{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T10:28:29Z","timestamp":1786616909856,"version":"build-2736575974"},"reference-count":70,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Sirius Federal Territory","award":["IMB-BFT-2403"],"award-info":[{"award-number":["IMB-BFT-2403"]}]},{"award":["IMB-BFT-2403"],"award-info":[{"award-number":["IMB-BFT-2403"]}],"id":[{"id":"https:\/\/ror.org\/05fk5tr28","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: One of the key hallmarks of aging is the age-related decline in immune system function, accompanied by a chronic low-grade inflammation, or \u201cinflammaging\u201d. Simultaneously, a reduced capacity of immune cells to recognize and eliminate pathogens, along with immune exhaustion, is also defined as a sign of aging. Cynomolgus macaques (Macaca fascicularis) belong to a group of non-human primates evolutionarily close to humans and are often used for preclinical research. Methods: In this study, we performed mRNA sequencing of bone marrow and peripheral blood samples from young (5 years old) and old (over 19\u201321 years old) cynomolgus macaques to identify key markers of immunosenescence. Results: Although an increase in p16 expression was detected, we did not observe the increase in the senescence-associated secretory phenotype (SASP) cytokines reported in previous studies. Instead, we observed a transcriptional profile characterized by increased lymphocyte cytotoxic activity combined with a decrease in proinflammatory signaling, reduced markers of myeloid cells, and lowered sensitivity to pathogen-associated patterns. Similar changes were detected in both blood and bone marrow: decreased expression of naive T-cell markers (CCR7, LEF1, SELL, and FOXO1), reduced markers of the myeloid lineage\u2014neutrophils and monocytes (CD177, CD14, CD163, FPR1, FPR2, and CXCR1)\u2014and downregulation of genes belonging to different pattern-recognition receptor families (TLR1, TLR2, TLR4, TLR5, TLR6, TLR8, TLR10, IFIH1, CLEC4E, NOD2, NLRC4, NLRP12, NLRX1, and NAIP). In contrast, the group of old animals showed increased expression of markers associated with terminally differentiated cytotoxic lymphocytes (CD8+ T cells and NK cells): GZMB, PRF1, KLRK1, FASLG, TBX21, CCR5, and GNLY. Conclusions: Our findings offer new perspectives on the molecular mechanisms of age-associated immune dysregulation in non-human primates, serving as a baseline for selecting key candidate genes in subsequent functional investigations.<\/jats:p>","DOI":"10.3390\/genes17080944","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:31:09Z","timestamp":1786613469000},"page":"944","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Transcriptomic Markers of Immunosenescence in Cynomolgus Macaques: A Pilot Study"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-5304-7876","authenticated-orcid":false,"given":"Viktoria M.","family":"Petrova","sequence":"first","affiliation":[{"name":"Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sirius 354340, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry V.","family":"Bulgin","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena Yu.","family":"Radomskaya","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vsevolod A.","family":"Shevelov","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darya S.","family":"Zhukova","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga. P.","family":"Chzhu","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5163-8747","authenticated-orcid":false,"given":"Andrey D.","family":"Manakhov","sequence":"additional","affiliation":[{"name":"Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sirius 354340, Russia"},{"name":"Department of Genomics and Human Genetics, Vavilov Institute of General Genetics, Russian Academy of Sciences, Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander V.","family":"Popov","sequence":"additional","affiliation":[{"name":"Kurchatov Medical Primatology Center, National Research Center \u201dKurchatov Institute\u201d, Sochi 354376, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7786-1878","authenticated-orcid":false,"given":"Stanislav A.","family":"Rybtsov","sequence":"additional","affiliation":[{"name":"Research Center for Genetics and Life Sciences, Sirius University of Science and Technology, Sirius 354340, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Rosso, M.C., Badino, P., Ferrero, G., Costa, R., Cordero, F., and Steidler, S. (2016). Biologic Data of Cynomolgus Monkeys Maintained under Laboratory Conditions. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0157003"},{"key":"ref_2","unstructured":"Bluemel, J., Korte, S., Schenck, E., and Weinbauer, G.F. (2015). The Nonhuman Primate in Nonclinical Drug Development and Safety Assessment, Elsevier."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Karal-ogly, D.D., Shumeev, A.N., Keburiya, V.V., Mintel, M.V., and Rybtsov, S.A. (2023). Age-Related Changes in the Clustering of Blood Populations in Cynomolgus Monkeys Depend on Sex and Immune Status. Life, 13.","DOI":"10.3390\/life13020316"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"100047","DOI":"10.1016\/j.mocell.2024.100047","article-title":"Meta-Analysis of the Transcriptome Identifies Aberrant RNA Processing as Common Feature of Aging in Multiple Species","volume":"47","author":"Lee","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"100137","DOI":"10.1016\/j.mocell.2024.100137","article-title":"Genetic and Epigenetic Alterations in Aging and Rejuvenation of Human","volume":"47","author":"Park","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2733","DOI":"10.1016\/j.bbadis.2017.07.008","article-title":"Non-Human Primates as a Model for Aging","volume":"1864","author":"Colman","year":"2018","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fulop, T., Franceschi, C., Hirokawa, K., and Pawelec, G. (2019). Nonhuman Primate Models of Immunosenescence. Handbook of Immunosenescence, Springer International Publishing.","DOI":"10.1007\/978-3-319-99375-1"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41514-024-00158-0","article-title":"Transcriptome Analysis of Cynomolgus Macaques throughout Their Lifespan Reveals Age-Related Immune Patterns","volume":"10","author":"Cho","year":"2024","journal-title":"npj Aging"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1016\/j.immuni.2025.10.009","article-title":"Human Immune Aging","volume":"58","author":"Terekhova","year":"2025","journal-title":"Immunity"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/s41392-025-02371-z","article-title":"Immunosenescence: Signaling Pathways, Diseases and Therapeutic Targets","volume":"10","author":"Fu","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1007\/s11357-023-00962-8","article-title":"Immune Cell Composition Varies by Age, Sex and Exposure to Social Adversity in Free-Ranging Rhesus Macaques","volume":"46","author":"Rosado","year":"2023","journal-title":"GeroScience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.exger.2014.04.004","article-title":"Aged Chinese Rhesus Macaques Suffer Severe Phenotypic T- and B-Cell Aging Accompanied with Sex Differences","volume":"55","author":"Zheng","year":"2014","journal-title":"Exp. Gerontol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.smim.2012.04.005","article-title":"Changes in Primary Lymphoid Organs with Aging","volume":"24","author":"Chinn","year":"2012","journal-title":"Semin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"30842","DOI":"10.1038\/srep30842","article-title":"The Aged Lymphoid Tissue Environment Fails to Support Na\u00efve T Cell Homeostasis","volume":"6","author":"Becklund","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Egorov, E.S., Kasatskaya, S.A., Zubov, V.N., Izraelson, M., Nakonechnaya, T.O., Staroverov, D.B., Angius, A., Cucca, F., Mamedov, I.Z., and Rosati, E. (2018). The Changing Landscape of Naive T Cell Receptor Repertoire With Human Aging. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01618"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e13671","DOI":"10.1111\/acel.13671","article-title":"Age-related Thymic Involution: Mechanisms and Functional Impact","volume":"21","author":"Liang","year":"2022","journal-title":"Aging Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1073\/pnas.1617959114","article-title":"Phylogenetic Analysis of the Human Antibody Repertoire Reveals Quantitative Signatures of Immune Senescence and Aging","volume":"114","author":"Angel","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e158122","DOI":"10.1172\/JCI158122","article-title":"Longitudinal Analysis Reveals Age-Related Changes in the T Cell Receptor Repertoire of Human T Cell Subsets","volume":"132","author":"Sun","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8171","DOI":"10.1038\/s41467-024-52522-z","article-title":"Quantifiable Blood TCR Repertoire Components Associate with Immune Aging","volume":"15","author":"Hu","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"vkaf283.2616","DOI":"10.1093\/jimmun\/vkaf283.2616","article-title":"Age-Related BCR Heavy Chain Repertoire Changes in Young and Older Adults Tracked for a Decade 9178","volume":"214","author":"Skatova","year":"2025","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s41232-026-00419-3","article-title":"Senescence of T Cells and Organ Aging","volume":"46","author":"Ohyagi","year":"2026","journal-title":"Inflamm. Regen."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e12675","DOI":"10.1111\/acel.12675","article-title":"Human CD 8+ EMRA T Cells Display a Senescence-associated Secretory Phenotype Regulated by P38 MAPK","volume":"17","author":"Callender","year":"2018","journal-title":"Aging Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1111\/imr.13206","article-title":"Senescent T Cells: Beneficial and Detrimental Roles","volume":"316","author":"Laphanuwat","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1016\/j.apsb.2024.01.008","article-title":"Macrophage Senescence in Health and Diseases","volume":"14","author":"Wang","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1742-4933-2-8","article-title":"Innate Immunity and Inflammation in Ageing: A Key for Understanding Age-Related Diseases","volume":"2","author":"Licastro","year":"2005","journal-title":"Immun. Ageing"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s12016-021-08909-7","article-title":"Immunosenescence, Inflammaging, and Frailty: Role of Myeloid Cells in Age-Related Diseases","volume":"64","author":"Bleve","year":"2022","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1111\/imr.13153","article-title":"Neutrophils in Aging and Aging-related Pathologies","volume":"314","author":"Strecker","year":"2023","journal-title":"Immunol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"346","DOI":"10.1016\/j.arr.2010.10.007","article-title":"Dysregulation of Human Toll-like Receptor Function in Aging","volume":"10","author":"Shaw","year":"2011","journal-title":"Ageing Res. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1007\/s40520-018-1064-0","article-title":"Aging Leads to Dysfunctional Innate Immune Responses to TLR2 and TLR4 Agonists","volume":"31","author":"Bailey","year":"2019","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1007\/s44466-026-00040-6","article-title":"Toll-like Receptors in Innate Immunity and Inflammation: From Fundamental Biology to Clinic Insights","volume":"2","author":"Qian","year":"2026","journal-title":"Immun. Inflamm."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Agrawal, A., Agrawal, S., and Gupta, S. (2017). Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00896"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hartnell, L., Agudelo-Romero, P., Montgomery, S.T., Ben-Othman, R., Verhasselt, V., Stick, S.M., and Kollmann, T.R. (2025). What Goes up Must Come down: Dynamics of Type 1 Interferon Signaling across the Lifespan. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1654604"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1016\/S0047-6374(01)00285-8","article-title":"Neutrophil Ageing and Immunesenescence","volume":"122","author":"Lord","year":"2001","journal-title":"Mech. Ageing Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"qiaf117","DOI":"10.1093\/jleuko\/qiaf117","article-title":"The Complex Role of Neutrophils in Healthy Aging, Inflammaging, and Frailty","volume":"117","author":"Abdullah","year":"2025","journal-title":"J. Leukoc. Biol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Lysakova, E.V., Burak, M.Y., Larin, I., Chuvpilo, S.A., Laktyushkin, V.S., Shumeev, A.N., Pismennyi, I.E., Toshchakov, V.Y., Bobrov, M.Y., and Rybtsov, S.A. (2025). Stability of Myeloid Cell Phenotype and Function Across a Broad Age Range in Humans and Cynomolgus Monkeys, and a Dominant Contribution of Humoral Factors in the Control of Bacterial Infection. Biomedicines, 14.","DOI":"10.3390\/biomedicines14010071"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"The Tabula Muris Consortium, Almanzar, N., Antony, J., Baghel, A.S., Bakerman, I., Bansal, I., Barres, B.A., Beachy, P.A., Berdnik, D., and Bilen, B. (2020). A Single-Cell Transcriptomic Atlas Characterizes Ageing Tissues in the Mouse. Nature, 583, 590\u2013595.","DOI":"10.1038\/s41586-020-2496-1"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Kwon, M., Kim, B.S., Yoon, S., Oh, S.-O., and Lee, D. (2024). Hematopoietic Stem Cells and Their Niche in Bone Marrow. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25136837"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e70385","DOI":"10.1111\/acel.70385","article-title":"Aging of the Hematopoietic System: Mechanisms, Consequences, and Systemic Interactions","volume":"25","author":"Miyawaki","year":"2026","journal-title":"Aging Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e14353","DOI":"10.1002\/advs.202514353","article-title":"Single-Cell Profiling Across Immune Tissues and Organs Reveals Immunosenescence Signatures in Male Rhesus Monkeys","volume":"13","author":"Wang","year":"2026","journal-title":"Adv. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"18052","DOI":"10.3402\/pba.v2i0.18052","article-title":"Age-Dependent Changes in Innate Immune Phenotype and Function in Rhesus Macaques (Macaca mulatta)","volume":"2","author":"Asquith","year":"2012","journal-title":"Pathobiol. Aging Age Relat. Dis."},{"key":"ref_41","unstructured":"(2021). Sanitary and Epidemiological Requirements for the Maintenance of the Territories of Urban and Rural Settlements, Water Bodies, Drinking Water and Drinking Water Supply, Atmospheric Air, Soils, Residential Premises, the Operation of Industrial and Public Premises, the Organization and Implementation of Sanitary and Anti-Epidemic (Preventive) Measures (Standard No. SanPiN 2.1.3684-21)."},{"key":"ref_42","unstructured":"(2021). Hygienic Standards and Requirements for Ensuring the Safety and (or) Harmlessness of Environmental Factors for Humans (Standard No. SanPiN 1.2.3685-21)."},{"key":"ref_43","unstructured":"Andrews, S. (2026, July 08). FastQC: A Quality Control Tool for High Throughput Sequence Data, Available online: https:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Schubert, M., Lindgreen, S., and Orlando, L. (2016). AdapterRemoval v2: Rapid Adapter Trimming, Identification, and Read Merging. BMC Res. Notes, 9.","DOI":"10.1186\/s13104-016-1900-2"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1038\/s41587-019-0201-4","article-title":"Graph-Based Genome Alignment and Genotyping with HISAT2 and HISAT-Genotype","volume":"37","author":"Kim","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_47","unstructured":"Broad Institute (2026, July 08). Picard Toolkit, Available online: https:\/\/broadinstitute.github.io\/picard\/."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1038\/nprot.2009.97","article-title":"Mapping Identifiers for the Integration of Genomic Datasets with the R\/Bioconductor Package biomaRt","volume":"4","author":"Durinck","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes Among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"OMICS J. Integr. Biol."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"The Gene Ontology Consortium, Aleksander, S.A., Balhoff, J.P., Carbon, S., Cherry, J.M., Ebert, D., Feuermann, M., Gaudet, P., Harris, N.L., and Hill, D.P. (2026). The Gene Ontology Knowledgebase in 2026. Nucleic Acids Res., 54, D1779\u2013D1792.","DOI":"10.1093\/nar\/gkaf1292"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for Taxonomy-Based Analysis of Pathways and Genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_53","unstructured":"Yu, G. (enrichplot: Visualization of Functional Enrichment Result, 2026). enrichplot: Visualization of Functional Enrichment Result, Version 1.30.5."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1038\/s41467-019-09234-6","article-title":"Metascape Provides a Biologist-Oriented Resource for the Analysis of Systems-Level Datasets","volume":"10","author":"Zhou","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Wickham, H. (2009). Ggplot2: Elegant Graphics for Data Analysis, Springer.","DOI":"10.1007\/978-0-387-98141-3"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6739","DOI":"10.4049\/jimmunol.0904193","article-title":"Loss of Naive T Cells and Repertoire Constriction Predict Poor Response to Vaccination in Old Primates","volume":"184","author":"Currier","year":"2010","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Fraser, C., and Owen, B.M. (2024). Na\u00efve T-Cell Decline Is a Significant Contributor to Expression Changes in Ageing Blood. Front. Aging, 5.","DOI":"10.3389\/fragi.2024.1389789"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1093\/cei\/uxae038","article-title":"NK-like CD8 T Cell: One Potential Evolutionary Continuum between Adaptive Memory and Innate Immunity","volume":"217","author":"Wang","year":"2024","journal-title":"Clin. Exp. Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Pereira, B.I., and Akbar, A.N. (2016). Convergence of Innate and Adaptive Immunity during Human Aging. Front. Immunol., 7.","DOI":"10.3389\/fimmu.2016.00445"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2320","DOI":"10.1093\/gerona\/glaa216","article-title":"Frailty Is Associated With Neutrophil Dysfunction Which Is Correctable With Phosphoinositol-3-Kinase Inhibitors","volume":"75","author":"Wilson","year":"2020","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1016\/j.cyto.2013.01.016","article-title":"Activation Profile of CXCL8-Stimulated Neutrophils and Aging","volume":"61","author":"Dalboni","year":"2013","journal-title":"Cytokine"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1192","DOI":"10.1016\/j.humimm.2014.10.004","article-title":"Anti-Pneumococcal Deficits of Monocyte-Derived Macrophages from the Advanced-Age, Frail Elderly and Related Impairments in PI3K-AKT Signaling","volume":"75","author":"Verschoor","year":"2014","journal-title":"Hum. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e14306","DOI":"10.1111\/acel.14306","article-title":"Loss of Immune Cell Identity with Age Inferred from Large Atlases of Single Cell Transcriptomes","volume":"23","author":"Connolly","year":"2024","journal-title":"Aging Cell"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1111\/j.1474-9726.2009.00489.x","article-title":"Expression of P16INK4a in Peripheral Blood T-cells Is a Biomarker of Human Aging","volume":"8","author":"Liu","year":"2009","journal-title":"Aging Cell"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"5732","DOI":"10.21037\/tcr.2020.03.39","article-title":"P16 a Biomarker of Aging and Tolerance for Cancer Therapy","volume":"9","author":"Muss","year":"2020","journal-title":"Transl. Cancer Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"100113","DOI":"10.1016\/j.mocell.2024.100113","article-title":"The Role of P21 in Cellular Senescence and Aging-Related Diseases","volume":"47","author":"Yan","year":"2024","journal-title":"Mol. Cells"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s12979-025-00550-8","article-title":"CD8+ T Cell Heterogeneity in Aging: Insights from Single-Cell Profiling","volume":"23","author":"Filippov","year":"2025","journal-title":"Immun. Ageing"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Wensveen, F.M., Jelen\u010di\u0107, V., and Poli\u0107, B. (2018). NKG2D: A Master Regulator of Immune Cell Responsiveness. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.00441"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.coi.2019.04.013","article-title":"Granulysin: Killer Lymphocyte Safeguard against Microbes","volume":"60","author":"Dotiwala","year":"2019","journal-title":"Curr. Opin. Immunol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s00109-021-02161-4","article-title":"Aging Whole Blood Transcriptome Reveals Candidate Genes for SARS-CoV-2-Related Vascular and Immune Alterations","volume":"100","author":"Freire","year":"2022","journal-title":"J. Mol. Med."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/944\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T09:38:22Z","timestamp":1786613902000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/8\/944"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":70,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["genes17080944"],"URL":"https:\/\/doi.org\/10.3390\/genes17080944","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]}}}