamate receptor 1 (GluR1) and N-methyl-D-aspartate receptor subunit 2B (NMDAR2B), which are markers of synaptic plasticity.
These findings suggest that chronic oxytocin treatment is associated with enhanced neurogenesis and synaptic plasticity, which may contribute to improved cognition in aged mice. Our results support oxytocin as a potential therapeutic agent for age-related cognitive decline.
View the full article at FightAging
How Senescent Cells Encourage Melanoma Growth 20 November 2025 - 06:04 PM
Researchers publishing in Aging Cell have documented a key reason why older people are much more likely to get melanoma.
Why older people have significantly worse melanoma cases
While melanoma is much more treatable now than in the past, it still remains a serious danger. Melanoma can develop resistance to otherwise effective techniques [1], meaning that they only delay instead of permanently stop the disease.
Fortunately, the origins of melanoma are largely well-understood. The first thing that drives most melanoma cases is a point mutation of the BRAF gene [2]. This does not trigger melanoma by itself, but further mutations of other genes lead to malignancy [3].
The severity of melanoma is measured by its thickness, as it has been known for over half a century that thicker melanomas are much more dangerous [4]. The cancer’s transition from horizontal to vertical growth is associated with increasing mutation frequency [5], and, unsurprisingly, older people are typically diagnosed with considerably thicker melanomas than younger people are [6].
The researchers of this study have pinpointed cellular senescence as the most likely driver of this increase in severity, and significant previous work has been done to establish the connection between these cells’ potentially dangerous SASP secretions and melanoma [7]. However, that previous work did not completely elucidate the biological relationship between the two, which is what this study was created to find.
Melanoma is attracted to senescent cells
In their first experiment, the researchers confirmed a direct relationship between the prevalence of senescent skin fibroblasts and the incidence of melanoma. While p16 is a tumor suppressor and appears in both the benign and malignant portions of melanoma, it is bypassed by other cancerous mutations [8]. Injecting melanoma cells together with senescent or non-senescent fibroblasts into the skin of mice confirmed this relationship: the mice given senescent fibroblasts had tumors that were ten times as thick.
The researchers then looked into why this is the case. Cultivating melanoma in conditioned media that contains secretions from senescent fibroblasts, but not non-senescent fibroblasts, greatly increases the cancer’s growth. The researchers found two compounds of particular interest: GCL-2 and ENA-78, which melanoma cells were discovered to actively grow towards in a chemotaxic response, resulting in independent, unanchored growth. Neutralizing these compounds in conditioned media through antibodies greatly reduces the growth of melanoma, and enhancing GCL-2 production in non-senescent cells causes their related conditioned media to encourage the growth of this cancer.
These two compounds, which are considerably more abundant in the skin of older adults compared to young adults, are generated by senescent fibroblasts and not significantly by other cell types.
Further work found that GCL-2 is considerably more important than ECL-78 in encouraging the growth of cancer cells, as silencing GCL-2 had significant effects on the growth of melanoma in mice but silencing ECL-78 did not. Furthermore, senescent fibroblasts were confirmed to be the source of the harmful GCL-2, as silencing this compound in the melanoma itself had no significant effect.
The protein that drives melanoma’s growth
A more in-depth examination found this to be due to the phosphorylation of the cAMP-responsive element binding protein (CREB). CREB activation leads to tumor progression in melanoma, activating several related cancer genes, and GCL-2 was found to significantly drive this effect, with ECL-78’s effect being much weaker. Removing GCL-2 from the environment of melanoma was found to almost completely stop CREB activation, both in conditioned media and in mice.
The researchers found that significant CREB activation occurs only in the malignant part of melanoma, not the benign part. It drives glycolysis, a form of energy use that encourages cancer progression. Directly inhibiting this process, either by suppressing CREB or suppressing glycolysis in these cells, prevents the related acceleration of cancer, thus providing strong evidence that this is indeed the biological cause. An examination of naturally occurring melanomas confirmed their glycolytic nature.
As the researchers note, their data “allows several options for novel strategies for therapeutic intervention.” While fighting fibroblast senescence itself would be an ideal solution, targeting GCL-2 or its receptors offers a few potential avenues, and directly targeting CREB offers another. As targeting GCL-2 receptors is already being investigated in the context of other cancers [9], it may be that translating these drugs to melanoma is on the short-term horizon.
Literature
[1] Kim, K. B., Kefford, R., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., … & Lewis, K. D. (2013). Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of Clinical Oncology, 31(4), 482-489.
[2] Gray-Schopfer, V. C., Dias, S. D. R., & Marais, R. (2005). The role of B-RAF in melanoma. Cancer and Metastasis Reviews, 24(1), 165-183.
[3] Dankort, D., Curley, D. P., Cartlidge, R. A., Nelson, B., Karnezis, A. N., Damsky Jr, W. E., … & Bosenberg, M. (2009). Braf V600E cooperates with Pten loss to induce metastatic melanoma. Nature genetics, 41(5), 544-552.
[4] Breslow, A. (1970). Thickness, cross-sectional areas and depth of invasion in the prognosis of cutaneous melanoma. Annals of surgery, 172(5), 902.
[5] Greene, V. R., Johnson, M. M., Grimm, E. A., & Ellerhorst, J. A. (2009). Frequencies of NRAS and BRAF mutations increase from the radial to the vertical growth phase in cutaneous melanoma. Journal of investigative dermatology, 129(6), 1483-1488.
[6] Kruijff, S., Bastiaannet, E., Francken, A. B., Schaapveld, M., Van Der Aa, M., & Hoekstra, H. J. (2012). Breslow thickness in the Netherlands: a population-based study of 40 880 patients comparing young and elderly patients. British journal of cancer, 107(3), 570-574.
[7] Liu, J., Zheng, R., Zhang, Y., Jia, S., He, Y., & Liu, J. (2023). The cross talk between cellular senescence and melanoma: From molecular pathogenesis to target therapies. Cancers, 15(9), 2640.
[8] Mooi, W. J., & Peeper, D. S. (2006). Oncogene-induced cell senescence—halting on the road to cancer. New England Journal of Medicine, 355(10), 1037-1046.
[9] Campbell, L. M., Maxwell, P. J., & Waugh, D. J. (2013). Rationale and means to target pro-inflammatory interleukin-8 (CXCL8) signaling in cancer. Pharmaceuticals, 6(8), 929-959.
View the article at lifespan.io
Mixed Results in a Meta-Analysis of Epigenetic Clocks and Frailty 20 November 2025 - 11:22 AM
Epigenetic clocks have existed for long enough for numerous large study databases to include data on their use. Thus meta-analysis papers are emerging to assess this body of data as a whole. This is a necessary part of the process of gaining confidence in the ability of epigenetic clocks, and indeed aging clocks in general, to rapidly assess the potential of any novel form of intervention intended to slow or reverse aspects of aging. This is a much needed capability. In many ways, efforts to treat aging as a medical condition proceed blindly, given just how much time and funding is required in order to understand whether one approach is better or worse than another. If there was a way to quickly assess the quality of an anti-aging therapy immediately after its application, then the field could adjust quickly to pursue the best paths forward. The hope is that aging clocks can be that tool - but we are clearly not there yet.
Frailty is an age-related condition characterised by multisystem physiological decline, which increases vulnerability to adverse outcomes. Biomarkers of ageing might identify individuals at risk and enable early interventions. This systematic review and meta-analysis aimed to examine cross-sectional and longitudinal associations between DNA methylation-based biological age metrics (eg, DNA methylation age, epigenetic-age acceleration [EAA], and age deviation) and frailty.
24 studies met the inclusion criteria (17 cross-sectional studies, one longitudinal study, and six studies that were both cross-sectional and longitudinal), encompassing 28,325 participants (14,757 female; median of mean age 65.2 years). DNA methylation age and age deviation showed no association with frailty. In cross-sectional meta-analyses, higher Hannum EAA (nine studies; n=11,162; standardised β coefficient 0.06), PhenoAge EAA (eight studies; n=10,371; standardised β coefficient 0.07), GrimAge EAA (eight studies; n=10,371; standardised β coefficient 0.11), and pace of ageing (five studies; n=7,895; standardised β coefficient 0.10) were significantly associated with higher frailty. In longitudinal meta-analyses, higher GrimAge EAA (five studies; n=6,143; standardised β coefficient 0.02) was significantly associated with increases in frailty, whereas PhenoAge EAA and pace of ageing were not significantly associated with frailty.
In conclusion, higher GrimAge EAA is consistently associated with higher frailty. Future research should focus on developing and validating DNA methylation clocks that integrate molecular surrogates of health risk and are specifically trained to predict frailty in large, harmonised, longitudinal cohorts, enabling their translation into clinical practice.
Link: https://doi.org/10.1016/j.lanhl.2025.100773
View the full article at FightAging
MicroRNA-126 Expression as a Way to Prevent TDP-43 Aggregation in Amyotrophic Lateral Sclerosis 20 November 2025 - 11:11 AM
TDP-43 is one of a small number of proteins in the brain that can misfold or otherwise become altered in ways that allow toxic aggregates to form, or even encourage other molecules of the same protein to become dysfunctional in the same way. TDP-43 aggregation in later life is a relatively recent discovery, and has a neurodegenerative condition newly named for it, limbic-predominant age-related TDP-43 encephalopathy (LATE). It has also been found that TDP-43 is likely important in amyotrophic lateral sclerosis (ALS), and thus progress on that front seems likely to help with other forms of TDP-43 pathology. Here, researchers report a promising discovery in the biochemistry of TDP-43 aggregation in the context of ALS.
Amyotrophic lateral sclerosis (ALS) is a lethal adult-onset motor neuron disease, characterized by disruption of neuromuscular junctions (NMJs), axonal degeneration and neuronal death. Most ALS cases are linked to TDP-43 pathology, characterized by its mislocalization from the nucleus to the cytoplasm and the formation of phosphorylated aggregates. TDP-43 is a multifunctional DNA-binding/RNA-binding protein with roles in transcriptional and splicing regulation, RNA processing and RNA transport/subcellular localization.
Recently, we showed that TDP-43 co-localizes with the core stress granule component G3BP1 in axonal condensates of patients with ALS and mice. These TDP-43-G3BP1 condensates sequester RNA and inhibit local protein synthesis, resulting in mitochondrial malfunction and NMJ disruption with subsequent axonal degeneration. Furthermore, recent studies revealed aggregation of TDP-43 in peripheral motor axons of patients with ALS during initial diagnosis. Thus, axonal TDP-43 condensates exert pathological regulation over essential local synthesis events.
Here, we studied the localized accumulation of TDP-43 in axons and NMJs. Our findings highlight the presence of distal TDP-43 pathology in patients with SOD1 ALS and mouse models. We found that TDP-43 accumulates at NMJs due to aberrant local synthesis triggered by a reduction in miR-126a-5p within muscle extracellular vesicles. This chain of events ultimately initiates neurodegeneration. Notably, delivery of miR-126 is neuroprotective in neuromuscular co-cultures, delays TDP-43 accumulation at NMJs, and postpones the onset of motor symptoms in the SOD1G93A mouse model of ALS.
Link: https://doi.org/10.1038/s41593-025-02062-6
View the full article at FightAging
