Wyles, Saranya

Abstract Senescent cells accumulate with age and contribute to tissue dysfunction, yet their identification in tissues is challenging due to low abundance, heterogeneous phenotypes, and the lack of specific markers. Senescence-associated features span multiple subcellular compartments, including nuclear DNA damage foci, cytosolic protein changes, and perinuclear alterations, each requiring tailored detection strategies. To overcome these challenges, we developed SenoQuant ( https://github.com/HaamsRee/senoquant ), a versatile software designed for comprehensive, accurate, and unbiased spatial quantification and prediction of senescence markers across diverse tissue contexts. Utilizing AI models, SenoQuant enables precise nuclear and cytoplasmic segmentation and detection of senescence markers across low- and high-plex imaging modalities, applicable to cultured cells and tissue sections from mice and humans. The platform also supports custom AI models; for example, we built SenCeption, a proof-of-concept predictor of single-cell p21 status from DAPI-stained nuclei in human skin. Available as a free napari plugin, SenoQuant is widely accessible to researchers. By providing a unified approach to senescence analysis and prediction, SenoQuant opens new opportunities for exploring the complex biology of senescence and its impacts on aging and disease.

BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have expanded from metabolic therapeutics to agents with broad effects on inflammation, tissue repair, cutaneous and adipose biology, and aging-related pathways. Clinicians increasingly encounter cutaneous manifestations and aesthetic sequelae with important implications for dermatologic counseling and multidisciplinary care. OBJECTIVE To review current evidence regarding GLP-1RA effects on skin biology, inflammatory dermatoses, wound healing, cutaneous adverse events, and aesthetic aging. MATERIALS AND METHODS A narrative review of clinical, translational, and mechanistic literature was performed, emphasizing psoriasis, hidradenitis suppurativa, wound repair, skin hypersensitivity reactions, autoimmune blistering disease, and facial volume loss associated with pharmacologic weight reduction. RESULTS GLP-1RAs are hypothesized to improve inflammatory skin conditions and wound repair through anti-inflammatory, immunometabolic, and proreparative pathways. Yet, their use may also be associated with injection-site reactions, hypersensitivity eruptions, rare autoimmune blistering disorders, and clinically significant facial deflation and skin laxity. Current evidence is strongest for mechanistic plausibility and observational clinical signals, whereas dermatology-specific randomized trials remain limited. CONCLUSION GLP-1RAs exert bidirectional effects on cutaneous biology. Recognition of both therapeutic opportunities and potential aesthetic or adverse sequelae is important, with patient counseling ideally occurring within a multidisciplinary framework that integrates metabolic benefits with skin health and appearance.

BACKGROUND Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert systemic metabolic and anti-inflammatory effects that may be relevant to cellular senescence, a key driver of skin aging. However, human cutaneous data are lacking. OBJECTIVE To explore whether systemic GLP-1RA therapy translates to a detectable reduction in cutaneous senescence, quantified by epidermal p21 expression and supported by AI-driven facial imaging. MATERIALS AND METHODS In this controlled observational pilot study, 3 male adults (GLP-1RA n = 2; GLP-1RA–naïve control n = 1) underwent 3-mm punch biopsies from a standardized, sun-protected gluteal site to isolate intrinsic aging. Senescence was quantified through blinded whole-epidermis digital annotation of p21-positive nuclei. Clinical phenotypes were assessed using noninvasive cheek measurements and AI-based facial age estimation. RESULTS The cohort demonstrated divergence in senescence-associated biomarkers correlating with GLP-1RA exposure. The GLP-1RA–naïve control exhibited 8.0% ( n = 2,062 nuclei) epidermal senescence. By contrast, participants with 163 and 62 days of GLP-1RA exposure showed reduced senescence burdens of 2.4% ( n = 2,045) and 0.6% ( n = 1,636), respectively. Automated facial age estimation remained concordant with chronological age across subjects. CONCLUSION Systemic GLP-1RA exposure is associated with a substantial reduction in epidermal p21 expression in some subjects, suggesting a senomorphic effect and supporting further mechanistic studies at the interface of metabolic regulation and skin aging.

Objective: Diabetes mellitus affects over 25% of adults aged 65+ in the United States and is associated with a heightened risk of developing diabetic foot ulcers. Accumulation of senescent cells within the wound microenvironment can impair cutaneous repair, and senolytic therapies offer a promising approach to accelerate wound healing. Approach: In this study, topical fisetin, a flavonoid that promotes apoptosis of senescent cells, was evaluated for its impact on diabetic wound repair. Full-thickness excisional wounds were created on the dorsal skin of diabetic (db/db) mice. Animals were randomized to receive either topical vehicle ( n = 12) or fisetin ( n = 12) for three consecutive days per week, and wound healing outcomes were longitudinally assessed. Results: Topical fisetin significantly increased the ratio of healthy dermis to granulation by day 7 ( p = 0.04) and reduced dermal fibrosis by day 21 ( p = 0.03). Fisetin decreased p16+ cells ( p = 0.01) but increased p21+ cells ( p = 0.02) at day 7 in the dermis, indicating varied effects on senescent cells. M1 macrophages (CD80+) were decreased in the fisetin-treated group ( p = 0.05) at day 21, accompanied by a decrease in pro-inflammatory senescence-associated secretory phenotype cytokines, tumor necrosis factor alpha ( p = 0.03), and interleukin-1beta ( p = 0.01) at day 7. Innovation: Fisetin is the first topical seno-modulatory agent shown to enhance wound repair when administered after injury onset. Its favorable safety and efficacy in both modulating senescence and inflammation highlight its potential as a novel therapy for diabetic wounds. Conclusion: Topical fisetin enhances diabetic wound healing by reducing fibrosis and promoting healthy dermal regeneration through senescence and inflammation modulation. Saranya Wyles, MD, PhD

Abstract Regenerative medicine is a rapidly advancing field, particularly within the field of physical medicine and rehabilitation. While orthobiologics are currently being used in clinical practice, there remains a need for high-quality clinical trials and translational research to standardize treatments and improve patient outcomes. Education is vital for streamlining development of evidence-based, practical, and effective treatments. In this article, we highlight the need for a 1-yr advanced fellowship in translational orthobiologics aiming to create a standardized core curriculum targeting physicians involved in treating musculoskeletal diseases. The fellowship’s objectives include advancing translational orthobiologics research, ethical considerations, and promoting effective communication regarding orthobiologic therapies. Such a program would serve as a foundation for physicians interested in conducting clinically oriented orthobiologics research for musculoskeletal disorders while improving the development of safe and effective therapeutics related to musculoskeletal disorders.

Background: The primary aim of this study was to demonstrate the benefits of topical human platelet exosome extract (HPE) (plated) hair serum for improving hair and scalp health in participants with self-perceived thinning hair. Methods: This single-center, placebo-controlled, double-blind study enrolled 39 healthy men and women 18–65 years of age with self-perceived thinning hair. Participants applied either HPE for 9 months or a topical placebo for 6 months with the option to cross over to HPE at 6 months for an additional 3 months. End points included improvements in the global aesthetic appearance of hair, as assessed by a blinded live evaluator; participant-reported outcomes; hair trichoscopy; and independent physician photograph evaluations. Safety data included monitoring for adverse events. Results: Blinded live evaluator assessments demonstrated statistically significant improvements in the global aesthetic appearance of hair for volume/fullness, density, scalp coverage, and appearance, with all P values less than 0.0001 within the HPE group and statistical improvement over the control at months 3 and 6 for volume/fullness, density, and scalp coverage. Participant-reported outcomes for within-group changes for HPE were statistically significant for all hair health parameters, including density, volume fullness, scalp coverage, scalp health, thickness, amount, quality, color, dryness, strength, and overall health of the hair. Hair trichoscopy analyses were significantly improved from baseline within the HPE group. Independent physician photography review demonstrated greater improvements within the HPE group. No adverse effects were observed. Conclusions: This study demonstrates that topical HPE (plated) hair serum with Renewosome technology significantly improves hair and scalp health and is safe and well tolerated.