Transcriptomic Markers of Immunosenescence in Cynomolgus Macaques: A Pilot Study.

One of the key hallmarks of aging is the age-related decline in immune system function, accompanied by a chronic low-grade inflammation, or "inflammaging". 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. In this study, we performed mRNA sequencing of bone marrow and peripheral blood samples from young (5 years old) and old (over 19-21 years old) cynomolgus macaques to identify key markers of immunosenescence. 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-neutrophils and monocytes (CD177, CD14, CD163, FPR1, FPR2, and CXCR1)-and 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. 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.