Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease
Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, t...
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Elsevier
2025-07-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747925000698 |
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| author | Valentina R. Garbarino Juan Pablo Palavicini Justin Melendez Nicolas R. Barthelemy Yingxin He Tiffany F. Kautz Marisa Lopez-Cruzan Julia J. Mathews Peng Xu Bin Zhang Afaf Saliba Nagarjunachary Ragi Kumar Sharma Dallin Mason Samuel Johnson Suzanne Hendrix Suzanne Craft Ronald C. Petersen Jair Machado Espindola-Netto Ailing Xue Tamara Tchkonia James L. Kirkland Arash Salardini Nicolas Musi Randall J. Bateman Mitzi M. Gonzales Miranda E. Orr |
| author_facet | Valentina R. Garbarino Juan Pablo Palavicini Justin Melendez Nicolas R. Barthelemy Yingxin He Tiffany F. Kautz Marisa Lopez-Cruzan Julia J. Mathews Peng Xu Bin Zhang Afaf Saliba Nagarjunachary Ragi Kumar Sharma Dallin Mason Samuel Johnson Suzanne Hendrix Suzanne Craft Ronald C. Petersen Jair Machado Espindola-Netto Ailing Xue Tamara Tchkonia James L. Kirkland Arash Salardini Nicolas Musi Randall J. Bateman Mitzi M. Gonzales Miranda E. Orr |
| author_sort | Valentina R. Garbarino |
| collection | DOAJ |
| description | Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D + Q), in older adults (N = 5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability. Herein, we present exploratory analyses of senescence and AD-associated analytes in blood, cerebrospinal fluid (CSF) and urine from this study in effort to guide biomarker development for future senolytic trials. Immunoassays, mass spectrometry and transcriptomics were performed and changes in analyte levels were assessed from baseline to post-treatment using paired t-tests. Targeted cytokine and chemokine analyses revealed increases in plasma fractalkine and MMP-7 and CSF IL-6 from baseline to post-treatment. Mass spectrometry indicated stable levels of amyloid β and tau proteins in CSF, unchanged urinary metabolites, and modest treatment-associated lipid profile changes. Targeted transcriptomic analysis of peripheral blood mononuclear cells indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. The levels and treatment responses of the analytes identified here may help inform trial design and outcomes for senolytic studies. Independent validation will be necessary to develop standardized biomarker panels across senolytic trials for AD.ClinicalTrials.gov: NCT04063124. |
| format | Article |
| id | doaj-art-565aa2cb05da4e998b6de5ab9519d719 |
| institution | Kabale University |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-565aa2cb05da4e998b6de5ab9519d7192025-08-20T04:01:57ZengElsevierNeurotherapeutics1878-74792025-07-01224e0059110.1016/j.neurot.2025.e00591Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s diseaseValentina R. Garbarino0Juan Pablo Palavicini1Justin Melendez2Nicolas R. Barthelemy3Yingxin He4Tiffany F. Kautz5Marisa Lopez-Cruzan6Julia J. Mathews7Peng Xu8Bin Zhang9Afaf Saliba10Nagarjunachary Ragi11Kumar Sharma12Dallin Mason13Samuel Johnson14Suzanne Hendrix15Suzanne Craft16Ronald C. Petersen17Jair Machado Espindola-Netto18Ailing Xue19Tamara Tchkonia20James L. Kirkland21Arash Salardini22Nicolas Musi23Randall J. Bateman24Mitzi M. Gonzales25Miranda E. Orr26Glenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Cell Systems and Anatomy, University of Texas Health Science Center at San Antonio, San Antonio, TX, USADepartment of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USADepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, USADepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, USADepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, USAGlenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USABarshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, USA; Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USAGlenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Mount Sinai Center for Transformative Disease Modeling, Icahn School of Medicine at Mount Sinai, New York, NY, USACenter for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USACenter for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USACenter for Precision Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, USAPentara Corporation, Salt Lake City, UT, USAPentara Corporation, Salt Lake City, UT, USAPentara Corporation, Salt Lake City, UT, USADepartment of Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USADepartment of Neurology, Mayo Clinic, Rochester, MN, USADepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USADepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USADepartment of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USADepartment of Internal Medicine, Mayo Clinic, Rochester, MN, USAGlenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Neurology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USADepartment of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USADepartment of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, USAGlenn Biggs Institute for Alzheimer’s & Neurodegenerative Diseases, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; Department of Neurology, Cedars Sinai Medical Center, Los Angeles, CA, USA; Corresponding authors.Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA; Tracy Family SILQ Center for Neurodegenerative Biology, St. Louis, MO, USA; St Louis VA Medical Center, St Louis, MO, USA; Corresponding authors.Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials focused on cellular senescence are in early stages and have yet to establish reliable outcome measures reflecting senescent cell burden or response to senolytics, therapeutics that clear senescent cells. Results from the first open-label trial of senolytics, dasatinib plus quercetin (D + Q), in older adults (N = 5) with early AD demonstrated central nervous system penetration of dasatinib and favorable safety and tolerability. Herein, we present exploratory analyses of senescence and AD-associated analytes in blood, cerebrospinal fluid (CSF) and urine from this study in effort to guide biomarker development for future senolytic trials. Immunoassays, mass spectrometry and transcriptomics were performed and changes in analyte levels were assessed from baseline to post-treatment using paired t-tests. Targeted cytokine and chemokine analyses revealed increases in plasma fractalkine and MMP-7 and CSF IL-6 from baseline to post-treatment. Mass spectrometry indicated stable levels of amyloid β and tau proteins in CSF, unchanged urinary metabolites, and modest treatment-associated lipid profile changes. Targeted transcriptomic analysis of peripheral blood mononuclear cells indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. The levels and treatment responses of the analytes identified here may help inform trial design and outcomes for senolytic studies. Independent validation will be necessary to develop standardized biomarker panels across senolytic trials for AD.ClinicalTrials.gov: NCT04063124.http://www.sciencedirect.com/science/article/pii/S1878747925000698Alzheimer’s diseaseSenolyticsClinical trialBiofluidsBiomarkers |
| spellingShingle | Valentina R. Garbarino Juan Pablo Palavicini Justin Melendez Nicolas R. Barthelemy Yingxin He Tiffany F. Kautz Marisa Lopez-Cruzan Julia J. Mathews Peng Xu Bin Zhang Afaf Saliba Nagarjunachary Ragi Kumar Sharma Dallin Mason Samuel Johnson Suzanne Hendrix Suzanne Craft Ronald C. Petersen Jair Machado Espindola-Netto Ailing Xue Tamara Tchkonia James L. Kirkland Arash Salardini Nicolas Musi Randall J. Bateman Mitzi M. Gonzales Miranda E. Orr Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease Neurotherapeutics Alzheimer’s disease Senolytics Clinical trial Biofluids Biomarkers |
| title | Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease |
| title_full | Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease |
| title_fullStr | Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease |
| title_full_unstemmed | Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease |
| title_short | Evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild Alzheimer’s disease |
| title_sort | evaluation of exploratory fluid biomarkers from a phase 1 senolytic trial in mild alzheimer s disease |
| topic | Alzheimer’s disease Senolytics Clinical trial Biofluids Biomarkers |
| url | http://www.sciencedirect.com/science/article/pii/S1878747925000698 |
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