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10 April 2026 - 08:28 AM
Arg-1 Makes Macrophages More Inflammatory, Impairing Cartilage Regeneration with Age 09 April 2026 - 06:49 PM
Cartilage tissue exhibits a relatively poor capacity for regeneration even in youth, but this capacity for maintenance and repair diminishes with age. There are thus some gains to be made in understanding why this happens and developing means of rejuvenation, but ultimately some form of regenerative medicine above and beyond natural degrees of healing will be needed in order to completely address the very prevalent joint issues that occur in later life and culminate in disabling degrees of cartilage loss and osteoarthritis. While this is widely studied, cartilage has so far proven to be a difficult tissue for the tissue engineering community to reproduce and manipulate. The load-bearing capacity and resilience necessary for its function in the body requires an accurate recreation of the complex extracellular matrix structure and cell behavior; pseudo-tissues of the sort that work well in tissue engineering for many organs are not good enough for cartilage.
Returning to the question of why cartilage tissue becomes less regenerative with age, in today's open access paper the authors turn their attention to macrophages. Macrophages of the innate immune system are present in large numbers in tissues throughout the body, and are deeply involved in the intricate processes that accompany tissue regeneration and tissue maintenance. Researchers have discovered a regulatory gene for macrophage behavior in cartilage that biases these cells towards pro-regenerative, anti-inflammatory patterns of behavior. Expression declines with age, however, and thus macrophages become increasingly inflammatory, leading to a reduced capacity for cartilage tissue maintenance and regeneration. Given the expression of this gene as a target, therapies can now be designed and tested to improve cartilage maintenance in older individuals.
Aging is a significant factor influencing the recovery capacity following cartilage injury, with notable differences observed between older and younger animals. Studies indicate that younger animals exhibit enhanced regenerative potential, including better cartilage repair and reduced inflammatory responses, compared to their older counterparts. This disparity may be attributed to age-related declines in stem cell activity, extracellular matrix synthesis, and immune function.
Macrophages play a multifaceted and context-dependent role in the pathogenesis of cartilage injury, contributing to both inflammatory progression and tissue repair. In the synovial microenvironment, macrophages exhibit remarkable plasticity, dynamically shifting between pro-inflammatory (M1-like) and anti-inflammatory (M2-like) phenotypes in response to local signals. While M1-polarized macrophages drive joint inflammation through the production of cytokines such as tumor necrosis factor-α (TNF-α), Interleukin-1β (IL-1β), and Interleukin-6 (IL-6), M2-like macrophages promote resolution of inflammation and tissue remodeling. However, this dichotomy is oversimplified, as single-cell studies reveal a spectrum of macrophage activation states in cartilage injury, with distinct subsets associated with disease severity and treatment response. Furthermore, synovial macrophages interact with fibroblasts, T cells, and osteoclasts, forming a complex cellular network that perpetuates joint destruction.
Our study employed single-cell RNA sequencing (scRNA-seq) to investigate the differential recovery capacity between young and aged animals following cartilage injury, explicitly addressing the inherent heterogeneity of immune cells within the joint. Through comprehensive profiling of joint tissues before and after injury, we aimed to identify age-dependent molecular mechanisms that govern post-injury recovery. Our analysis revealed that young animals exhibit a significantly higher proportion of anti-inflammatory macrophage subsets compared to aged counterparts, suggesting a link between specific immune cell states and enhanced tissue repair potential.
Further network analysis pinpointed Arg-1 (Arginase-1) as a central regulator within anti-inflammatory macrophages. Functional validation through in vivo and in vitro experiments demonstrated that Arg-1 overexpression inhibited inflammation and reactive oxygen species release in aged animals, partially rescuing their impaired recovery phenotype. These results not only elucidate the mechanistic basis for age-related disparities in cartilage injury recovery but also highlight Arg-1 as a novel therapeutic target to improve joint repair in elderly individuals. By integrating single-cell omics with mechanistic validation, this study provides critical insights into anti-inflammation macrophage in cartilage injury and offers a potential strategy to mitigate age-associated decline in tissue regeneration.
View the full article at FightAging
A Combination NAD+ Treatment Has Benefits for Mice 09 April 2026 - 05:02 PM
Researchers have found that simultaneously supplying NAD+ through NMN and reducing its loss through apigenin restores muscle function and bone structure to aged mice.
A well-documented issue
NAD+ is one of the most well-documented compounds in biology, including within the context of aging. Precursor supplementation has been repeatedly documented to have measurable benefits; for example, a human clinical trial found that one precursor, nicotinamide riboside (NR) reduces mortality in chronic obstructive pulmonary disorder [1], and another found that a different precursor, nicotinamide mononucleotide (NMN), restores insulin senstivity [2].
However, CD38, an enzyme that consumes NAD+, increases with age [3]. Its inhibitor, apigenin [4], has also been researched and found to have beneficial effects in various organisms.
Combining NMN and apigenin into a formulation known as N + A has been previously researched as well. In muscle precursor cells, N + A was found to fight inflammation and senescence [5]. This study builds upon that work by administering this formulation to other types of cells along with in vivo experimentation.
Restoring NAD+ restores cellular function
At first, the researchers used biopsy data from publicly available datasets to measure four types of cells: myofibers, muscle stem cells, chondrocytes, and osteoblasts. As expected, samples derived from older people had fewer muscle stem cells than samples derived from younger people did. A gene expression analysis revealed that a broad swath of genes related to NAD+ were downregulated in the older samples.
The researchers then performed their own experiment, driving three types of musculoskeletal cells senescent through oxidative stress, doxocirubin, or replication. All three approaches reduced the prevalence of NAD+ within these cells while reducing the amount of available ATP and suppressing their differentiation capabilities.
Their next experiment involved administering NMN, apigenin, or their combination to cells that had been driven senescent through oxidative stress. Individually, NMN slightly restored NAD+ in treated cells while apigenin may have restored slightly more; their combination was stronger than either individually, restoring NAD+ levels nearly to that of a control group that had never been driven senescent.
In all three cell types, senescence increased levels of the pro-inflammatory chemokine CXCL8; NMN did little to alleviate this, but apigenin reduced it, and the combination appeared to reduce it down to nearly normal levels. Both NMN and apigenin reduced levels of the DNA damage marker γ-H2ax, while their combination reduced it further in these cells. There were benefits for mitochondrial respiration as well, as the combination restored ATP synthesis and promoted proper mitochondrial membrane potential.
N + A was also found to assist in cellular differentiation. Cell precursors of cartilage, bone, and muscle tissue all had their cell-specific differentation markers upregulated by the treatment.
Broad benefits in mice
The researchers then turned to mice. With natural aging, the muscles of mice visibly shrink, and senescent cells accumulate throughout musculoskeletal tissues. Fibrosis also becomes visible, and the gaits of the animals become noticeably impaired.
According to this study, N + A administration alleviated all of these age-related issues, although not quite to the levels of young mice. More vigorous voluntary movement was restored, and the treated mice had better limb strength. Like with the cellular study, the N + A combination was found to be stronger than either compound individually.
These benefits were found to be partially dependent on the sirtuin SIRT3. Aged mice that had been genetically modified to be deficient in SIRT3 enjoyed significantly fewer benefits from taking N + A than wild-type mice did, including in senescence biomarkers, serum NAD+, and muscle strength.
N + A also provided benefits for the gut. Treated wild-type mice had more diversity in the gut microbiome. Ferroptosis, a form of cellular death caused by iron, was reduced in the gut tissues of the treated group. Furthermore, administering fecal bacteria from aged mice that had been treated with N + A was found to have benefits in untreated aged mice, similarly to fecal bacteria derived from young mice. The intestinal metabolite phytosphingosine (PHS) was found to confer some of these benefits, and the researchers hold that it deserves further study.
Of course, these experiments were only performed in cells and mice. It is not known whether administering a combination of NMN and apigenin has side effects in human beings that outweigh any benefits. However, as the researchers contend, this “increasing income and reducing expenditure” approach has “potential clinical translational value” in restoring muscle, cartilage, and bone tissue; trials on larger animals, and possibly human clinical trials, can determine if this is indeed the case.
Literature
[1] Norheim, K. L., Ben Ezra, M., Heckenbach, I., Andreasson, L. M., Eriksen, L. L., Dyhre-Petersen, N., … & Scheibye-Knudsen, M. (2024). Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial. Nature aging, 4(12), 1772-1781.
[2] Yoshino, M., Yoshino, J., Kayser, B. D., Patti, G. J., Franczyk, M. P., Mills, K. F., … & Klein, S. (2021). Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science, 372(6547), 1224-1229.
[3] Camacho-Pereira, J., Tarragó, M. G., Chini, C. C., Nin, V., Escande, C., Warner, G. M., … & Chini, E. N. (2016). CD38 dictates age-related NAD decline and mitochondrial dysfunction through an SIRT3-dependent mechanism. Cell metabolism, 23(6), 1127-1139.
[4] Escande, C., Nin, V., Price, N. L., Capellini, V., Gomes, A. P., Barbosa, M. T., … & Chini, E. N. (2013). Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome. Diabetes, 62(4), 1084-1093.
[5] Wu, J., Singh, K., Lin, A., Meadows, A. M., Wu, K., Shing, V., … & Sack, M. N. (2022). Boosting NAD+ blunts TLR4-induced type I IFN in control and systemic lupus erythematosus monocytes. The Journal of clinical investigation, 132(5).
View the article at lifespan.io
PANoptosis in the Aging of the Heart 09 April 2026 - 10:22 AM
As the understanding of more recently discovered modes of programmed cell death are fleshed out, they receive greater attention from various groups focused on specific aspects of aging. In this review the programmed cell death mechanism is PANoptosis and the area of focus is the aging of the heart. Some means of preventing overly aggressive, maladaptive programmed cell death in the context of aging have performed fairly well in animal studies, but the details matter and progress towards useful therapies is ever slow and uncertain.
As the vital power organ of the human body, the health of the heart directly determines an individual's quality of life and longevity. With the accelerating global aging population, cardiac aging-related diseases have become a major public health threat. Although existing interventions (e.g., senolytics) can delay cardiac aging to some extent, their efficacy remains limited, necessitating the exploration of novel mechanisms to develop more effective therapeutic strategies.
lytic cell death modality, integrates core molecular mechanisms of pyroptosis, apoptosis, and necroptosis into a dynamically regulated "death signaling network". As a unique programmed cell death paradigm, it transcends classical boundaries of these pathways by forming the PANoptosome complex, which orchestrates caspase family members. It may contribute to cardiac functional decline by accelerating cardiomyocyte loss, fibrosis, and chronic inflammation. Targeting PANoptosis-based intervention strategies (e.g., gene editing, RNAi, combination therapy, and novel delivery systems) has demonstrated significant therapeutic potential, offering new preclinical avenues to delay or alleviate cardiac aging. This review summarizes the molecular mechanisms and roles of PANoptosis in cardiac aging, including its regulatory networks, key evidence driving cardiac aging, and targeted intervention strategies, thereby providing a theoretical foundation for developing PANoptosis-targeted therapies against cardiac aging.
Link: https://doi.org/10.3389/fcvm.2026.1759908
View the full article at FightAging
High Dose Influenza Vaccine Correlates with Greater Reduction in Dementia Risk 09 April 2026 - 10:06 AM
Does the correlation between late life vaccination and reduced risk of neurodegenerative conditions such as Alzheimer's disease exist because vaccination produces benefits such as reduced chronic inflammation via trained immunity, or because people who undergo vaccination tend to be more diligence in all matters relating to health? Mechanistic or behavioral, or both? And if both, how much of the overall observed effect size arises from each side? Researchers here find a way to obtain more insight into this correlation, as they show that different vaccine doses correlate with different degrees of reduced dementia risk. We should not expect this to be the case unless the outcome is driven by biological mechanisms resulting from vaccination.
Previous studies, including large cohort analyses comparing vaccinated and unvaccinated adults, suggest that routine immunizations such as inactivated influenza vaccines (IIVs) may reduce Alzheimer dementia (AD) risk. Whether AD risk differs after high-dose IIV (H-IIV) vs standard-dose IIV (S-IIV) remains unexamined. We hypothesized that AD risk would be lower among adults ≥65 years after H-IIV compared with S-IIV.
This retrospective cohort study analyzed data spanning 2014-2019 from IQVIA PharMetrics Plus for Academics, a US health care claims database. Eligible participants were ≥65 years with ≥2 years of continuous medical and pharmaceutical coverage and no previous diagnostic or pharmacotherapeutic indicators of cognitive impairment. Vaccinations were identified by name and Current Procedural Terminology codes. Participants were followed for up to 3 years postvaccination. Incident AD was defined using International Classification of Diseases codes and AD medication dispenses (cholinesterase inhibitors, memantine).
The H-IIV group included 120,775 unique participants (185,183 person-trials; mean age 74.4 ± 5.5 years; 57.3% female), and the S-IIV group included 44,022 participants (53,918 person-trials; mean age 73.0 ± 6.1; 56.4% female). H-IIV was associated with significantly lower AD risk during months 1-25 postvaccination. Further research is needed to clarify whether the observed difference reflects protection against influenza infection or non-infection-related mechanisms.
Link: https://doi.org/10.1212/WNL.0000000000214782
View the full article at FightAging
