{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:31:01Z","timestamp":1787646661738,"version":"build-2736575974"},"reference-count":49,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ilikia Brasil"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>Background\/Objectives: Calcium hydroxylapatite (CaHA) is widely used in aesthetic medicine as a biostimulatory dermal filler. While its ability to induce neocollagenesis is well established, its broader transcript-level effects on fibroblast biology under aging-like conditions remain incompletely characterized. This study aimed to compare the gene-expression responses induced by three commercially available CaHA formulations in an EX-527-induced aging-like human dermal fibroblast model. Methods: An aging-like fibroblast phenotype was induced in primary human dermal fibroblasts using the SIRT1 inhibitor EX-527, which was maintained in culture throughout the CaHA treatment period. Cells were exposed to three commercially available CaHA formulations (D, R, S) for 72 h. Gene expression was assessed by RT-qPCR, evaluating markers related to extracellular matrix remodeling, Ki67 expression, inflammatory and regulatory cytokine signaling, mitochondrial stress response and energy metabolism, and longevity-associated genes. Results: All CaHA formulations induced upregulation of COL1A1 and Ki67, with greater responses observed in samples S and R. ELN expression was more selectively increased, particularly in sample S. Distinct cytokine gene-expression profiles were observed, with sample D associated with increased TNF-\u03b1 expression, while samples R and S demonstrated reduced TNF-\u03b1 and increased IL-10 expression. Genes associated with mitochondrial stress response and energy metabolism, including PGC-1\u03b1, SOD2, and PINK1, were upregulated across groups, with the highest induction generally observed in sample S. FOXO3, SIRT1, and SIRT3 expression also increased following treatment, with sample S showing the most pronounced response for FOXO3 and SIRT3. Conclusions: These transcript-level findings suggest that CaHA exposure is associated with differential gene-expression responses involving markers related to extracellular matrix remodeling, inflammatory and regulatory signaling, mitochondrial stress response, and longevity-associated pathways. Functional and protein-level validation will be required to determine whether these transcriptional changes translate into meaningful biological effects in more complex models of aging skin.<\/jats:p>","DOI":"10.3390\/life16091400","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T08:00:48Z","timestamp":1787644848000},"page":"1400","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Modulation of Extracellular Matrix- and Longevity-Related Gene Expression by Calcium Hydroxylapatite Formulations"],"prefix":"10.3390","volume":"16","author":[{"given":"Alessandra","family":"Haddad","sequence":"first","affiliation":[{"name":"Department of Plastic Surgery, Federal University of S\u00e3o Paulo, S\u00e3o Paulo 04532-012, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-7370","authenticated-orcid":false,"given":"Maria Cl\u00e1udia Almeida","family":"Issa","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, Fluminense Federal University, Niter\u00f3i 24033-900, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-0184-6114","authenticated-orcid":false,"given":"Luiz","family":"Tonon","sequence":"additional","affiliation":[{"name":"Private Practice, S\u00e3o Paulo 04089-001, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6771-5768","authenticated-orcid":false,"given":"Beatriz","family":"Domenici de Oliveira","sequence":"additional","affiliation":[{"name":"Ilikia Brasil, S\u00e3o Paulo 01427-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibiana","family":"Franzen Matte","sequence":"additional","affiliation":[{"name":"Nucleo Vitro, Porto Alegre 91040-600, RS, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2046-9693","authenticated-orcid":false,"given":"Glaucia Maria","family":"Machado Santelli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-900, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2134-473X","authenticated-orcid":false,"given":"Renata","family":"Viana","sequence":"additional","affiliation":[{"name":"Ilikia Brasil, S\u00e3o Paulo 01427-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.1001\/archderm.138.11.1462","article-title":"Mechanisms of Photoaging and Chronological Skin Aging","volume":"138","author":"Fisher","year":"2002","journal-title":"Arch. 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