LongeCityNews Last Updated: 23 January 2026 - 11:22 PM

Chronic inflammation is a major component of degenerative aging. Short-term inflammatory signaling is necessary for the immune system to function, including its role in tissue regeneration following injury, as well as defense against malfunctioning, potentially cancerous cells. But when sustained over the long term without resolution, that same signaling becomes disruptive to tissue structure and function. It hinders regeneration, it encourages fibrosis and cancerous growth, and leads to an immune system less able to defend against pathogens.

The primary approach towards the development of novel means of suppressing unwanted inflammation is to interfere in specific inflammatory signals or the regulatory mechanisms that generate those signals. The challenge lies in the fact that the same signals and mechanisms are involved in both necessary short-term inflammation and undesirable long-term inflammation. Thus existing approaches produce an unwanted suppression of desirable features of the immune system, side-effects that harm long-term health.

Thus some researchers are attempting to identify aspects of the inflamed immune system that are (a) more relevant to chronic inflammation and less relevant to short-term inflammation, and (b) can be targeted in isolation of the rest of the immune system. In principle there should be ways to reduce undesirable effects while still obtaining benefit in adjusting the way in which the inflamed immune system operates. Today's open access paper reports on one such approach, a step in the right direction in that the researchers identify a way to suppress the contribution of monocyte cells to chronic inflammation without impairing the immediate inflammatory response.

Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans

The role of cytochrome P450-derived epoxy-oxylipins and their metabolites in human inflammation and resolution is unknown. We report that epoxy-oxylipins are present in blood of healthy, male volunteers at baseline and following intradermal injection of UV-killed Escherichia coli, an experimental model of acute resolving inflammation. At the site of inflammation, cytochrome P450s and epoxide hydrolase (EH) isoforms, which catabolise oxylipins to corresponding diols, are differentially upregulated throughout the inflammatory response, as is the biosynthesis of epoxy-oxylipins.

In this study we characterised the epoxy-oxylipin biosynthetic machinery in humans under baseline and inflammatory conditions demonstrating that blocking soluble epoxide hydrolase (sEH) significantly elevated the epoxy-oxylipins 12,13-EpOME and 14,15-EET. With little effect on the salient features of inflammation, except for accelerated pain resolution, sEH inhibition most notably reduced numbers of intermediate monocytes in blood and in inflamed tissue via the inhibition of p38 MAPK by 12,13-EpOME.

Reduced intermediate monocytes during tissue resolution uncovered potential a role for these cells in maintaining CD4 T cell viability and phenotype on the one hand, but also revealed their ability to drive cells death via cytotoxic CD8 T cells on the other. With clinical studies demonstrating that sEH inhibition is safe and well tolerated, therefore, sEH inhibition presents a hitherto unappreciated way of reducing inflammatory intermediate monocytes, which are implicated in the pathogenesis of chronic inflammatory disease.

A new study links exercise variety, defined as regularly engaging in several types of physical activity, to significantly lower all-cause mortality. Exercise amount matters as well, but the effect plateaus quickly [1].

How exactly is it good for you?

“Exercise is good for you” is a stale truism, but researchers continue to uncover new information about how the amount and specific types of physical activity affect our health. A new study from the Harvard T.H. Chan School of Public Health, published in the journal BMJ Medicine, focuses on the relationship between mortality and the variety of physical activity in two large cohorts of health professionals.

The researchers analyzed data from over 100,000 participants across two major long-term studies (the Nurses’ Health Study and the Health Professionals Follow-Up Study) over a period of 30 years. The former study included only women, while the latter only men. Both cohorts were free at baseline of diabetes, cancer, and any cardiovascular, respiratory, or neurological disease. The levels of physical activity were self-reported every two years. In total, almost 2.5 million person-years were recorded.

Metabolic equivalent of task (MET) is the amount of energy expended during an activity compared to energy expenditure at rest, and in this study, activity doses were expressed as MET-hours/week. For example, brisk walking has a MET value of 3.5 to 4.5, meaning it is about four times more energy-demanding than chilling on a couch.

Lower mortality rates for most types of exercise

Habitual engagement in most measured activities was associated with significantly lower mortality rates. For example, compared to people with the lowest activity levels, the people in the highest categories saw risk reductions of 17% for walking, 15% for tennis and other racquet sports, 14% for rowing/calisthenics, 13% for running and weight/resistance training, and 11% for jogging.

Two activities showed surprisingly low effect sizes: bicycling (4% risk reduction) and swimming (1% risk increase, but statistically insignificant). However, this might simply reflect measurement problems, which is a well-known issue for both cycling and swimming [2].

These mortality benefits from single activities appear more modest than in some earlier studies [3]. One possible reason is that in this study, the comparison group was the lowest quintile of activity, which may not reflect true inactivity, especially since these were groups of of health professionals. The authors also used robust protections against reverse causation (when people lower their activity levels after they become unhealthy), which tends to shrink associations.

Like many recent studies [4], this one shows that mortality risk plateaus at certain levels of activity rather than decreasing indefinitely. However, here, the benefits of exercise peter out rather quickly (at least for cardiovascular, cancer, and respiratory mortality), around 20 MET-hours per week, which may also be due to the reference group not being completely inactive.

Variety matters (usual caveats apply)

The researchers then compared participants with different levels of variety in physical activity, defined as the number of different types of activity that participants regularly performed. After adjusting for total physical activity, the highest-variety group had about a 19% lower all-cause mortality compared to the lowest, with comparable reductions across major causes.

When they combined people into groups by total activity and variety, the highest on both had about 21% lower mortality compared to the lowest-lowest reference group. The authors report no interaction here, signifying that variety helps across activity levels rather than only at high or low volume.

“People naturally choose different activities over time based on their preferences and health conditions. When deciding how to exercise, keep in mind that there may be extra health benefits to engaging in multiple types of physical activity, rather than relying on a single type alone,” said corresponding author Yang Hu, research scientist at the Department of Nutrition.

Anna Whittaker, Professor of Behavioral Medicine at the University of Stirling, who was not involved in this study, said: “This large-scale longitudinal study adds to what we know about the impact of physical activity on mortality by showing that engagement in a range of different types of physical activity is beneficial for longevity, independently of the total amount of physical activity engaged in. This is likely due to the different types of activity having different physiological effects and helping to meet all of the aspects currently outlined in physical activity guidelines (i.e. moderate intensity exercise, resistance exercise, vigorous intensity exercise, flexibility work, recovery activities).”

Like all populational studies, this one can only show correlation, but not causation, and the results depend on many design choices. While the authors did an admirable job controlling for possible confounders, which included age, race/ethnicity, family history of myocardial infarction and cancer, body mass index, smoking, alcohol intake, energy intake, diet quality, social integration, baseline hypertension and hypercholesterolemia, and (for women) postmenopausal hormone use, it is impossible to rule out residual confounding such as sleep, stress, or the built environment. For instance, it is possible that people who can find the time and energy for various types of activity have more free time, enjoy better sleep, and live in an environment better suited for exercise.

Literature

[1] Han, H., Hu, J., Lee, D. H., Zhang, Y., Giovannucci, E., Stampfer, M. J., Hu, F. B., Hu, Y., & Sun, Q. (2026). Physical activity types, variety, and mortality: Results from two prospective cohort studies. BMJ Medicine, 5(1), e001513.

[2] Harrison, F., Atkin, A. J., van Sluijs, E. M., & Jones, A. P. (2017). Seasonality in swimming and cycling: Exploring a limitation of accelerometer based studies. Preventive medicine reports, 7, 16-19.

[3] Arem, H., Moore, S. C., Patel, A., Hartge, P., De Gonzalez, A. B., Visvanathan, K., … & Matthews, C. E. (2015). Leisure time physical activity and mortality: a detailed pooled analysis of the dose-response relationship. JAMA internal medicine, 175(6), 959-967.

[4] Garcia, L., Pearce, M., Abbas, A., Mok, A., Strain, T., Ali, S., … & Brage, S. (2023). Non-occupational physical activity and risk of cardiovascular disease, cancer and mortality outcomes: a dose–response meta-analysis of large prospective studies. British Journal of Sports Medicine, 57(15), 979-989.

Cells react to physical forces placed upon them, and changes in the character of those forces will tend to result in altered cell behavior. Cells in a three dimensional extracellular matrix do not behave in the same way as cells in a petri dish. Further, the extracellular matrix in aged tissues differs from that in young tissues in ways that can meaningfully affect its material properties, and thus the forces placed on cells within that matrix. Researchers here demonstrate that some fraction of the undesirable changes occurring in cells within bone tissue are the result of reduced mechanical stimulation. Vibration to induce that mechanical stimulation can restore some of the lost function in aged mice.

Emerging evidence highlights a critical role for mechanical signaling in modulating transcriptional and epigenetic processes. Bone marrow mesenchymal stem/stromal cells (BMSCs) are embedded in a dynamic microenvironment where they continuously perceive and respond to mechanical cues, affecting cellular traction force and directing cell behavior. Aging significantly alters the physical properties of the bone microenvironment, disrupting the mechanical signals transmitted to cells.

In this work, we show that aging reduces intracellular traction forces in BMSCs and aged bone tissue, a deficiency that can be reversed in vitro and in vivo through appropriate mechanical stimulation to restore the cell mechanics. Mechanistically, the restoration of cellular traction force enhances chromatin accessibility, leading to the activation of FOXO1 expression. Importantly, FOXO1 knockdown abolished the mechanically rejuvenating effects, underscoring its critical role in mediating cellular responses to mechanical forces.

Beyond bone recovery, mechanical interventions (vibrational loading) in aged mice improved locomotor activity, alleviated physical frailty, and reduced systemic inflammation. These findings highlight both local and systemic benefits of mechanical stimulation, offering a straightforward approach with significant translational potential for combating age-related tissue decline.

Link: https://doi.org/10.1038/s41467-026-68387-3

A sizable fraction of degenerative aging involves chronic inflammation. Various forms of cell and tissue damage trigger maladaptive inflammatory signaling, such as the presence of lingering senescent cells and DNA released into the cytoplasm by dysfunctional mitochondria. Sustained inflammatory signaling changes cell behavior for the worse and is disruptive to tissue structure and function. Many of the important mediators of inflammatory signaling are well known, such as TNFα, but inhibiting these signals is a blunt tool that causes unwanted side effects, such as loss of necessary immune function and impaired long-term health.

Tumor necrosis factor α (TNFα) regulates inflammation in metabolic diseases and probably aging-associated inflammation. Here, TNFα´s role in aging-related liver inflammation and fibrosis and underlying mechanisms was assessed in mice. In male C57BL/6J mice, aging increased hepatic inflammation, senescence markers p16 and p21 and Tnfa mRNA expression in liver tissue. In a second study, 4 and 24-month-old TNFα knockout and wild-type (WT) mice were compared for senescence, liver damage, intestinal barrier function, and microbiota composition. 24-month-old TNFα knockout mice were significantly protected from the aging-associated increase in hepatic senescence, inflammation and fibrosis found in WT mice.

This protection was related with preserved stem cell marker expression, maintained small intestinal barrier function and lower bacterial endotoxin in portal blood. While differing from young mice, intestinal microbiota composition of old TNFα knockout mice differed markedly from age-matched WT mice. Also, TNFα was found to alter permeability and tight junction protein levels being reversed by the presence of an JNK inhibitor in an ex vivo intestinal tissue model. Taken together, our results suggest that TNFα plays a key role in the development of aging-related liver decline in male mice.

Link: https://doi.org/10.1038/s41514-025-00326-w