Microbial tryptophan (Trp) metabolites acting as aryl hydrocarbon receptor (AhR) ligands are shown to effectively improve metabolic diseases via regulating microbial community. However, the underlying mechanisms by which Trp metabolites ameliorate bone loss via gut‐bone crosstalk are largely unknown. In this study, supplementation with Trp metabolites, indole acetic acid (IAA), and indole‐3‐propionic acid (IPA), markedly ameliorate bone loss by repairing intestinal barrier integrity in ovariectomy (OVX)‐induced postmenopausal osteoporosis mice in an AhR‐dependent manner. Mechanistically, intestinal AhR activation by Trp metabolites, especially IAA, effectively repairs intestinal barrier function by stimulating Wnt/β‐catenin signaling pathway. Consequently, enhanced M2 macrophage by supplementation with IAA and IPA secrete large amount of IL‐10 that expands from intestinal lamina propria to bone marrow, thereby simultaneously promoting osteoblastogenesis and inhibiting osteoclastogenesis in vivo and in vitro. Interestingly, supplementation with Trp metabolites exhibit negligible ameliorative effects on both gut homeostasis and bone loss of OVX mice with intestinal AhR knockout (Villin ^Cre Ahr ^fl/fl ). These findings suggest that microbial Trp metabolites may be potential therapeutic candidates against osteoporosis via regulating AhR‐mediated gut‐bone axis.

Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) and poly (ADP‐ribose) polymerase 1 (PARP1) are closely linked to aging and aging‐related disorders. However, the underlying mechanisms of AHR‐PARP1 axis‐mediated DNA repair in countering aging remain largely unknown. In this study, it is found that both aged humans and mice exhibit marked intestinal aging, characterized by gut dysbiosis and dysfunction and DNA damage, compared to their young counterparts. Intriguingly, it is discovered that intestinal AHR activation by indole‐3‐acetic acid (IAA), which is derived from Lactobacillus salivarius rather than host cells, effectively mitigates intestinal aging by regulating DNA‐damage responses. Mechanistically, activated AHR by IAA interacts with PARP1, potentiating PARP1 activity and the polymerization of poly (ADP‐ribose) (PARylation) by binding to its promoter. This interaction enhances intestinal barrier function and suppresses inflammation and cell senescence. Finally, the interplay between AHR and PARP1 is confirmed by in vivo and in vitro experiments, including intestine‐specific Ahr knockout mice, Ahr and Parp1 knockdown, and Parp1 overexpression in enterocytes. These findings provide a potential intervention strategy targeting AHR‐PARP1 axis to mitigate age‐related intestinal dysfunction.

Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism have been shown to be highly associated with aging and age-related disorders. However, the underlying molecular mechanisms by which the AhR-mediated signaling pathway contributes to the aging process remain largely unknown. In this study, we find that aged Drosophila exhibits markedly reduced tryptophan metabolism leading to impaired AhR ligands, especially indole acetic acid (IAA), compared with their young controls. Supplementation with IAA, produced from Lactobacillus spp., dose-dependently extends the lifespan of Drosophila and improves healthy aging with resistance to starvation and oxidative stress. Mechanistically, activation of AhR by IAA markedly enhances Sirt2 activity by binding to its promoter, thereby inhibiting downstream TOR signaling and related fatty acid and amino acid metabolism. Both Ahr and Sirt2 mutant flies with IAA supplementation display a negligible lifespan extension, suggesting that AhR-mediated Sirt2 signaling contributes to lifespan extension in flies upon IAA supplementation. From the perspective of host metabolism, IAA supplementation significantly increases unsaturated fatty acids (UFAs) in aged flies, which are regarded to be beneficial for healthy status. These findings provide new insights into the physiological functions of AhR involved in the aging process by mediating Sirt2 signaling. IMPORTANCE: Disruption of aryl hydrocarbon receptor (AhR) signaling and aberrant tryptophan metabolism contribute to aging and age-related disorders, but the underlying molecular mechanisms are largely unknown. Using multiomics analyses combined with biochemical assays, this study reveals that AhR activation by indole acetic acid (IAA) effectively extends the lifespan accompanied by improved healthy aging in Drosophila via the AhR-Sirt2 pathway.

Mental health issues among older adults represent a major burden of disease worldwide. In China, WeChat applets have emerged as a promising tool for delivering mental health support, offering a solution to the accessibility and personalization limitations of conventional psychotherapy. However, the perceptions and needs of older adults regarding mental health WeChat applets remain unclear. To explore older adults’ perceptions and needs for mental health WeChat applets. We carried out a qualitative descriptive design. Sixteen participants were recruited from four communities in Wuhan, Hubei Province, using purposive sampling and snowball sampling. Face to face semi-structured in-depth interviews were conducted with them from January 15 to 25, 2025. Data were analysed using inductive content analysis. Three main themes were identified in this study: (1) Attitudes and perceptions, (2) Functional needs, and (3) Preferences for design and usability. Nine sub-themes were also identified. This study explored older adults’ attitudes and needs regarding mental health WeChat applets. The findings highlighted the importance of user-centered design, transparent data protection, and digital literacy support. Additionally, policy efforts should integrate mental health awareness into public health strategies and engage multiple stakeholders, including healthcare providers, community workers, policymakers, technology developers, and family members, to enhance the acceptance and effectiveness of digital mental health tools for older adults.

Background: Ceramide, acting as an important second messenger, plays a pivotal role in the induction of apoptosis in cancer cells. As one of the active prenylflavonoid ingredients in Epimedium , icariside I (GH01) has been shown to exhibit significant anticancer activity. However, the mechanism by which GH01 induces tumor cell apoptosis by targeting ceramide-orchestrated signaling remains unclear. Purpose: This study aimed to analyze the potential mechanism of GH01 for cancer therapy by generating ceramide formation in vivo and in vitro . Methods: A B16F10 melanoma-bearing mouse model was first established and treated with GH01 at different doses. Targeted quantification of ceramide was performed in vivo and in vitro using HPLC–QQQ-MS. A series of biological assays coupled with immunofluorescence staining and confocal microscope were utilized to analyze the apoptotic mechanism of tumor cells. Results: GH01 treatment markedly enhanced ceramide levels through the activation of ceramide de novo synthesis and sphingomyelin hydrolysis pathways coupled with the simultaneous suppression of sphingosine 1-phosphate generation. Consequently, high levels of ceramide promoted tumor cell apoptosis via both intrinsic and extrinsic apoptosis pathways. Notably, ceramide induced by GH01 interacted with mitochondria, thus releasing cytochrome c, which in turn activated caspase-9 and caspase-3, ultimately triggering cellular apoptosis. Additionally, the supplementation of inhibitors of caspase-3 and exogenous ceramide further confirmed the above apoptosis mechanism.