Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies

Nan, Li; Guo, Pengchao; Hui, Wang; Xia, Fang; Yi, Chenggang

doi:10.3389/fphar.2025.1592596

Cited by 84Telomeres, Telomerase, and SenescenceSkin Protection and AgingTGF-β signaling in diseases

Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies

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Nan, Li, Guo, Pengchao, Hui, Wang, Xia, Fang, Yi, Chenggang·2025·Frontiers in Pharmacology

DOI 10.3389/fphar.2025.1592596PMC PMC12213903

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Abstract

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.

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Chronic exposure to UVB radiation induces inflammation-mediated skin aging by upregulating pro-inflammatory cytokines such as TNF-α and IL-6, which accelerate matrix degradation and impair skin homeostasis.
“Chronic exposure to UVB radiation induces inflammation-mediated skin aging by upregulating pro-inflammatory cytokines such as TNF-α and IL-6, which accelerate matrix degradation and impair skin homeostasis [33].”
From Oral Centella asiatica Extract Attenuates UVB-Induced Skin Photoaging via Antioxidant, Anti-Inflammatory, and Extracellular Matrix-Preserving Effects in Hairless Mice (2025) · cites this paper as [33]
Section 3.4 identifies TNF-α and IL-6 as inflammatory cytokines in aging skin and links senescent-fibroblast secretions to extracellular-matrix degradation and tissue dysfunction. It also reports a pro-inflammatory response in UVB-induced fibroblast models, while section 3.2 links chronic UV exposure to matrix degradation. The copy does not establish the claim’s specific sequence that chronic UVB exposure upregulates TNF-α and IL-6, which then impair skin homeostasis. (LLM, conf=0.85)
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Liu, J., Yu, H., Tian, Y., & Liu, N. (2024) · Springer eBooks · doi:10.1007/978-981-97-5536-3_14 · Cited by 2 · see citing works

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Inflammaging: triggers, molecular mechanisms, immunological consequences, sex differences, and cutaneous manifestations
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“Chronic exposure to UVB radiation induces inflammation-mediated skin aging by upregulating pro-inflammatory cytokines such as TNF-α and IL-6, which accelerate matrix degradation and impair skin homeostasis [33].”
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Adipocytes as core drivers of skin aging and novel targets for regeneration
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Expression and identification of a novel high-activity recombinant humanized type I collagen SynthCol1 in Pichia pastoris GS115
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Inflammaging and Senescence-Associated Secretory Phenotype (SASP) in Psoriasis – A Narrative Review of Potential Mechanisms and Anti-Inflammaging Strategies
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Multifunctional sericin-based biomaterials for wound healing: Cellular mechanisms and advanced therapeutic strategies
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Advanced Functional Wound Dressings in Precision Surgery: Immunometabolic Reprogramming, Bioadaptive Biomaterials, and Intelligent Regenerative Interfaces
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Skin Anti-Aging Potential of the Traditional Thai Longevity Formula Mai-Kae-Den-Klong: Integrative Insights from Network Pharmacology, Molecular Docking, and in Vitro AssaysPreprint
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The First Simplified Heparan Sulphate—Alginate Hybrid Trisaccharides: Synthesis and Biological Effects on Human Dermal Fibroblasts
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Geroprotective effect of Apigenin against skin senescence induced by an acute dose of gamma rays in male rats is associated with p-AMPK mediated autophagic flux
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Decoding Skin Aging Through Transcriptomic Clocks: Gene Expression Signatures, Associated Pathways, and Explainable AI
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Senescent tenocytes drive an age-associated loss of cell-extracellular matrix homeostasis, which can be partially restored using dihydroresveratrolPreprint
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Authors: Nan, L., Guo, P., Hui, W., Xia, F., & Yi, C.
Affiliations: Second Affiliated Hospital of Zhejiang University (CN)
Corresponding author: Yi, Chenggang
ORCID: Yi, Chenggang
Venue: Frontiers in Pharmacology
Publisher: Frontiers Media SA
Published: 2025-06-18
Volume: 16
Pages: 1592596-1592596
ISSN: 1663-9812 (ISSN-L)
DOI: 10.3389/fphar.2025.1592596
PMC: PMC12213903
OpenAlex: W4411394747
Cited by: 84
References: 172
Citations by year: 2026: 68 · 2025: 16
FWCI: 10.99
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Frontiers in Pharmacology (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics: Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
Health Sciences › Medicine › Dermatology › Skin Protection and Aging
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
Keywords: dermal fibroblasts, cellular senescence, skin aging, senescence-associated secretory phenotype, extracellular matrix degradation, matrix metalloproteinases, chronic inflammation, DNA damage, mitochondrial dysfunction, oxidative stress, telomere shortening, p53, NF-κB, mTOR, TGF-beta, senolytics, extracellular vesicles, metabolic reprogramming, anti-aging therapy

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Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies

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