Senescence increases the risks of inflammatory bowel diseases and colon cancer. Intestinal stem cells (ISCs) in crypts differentiate into epithelial cells and thereby maintain intestinal homeostasis. However, the influence of aging on the functions of ISCs is largely unknown. The mutation rate is highest in the small and large intestines. Numerous types of naturally occurring DNA damage are removed by the DNA damage response (DDR). This response induces DNA repair and apoptosis; therefore, its dysregulation leads to accumulation of damaged DNA and consequently cellular dysfunctions, including tumorigenesis. This study investigated whether aging affects the DDR in mouse ISCs. Young (2–3-month-old) and old (> 19-month-old) Lgr5-EGFP-IRES-creERT2 mice were irradiated. The DDR in Lgr5-positive ISCs was compared between these mice by immunohistochemical analyses. Induction of DDR marker proteins (phosphorylated ATR and 53BP1), inflammatory factors (phosphorylated NF-κB and interleukin-6), and a mitochondrial biogenesis-associated gene (peroxisome proliferator-activated receptor-γ coactivator 1α) was lower in old ISCs than in young ISCs in vivo. The competence of the DDR in ISCs declines with age in vivo.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease characterized by immune dysregulation, microvascular injury, and progressive cutaneous and internal organ fibrosis. Despite advances in the understanding of SSc pathogenesis, effective disease-modifying therapies remain limited, and there is ongoing interest in targeted approaches that may modulate early inflammatory-vascular mechanisms linked to subsequent fibrotic remodeling. The IL-23/Th17 axis contributes to SSc biology, providing a rationale for IL-23p19 blockade as a potential therapeutic strategy. This focused narrative review summarizes currently available clinical signals of IL-23p19 inhibition in SSc, centered on guselkumab, and interprets reported outcomes using a domain-based framework. Published evidence remains confined to uncontrolled reports totaling 4 patients (one case report of early limited cutaneous SSc and a three-patient case series of early diffuse cutaneous SSc with comorbid psoriasis). Across these reports, investigators described improvements most consistently in the cutaneous domain (modified Rodnan skin score [mRSS], modified Rodnan total skin score [mRTSS], and the American College of Rheumatology Combined Response Index in Systemic Sclerosis [CRISS]) and in microvascular manifestations, including Raynaud’s phenomenon and nailfold microangiopathy, whereas pulmonary and gastrointestinal findings remain preliminary. We discuss key limitations of the current literature, including publication and reporting bias, the heterogeneity of phenotypes and endpoints, and confounding by comorbid psoriatic disease and natural disease fluctuation. Overall, IL-23p19 inhibition offers a pathway-specific approach in SSc, but establishing efficacy and defining responsive phenotypes requires adequately powered controlled evidence. Findings pertain specifically to guselkumab and cannot be generalized to IL-23 inhibition as a class.

Background: Aging alters the systemic steroid environment, including reductions in circulating androgens. In peripheral tissues, androgen exposure is regulated mainly by local steroid metabolism, which can activate or inactivate androgens independently of systemic concentrations. In the scalp, 5α-reductase–mediated generation of dihydrotestosterone (DHT) has been studied extensively in relation to conditions such as androgenetic alopecia. In contrast, age-related regulation of DHT-inactivating pathways, including the aldo–keto reductase family 1 member C (AKR1C) family, remains insufficiently defined. Methods: We examined AKR1C1–4 expression in scalp tissues from individuals of different ages, sexes, and hair loss conditions using immunohistochemistry (IHC), quantitative PCR (qPCR), and reanalysis of publicly available RNA-sequencing (RNA-seq) datasets. Androgen receptor (AR) localization was assessed in multiple scalp compartments. AKR1C expression was also analyzed in immortalized human sebaceous gland cells (SEB-1) and dermal papilla cells (DPCs). In addition, the effect of sulforaphane on AKR1C expression was evaluated. Results: AKR1Cs were strongly expressed in male sebaceous glands (SGs) but declined with age. AKR1C4, previously considered liver specific, was detected in SGs and hair follicles (HFs) by IHC and further confirmed by qPCR in SEB-1 cells and DPCs. AR expression was predominant in SGs, with lower levels in sweat glands, the epidermal granular layer, and the HF infundibulum, but not detected in dermal papillae and bulge regions. AR localization was cytoplasmic in the epidermis but nuclear in SGs and sweat glands, and was unaffected by age, sex, or hair loss condition. Sulforaphane treatment upregulated AKR1C expression in both SEB-1 cells and DPCs. Conclusions: We identify scalp SGs as a principal site of AR expression and AKR1C-mediated androgen inactivation, including AKR1C4, and demonstrate that AKR1C expression in SGs is sex dependent and declines with age. These findings suggest that age-associated changes in SG steroid metabolism may influence local androgen metabolism within the scalp microenvironment, with implications for HF homeostasis during aging.