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20 February 2026 - 05:07 AM
IL-6 as a Measure of Peripheral Inflammation is More Often Elevated in Cognitively Impaired Individuals 19 February 2026 - 07:30 PM
The immune system is a very complex array of interacting cell populations, constantly changing over time. The inflammatory response is similarly complex, arising from many different inciting events and cascades of signaling and interaction between various immune cell types. Thus there are no simple measures of inflammation, no matter that the medical community has certainly tried very hard to make that goal a reality. Or perhaps it is better to say that simple measures of, say, one signaling molecule (in practice often C-reactive protein), paint a limited picture of what is actually going on. Sometimes that limited picture is useful, sometimes it is misleading.
Today's open access paper is a good illustration of the limits of what one can learn from a single marker, or two related markers. Circulating C-reactive protein and IL-6 are linked mechanistically in that C-reactive protein rises in response to IL-6. These are also the most commonly used measures of inflammation, so the research and medical communities have a fair grasp on the limitations. Nonetheless because they are commonly assessed markers, there is a tendency to continue to use them, as then at least there is a large body of existing data to compare against.
"Inflammaging" describes chronic low-grade inflammation observed in aging individuals. It may play a major role in neurodegeneration. Interleukin-6 (IL-6) and C-reactive protein (CRP) were assessed in 514 Canadian individuals in COMPASS-ND, a detailed study of cognitive impairment in the elderly. Cumulative link model (CLM) was used to investigate the relationship between inflammation status (low, medium, or high tertiles) and demographic and lifestyle factors along with cognitive function and cognitive diagnoses.
We found that 12% of cognitively normal older adults had IL-6 levels in the highest tertile, but this increased in cognitively impaired cohorts - 36% in Alzheimer's disease, 55% mixed dementia, 30% mild cognitive impairment, and 39% vascular mild cognitive impairment. We found that 36% of cognitively unimpaired older individuals display "elevated" IL-6 (middle and high tertile values), while approximately 70% of those with cognitive impairment also do so. Inflammation markers increased most robustly in association with age, higher body mass index, and higher Fazekas (MRI white matter hyperintensity) score. There were also weaker associations with female sex, nutrition, number of comorbidities, and poor sleep.
In conclusion, peripheral low-grade inflammation was common, particularly in individuals with cognitive impairment; and obesity and age were the main drivers. It remains unclear whether treatment targeting such inflammation might have a therapeutic role in dementia prevention.
View the full article at FightAging
A Circulating Inflammation Suppressor Decreases Mortality 19 February 2026 - 05:16 PM
Researchers publishing in Aging have used Mendelian randomization to conclude that the inflammatory factor IL6 causes increased mortality and that its circulating receptor, IL6R, decreases it.
Looking for a proof of danger
Chronic, age-related inflammation (inflammaging) is very well-known to be closely connected to negative age-related outcomes, to the point that it has been addressed by the Hallmarks of Aging authors [1]. However, as these researchers note, proving causation in this case is particularly difficult; inflammation often comes with a large variety of confounding factors, and reverse causation must also be ruled out [2].
To accomplish that, the researchers turned to Mendelian randomization, a technique that uses large genomic datasets derived from very large groups of people, to discover the effects of various conditions in a way that is far less prone to confounding and reverse causation. They chose the well-studied inflammatory factor IL6, along with its soluble receptor IL6R, which leads this inflammatory factor down a different and possibly contradictory pathway [3].
Ruling out other factors
This study found that increases in IL6R cause increased longevity and protected against a variety of conditions. While Alzheimer’s and kidney diseases were unaffected, increases in IL6R were found to be protective against lung cancer, diabetes, stroke, and coronary artery disease. People with more circulating IL6R had less all-cause mortality.
Similarly, increases in IL6 were found to cause more overall mortality, and genetic propensities for the various conditions that cause mortality, such as heart disease, were not connected to this increase in IL6, meaning that reverse causality was not a factor. C-reactive protein and GDF15, two other inflammation-related compounds frequently studied in aging, were not found to have any effects.
The researchers noted that, because very few genes are associated with increased inflammation, they had to use only those genes that were very significantly and strongly associated in order to avoid creating data from weak instruments. Additionally, by using repeated leave-one-out analyses, the researchers made sure that the associations that they discovered stood on their own. None of the individual genes responsible for the IL6 increase was found to be the cause; instead, the cause was, indeed, the increased IL6.
A cardiovascular focus
The researchers noted that most of the causes of increased mortality linked to IL6 were cardiovascular in nature. They note that IL6R is not abundant in the walls of blood vessels or heart tissue, and therefore, increases in this anti-inflammatory factor throughout the bloodstream bring it to where it is needed. By binding to and taking away IL6, the researchers reason, IL6R prevents this inflammatory compound from worsening various cardiovascular conditions, such as thrombosis and dysfunction of the endothelium, providing a “clear mechanistic pathway” for its beneficial effects.
The researchers sum up their findings simply: “Taken together, the results of the current mendelian randomization study strengthen the rationale for IL6R antagonism as a potential strategy to reduce cardiovascular disease and associated mortality.” Fortunately, an IL6R antagonist already exists in the clinic: tocilizumab is already approved by the FDA and has been found to reduce mortality in both the contexts of COVID-19 [4] and giant cell arteritis [5].
However, this approach still needs to be examined carefully. Experiments will need to be performed in animals and people to determine if artificially increasing circulating IL6R through tocilizumab or other methods is a viable method of reducing overall cardiovascular disease risk.
Literature
[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243-278.
[2] Emerging Risk Factors Collaboration. (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. The Lancet, 375(9709), 132-140.
[3] Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. (2012). The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. The Lancet, 379(9822), 1214-1224.
[4] Rosas, I. O., Bräu, N., Waters, M., Go, R. C., Hunter, B. D., Bhagani, S., … & Malhotra, A. (2021). Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. New England Journal of Medicine, 384(16), 1503-1516.
[5] Stone, J. H., Tuckwell, K., Dimonaco, S., Klearman, M., Aringer, M., Blockmans, D., … & Collinson, N. (2017). Trial of tocilizumab in giant-cell arteritis. New England Journal of Medicine, 377(4), 317-328.
View the article at lifespan.io
Plaque Volume Predicts Risk of Major Adverse Cardiovascular Events 19 February 2026 - 11:22 AM
Imaging of atherosclerotic plaque, particularly via CT scan, has improved immensely over the past decade in its ability to quantify plaque and discern plaque composition, particularly with advances in machine learning approaches to analysis. Here, researchers demonstrate that plaque volume correlates with risk of severe cardiovascular events. The volume of softer, more fatty plaque also correlates with risk, much as one might expect. It is these less stable plaques that are more likely to fragment, leading to a downstream blockage. Imaging will become more important as cardiovascular therapies improve to point of being able to produce rapid stabilization or even regression of plaque, capabilities that do not currently exist. The best that can be done with the present standard of care, focused on lowering LDL cholesterol, is a slowing of plaque growth and some degree of stabilization over years of sustained use.
Despite the increasing use of coronary computed tomographic angiography (CCTA) in patients with known or suspected coronary artery disease (CAD), comparatively little is known about its predictive value for adverse events or clinical applicability of volumetric plaque analysis. This post hoc analysis involved a prospective randomized clinical trial conducted across 193 clinical sites in North America. Participants were symptomatic outpatients without known CAD who were randomized to receive CCTA. Core laboratory-based quantitative plaque measures including total plaque volume (TPV), calcified (CPV) and noncalcified (NCPV) plaque volume, low-attenuation plaque volume (LAPV), total plaque burden (TPB), and noncalcified plaque burden (NCPB), normalized with vessel volume.
The primary outcome was major adverse cardiovascular events, MACE (composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina). Among 4,267 patients, the mean age was 60.4 ± 8.2 years; 2199 patients (51.5%) were female and 2068 (48.5%) were male. Higher total plaque volume (≥87 mm), total plaque burden (≥35%), and noncalcified plaque burden (≥20%) were associated with an increased risk of MACE, independent of atherosclerotic cardiovascular disease risk, statin use, 50% or more stenosis, coronary artery calcium score, and high-risk plaque.
Link: https://doi.org/10.1001/jamacardio.2025.5520
View the full article at FightAging
Partial Reprogramming of Neurons Encoding Memory Improves Cognitive Function in Aged Mice 19 February 2026 - 11:11 AM
Partial reprogramming involves the short-term expression of Yamanaka factors to restore youthful epigenetic control over nuclear DNA structure and gene expression. The primary challenge is to avoid accidental full reprogramming of cells into induced pluripotent stem cells, or otherwise losing necessary cell state, in a tissue environment in which different cell types require different degrees of exposure to pass various reprogramming-related thresholds. Interestingly, much of the present development of partial reprogramming as a basis for rejuvenation therapies has converged on the central nervous system as a target. For example, here researchers are interested in the neurons that encode memory, and find that partial reprogramming can improve memory function in aged mice.
Partial cellular reprogramming has emerged as one of the most promising strategies in regenerative medicine. Cyclic expression of the four Yamanaka factors (Oct4, Sox2, Klf4, and cMyc - OSKM), or a partial combination thereof (OSK), holds the potential to orchestrate rejuvenation of cellular function in aging while at the same time preventing changes in cell identity and tumorigenesis.
Memories are encoded in sparse neuronal ensembles termed engrams, which are found in different brain regions, with specific contributions to recall during memory consolidation. Thus, engrams in the hippocampus, and in particular in the dentate gyrus (DG), are predominantly important for learning and recent recall, whereas engrams in the medial prefrontal cortex (mPFC) become gradually more relevant for remote memory expression. Importantly, during physiological aging and in mouse models of Alzheimer's disease (AD), engram impairments interfere with memory recall, suggesting that engram dysfunction may underlie age- and disease-related memory decline.
Here, we report that partial reprogramming of engram neurons - bona fide memory trace cells - by OSK-mediated gene therapy reversed the expression of senescence-related and disease-related cellular hallmarks in aged mice and models of Alzheimer's disease (AD), re-established aberrant epigenetic-transcriptional patterns pertaining to synaptic plasticity, and counteracted AD-typical neuronal hyperexcitability. Importantly, irrespective of the brain area targeted or the behavioral paradigm employed, engram reprogramming also recovered learning and memory capacities to levels of healthy young animals, suggesting cognitive rejuvenation. These results posit that partial reprogramming of specific cell populations in the brain can be exploited for cognitive restoration in aging and disease.
Link: https://doi.org/10.1016/j.neuron.2025.11.028
View the full article at FightAging
