Dermal Fibroblast Senescence: The Central Hub of Skin Aging-From Intrinsic Dysfunction to Microenvironmental Remodeling.

Human skin aging, a complex process influenced by intrinsic aging and extrinsic photoaging, is marked by the accumulation of reactive oxygen species (ROS) that cause DNA damage, impaired dermal fibroblast function, and wrinkle formation. External stressors, such as ultraviolet (UV) radiation, can trigger cellular senescence. Sirtuin-1 (SIRT1), an NAD+-dependent enzyme in the sirtuin family, plays a crucial role in deacetylating p53, thereby inhibiting its nuclear translocation and reducing skin senescence. Galangin, a flavonoid found in honey and Alpinia officinarum root, has antioxidant and anti-inflammatory properties. This study investigates the protective mechanism of galangin against UVB-induced senescence in human dermal fibroblasts (HDFs) by examining its effects on SIRT1 and its target, acetylated-p53. An in vitro model of UVB-induced senescence using HDFs and an in vivo model using nude mice were employed to assess the dermal protective effects of galangin. The results demonstrate that while UVB exposure does not decrease SIRT1 protein levels, it impairs its enzymatic function. However, galangin treatment counteracts these adverse effects. Additionally, UVB exposure significantly reduces cell viability and upregulates senescence markers like p16, p21, and p53 nuclear transactivation. An increase in senescence-associated β-galactosidase (SA-β-gal) positive cells was observed in UVB-exposed dermal fibroblasts. Galangin treatment mitigates UVB-induced cellular senescence by enhancing SIRT1-mediated p53 deacetylation, thereby inhibiting nuclear translocation and reducing dermal senescence. These findings suggest that galangin is a promising agent for alleviating UVB-induced skin aging and could be a potential component in antiaging cosmetic formulations.

Cellular senescence plays a crucial role in skin aging, with senescent dermal fibroblasts contributing to reduced skin elasticity and increased inflammation. This study investigated the potential of Ganoderma lucidum (Reishi) ethanol extract to modulate the senescent phenotype of human dermal fibroblasts. Reishi powder of two different vendors was used. The extract was produced by extracting the Reishi powder for at least three weeks in 40% ethanol at room temperature. Etoposide-induced senescent fibroblasts were treated with Reishi extracts from two commercial sources for 14 days. Gene expression analysis was performed using qPCR to assess senescence makers, antioxidant defense, and extracellular matrix remodeling. Results showed that Reishi extracts significantly upregulated antioxidant and cytoprotective genes, including Heme oxygenase 1 (HO-1), γ-Glutamylcysteine synthetase (γGCS-L), and NAD(P)H dehydrogenase [quinone] 1 (NQO1), compared to untreated controls. Importantly, Reishi treatment suppressed the expression of p16INK4a, a key marker of cellular senescence, while transiently upregulating p21Cip1. The extracts also demonstrated potential senolytic properties, reducing the percentage of senescent cells as measured by senescence-associated β-galactosidase staining. However, Reishi treatment did not mitigate the upregulation of MMP1 and IL-8 in one Reishi treatment group, indicating differences in the preparations of different vendors. These findings suggest that Ganoderma lucidum extract may help alleviate some aspects of cellular senescence in dermal fibroblasts, primarily through enhanced antioxidant defense and cytoprotection, potentially offering a novel approach to combat skin aging.

Metformin loaded cholesterol-lysine conjugate nanoparticles: A novel approach for protecting HDFs against UVB-induced senescence.

This study aims to explore the plastic changes in cell lineages during the progression of osteoarthritis (OA) and their relationship with dysregulation of signaling pathways and provide new molecular targets for precise treatment. Single-cell RNA sequencing (scRNA-seq) technology was utilized to perform high-resolution cell lineage analysis of OA patients. The mappings of distinct cell subpopulations were systematically constructed and revealed the changes in key cell types and their transformation trajectories throughout the progression of OA. Furthermore, KEGG and GO enrichment and pseudotime trajectory analysis were applied to elucidate the functional reprogramming of different cell types and the dynamic imbalance of their signaling networks in OA. Additionally, in vitro experiments were conducted to validate the biological functions of candidate genes in OA. Articular cartilage showed a transcriptional cellular heterogeneity in OA by scRNA-seq analysis; the annotated PreFC, FC, and PreHTC subsets accounted for the main part of OA samples. PreFC cells revealed transcription, signaling, and metabolic reprogramming in OA; pseudotime trajectory found that PreFC transformed to FC cells under the condition of hypoxia and metabolic reprogramming, while fibrosis and ECM degradation pathways showed intense upregulation in preHTC evolved from PreFC cells. HIF1A and ANGPTL4 were identified as key molecular regulators of OA progression, contributing to ECM degradation, inflammation, and apoptosis in chondrocytes, as confirmed through functional validation. The cellular trajectories of OA show significant plasticity changes which are influenced by the dysregulation of multiple signaling pathways. This research provides new insights into the pathological process of OA and offers potential targets for therapeutic strategies targeting these abnormal mechanisms.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10238-025-01947-x.

Effect of Cellular Senescence and Retinoic Acid on the Expression of Cellular Retinoic Acid Binding Proteins in Skin Fibroblasts

Dermal fibroblasts, the primary stromal cells of the dermis, exhibit remarkable plasticity in response to various stimuli, playing crucial roles in tissue homeostasis, wound healing, and ECM production. This study examines the molecular mechanisms underlying fibroblast plasticity, including key signaling pathways, epigenetic regulation, and microRNA-mediated control. The impact of aging on ECM synthesis and remodeling is discussed, and the diminished production of vital components such as collagen, elastin, and glycosaminoglycans are highlighted, alongside enhanced ECM degradation through upregulated matrix metalloproteinase activity and accumulation of advanced glycation end products. The process of cellular senescence in dermal fibroblasts is explored, with its role in skin aging and its effects on tissue homeostasis and repair capacity being highlighted. The senescence-associated secretory phenotype (SASP) is examined for its contribution to chronic inflammation and ECM disruption. This review also presents therapeutic perspectives, focusing on senolytics and geroprotectors as promising strategies to combat the negative effects of fibroblast senescence. Current challenges in translating preclinical findings to human therapies are addressed, along with future directions for research in this field. This comprehensive review explores the complex interplay between dermal fibroblast plasticity, cellular senescence, and extracellular matrix (ECM) remodeling in the context of skin aging. In conclusion, understanding the complex interplay between dermal fibroblast plasticity, cellular senescence, and extracellular matrix (ECM) remodeling is essential for developing effective anti-aging interventions, which highlights the need for further research into senolytic and geroprotective therapies to enhance skin health and longevity. This approach has shown promising results in preclinical studies, demonstrating improved skin elasticity and reduced signs of aging.

Aging is accompanied by impaired mitochondrial function and accumulation of senescent cells. Mitochondrial dysfunction contributes to senescence by increasing the levels of reactive oxygen species and compromising energy metabolism. Senescent cells secrete a senescence‐associated secretory phenotype (SASP) and stimulate chronic low‐grade inflammation, ultimately inducing inflammaging. Mitochondrial dysfunction and cellular senescence are two closely related hallmarks of aging; however, the key driver genes that link mitochondrial dysfunction and cellular senescence remain unclear. Here, we aimed to elucidate a novel role of carnitine acetyltransferase (CRAT) in the development of mitochondrial dysfunction and cellular senescence in dermal fibroblasts. Transcriptomic analysis of skin tissues from young and aged participants showed significantly decreased CRAT expression in intrinsically aged skin. CRAT downregulation in human dermal fibroblasts recapitulated mitochondrial changes in senescent cells and induced SASP secretion. Specifically, CRAT knockdown caused mitochondrial dysfunction, as indicated by increased oxidative stress, disruption of mitochondrial morphology, and a metabolic shift from oxidative phosphorylation to glycolysis. Mitochondrial damage induced the release of mitochondrial DNA into the cytosol, which activated the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) and NF‐ĸB pathways to induce SASPs. Consistently, fibroblast‐specific CRAT‐knockout mice showed increased skin aging phenotypes in vivo, including decreased cell proliferation, increased SASP expression, increased inflammation, and decreased collagen density. Our results suggest that CRAT deficiency contributes to aging by mediating mitochondrial dysfunction‐induced senescence.

Accumulation of senescent fibroblasts, chronic inflammation, and collagen remodeling due to aging-related secretory phenotypes have been hypothesized to cause age-related skin aging, which results in wrinkles and loss of skin elasticity, thus compromising appearance attractiveness. However, the rejuvenating effects of removing senescent cells from the human skin and the efficacy of related therapeutic agents remain unclear. Here, we investigated the effects of fisetin, a potential anti-aging component found in various edible fruits and vegetables, on senescent human dermal fibroblasts (HDFs) and aging human skin. Senescence was induced in primary HDFs using long-term passaging and treatment with ionizing radiation, and cell viability was assessed after treatment with fisetin and a control component. A mouse/human chimeric model was established by subcutaneously transplanting whole skin grafts from aged individuals into nude mice, which were treated intraperitoneally with fisetin or control a component for 30 d. Skin samples were obtained and subjected to senescence-associated-beta-galactosidase staining; the extent of aging was evaluated using western blotting, reverse transcription-quantitative PCR, and histological analysis. Fisetin selectively eliminated senescent dermal fibroblasts in both senescence-induced cellular models; this effect is attributable to cell death induction by caspases 3, 8, and 9-mediated endogenous and exogenous apoptosis. Fisetin-treated senescent human skin grafts showed increased collagen density and decreased senescence-associated secretory phenotypes (SASP), including matrix metalloproteinases and interleukins. No apparent adverse events were observed. Thus, fisetin could improve skin aging through selective removal of senescent dermal fibroblasts and SASP inhibition, indicating its potential as an effective novel therapeutic agent for combating skin aging.

Skin aging is a complex process that may be caused by factors that are intrinsic and extrinsic to the body. Ultraviolet (UV) radiation represents one of the main sources of skin damage over the years and characterizes a process known as photoaging. Among the changes that affect cutaneous tissue with age, the loss of elastic properties caused by changes in elastin production, increased degradation and/or processing produces a substantial impact on tissue esthetics and health. The occurrence of solar elastosis is one of the main markers of cutaneous photoaging and is characterized by disorganized and non-functional deposition of elastic fibers. The occurrence of UV radiation-induced alternative splicing of the elastin gene, which leads to inadequate synthesis of the proteins required for the correct assembly of elastic fibers, is a potential explanation for this phenomenon. Innovative studies have been fundamental for the elucidation of rarely explored photoaging mechanisms and have enabled the identification of effective therapeutic alternatives such as cosmetic products. This review addresses cutaneous photoaging and the changes that affect elastin in this process.

Introduction and aims Dermal fibroblasts play a critical role in regulating the dermal tissue layer, which is essential for providing the skin with mechanical strength. With age, the dermis atrophies and is affected by matrix regulation. Age-associated accumulation of senescence is also observed in the dermis, often as a consequence of stressors such as ultraviolet (UV)B-induced DNA damage. The pathogenicity of senescent cells is primarily linked to their deleterious secretory profile, this secretory profile requires high metabolic demands and persistent mammalian target of rapamycin complex 1 signalling at the lysosome. Therefore, expansion of the lysosomal compartment is crucial in supporting the senescent phenotype. Methods The research here characterizes the expansion and diminished health of lysosomes in an optimized UVB-induced senescence model in dermal human fibroblast. Specifically, flow cytometry and the use of fluorogenic substrates have been employed to demonstrate the diminished functionality of lysosomes in UVB-induced senescence. Results Biochemical analyses further identify enhanced lysosomal exocytosis in senescent cells, further exemplifying lysosomal dysfunction as part of the senescence programme. Conclusions It is hoped that collectively these data will emphasize the underappreciated role of lysosomal dysfunction in UVB-induced senescence, and postulate this dysfunction as a key player in the pathogenicity of senescence.

Aging is a multifactorial process that affects skin integrity through the progressive decline of dermal fibroblast function. Dermal fibroblasts are key regulators of extracellular matrix (ECM) composition, wound healing, and tissue homeostasis. However, their dysfunction contributes to structural deterioration, chronic inflammation, and impaired regenerative capacity. Cellular senescence, a fundamental characteristic of aging, results in the buildup of senescent fibroblasts that release growth factors, matrix-degrading enzymes, and pro-inflammatory cytokines, known as the senescence-associated secretory phenotype (SASP). This study examines the impact of fibroblast senescence on dermal aging, highlighting mechanisms such as DNA damage, mitochondrial dysfunction, oxidative stress, and telomere attrition. The role of SASP-driven ECM degradation, matrix metalloproteinases (MMPs) activation, and fibroblast-keratinocyte communication breakdown are explored, demonstrating their collective contribution to skin aging. Additionally, key signaling pathways, including p16INK4a/RB, p53, NF-κB, mTOR, and TGF-β, are implicated in fibroblast senescence and chronic inflammation. Recent advancements in therapeutic strategies targeting fibroblast aging, such as senolytics, extracellular vesicle-based interventions, and metabolic reprogramming, offer promising avenues for skin rejuvenation. This review delves into the molecular and cellular dynamics of dermal fibroblast aging, emphasizing their relevance for developing novel anti-aging interventions.

Integrin α11β1 as a Key Collagen Receptor in Human Skin Dermis: Insight into Fibroblast Function and Skin Dermal Aging.

246 Narcissus tazetta bulb extract delays cellular senescence by reducing mTOR pathway activation

Multiple myeloma (MM) is a hematologic disorder of B lymphocytes characterized by the accumulation of malignant plasma cells (PCs) in the bone marrow. The altered plasma cells overproduce abnormal monoclonal immunoglobulins and also stimulate osteoclasts. The host’s immune system and microenvironment are of paramount importance in the growth of PCs and, thus, in the pathogenesis of the disease. The interaction of MM cells with the bone marrow (BM) microenvironment through soluble factors and cell adhesion molecules causes pathogenesis of the disease through activation of multiple signaling pathways, including NF-κβ, PI3K/AKT and JAK/STAT. These activated pathways play a critical role in the inhibition of apoptosis, sustained proliferation, survival and migration of MM cells. Besides, these pathways also participate in developing resistance against the chemotherapeutic drugs in MM. The imbalance between inflammatory and anti-inflammatory cytokines in MM leads to an increased level of pro-inflammatory cytokines, which in turn play a significant role in dysregulation of signaling pathways and proliferation of MM cells; however, the association appears to be inadequate and needs more research. In this review, we are highlighting the recent findings on the roles of various cytokines and growth factors in the pathogenesis of MM and the potential therapeutic utility of aberrantly activated signaling pathways to manage the MM disease.

373 Effect of Haritaki fruit extract on Senescence Associated Secretory Phenotype and miR 30a-3p over-expression in senescent dermal fibroblasts’ extracellular vesicles