Abstract Body (Do not enter title and authors here): Mosaic loss of the Y chromosome (mLOY) in leukocytes, the most common acquired mutation in aging men, has been linked to increased incidence and mortality of heart failure (HF). However, the systemic biological consequences of mLOY remain poorly defined.
Methods:
Plasma proteomic profiles of 2923 distinct proteins were correlated with mLOY burden in peripheral blood of 20645 men of the UK biobank. The gene expression signature of peripheral blood mononuclear cells (PBMCs) lacking Y chromosome encoded genes was compared to cells harboring Y chromosome by single-cell RNA sequencing in 10 men with chronic HF in order to relate mLOY-associated plasma proteins to transcriptional changes in circulating leukocytes.
Results:
Proteomic analysis identified 173 mLOY- upregulated proteins to associate with incident HF, which can be clustered into four functional categories: profibrotic mediators (e.g. WFDC2, GDF15, MSLN, TFF2), general inflammatory markers (e.g. PLAUR, CXCL17), monocyte-specific activation markers (e.g. CD300E, LILRA5), and immune modulators or immune suppressive proteins (e.g. LAMP3, TNFRSF10B, CEACAM5). Transcriptomic analyses of circulating PBMCs lacking Y chromosome-encoded genes in men with chronic HF documented the concordant upregulation of 47 genes (=27%) coding for proteins significantly associated with incident HF with signature pathway enrichment related to fibrosis, inflammation, and immune dysfunction, concordant with the proteomic plasma signature. Detailed analysis of the concordantly upregulated proteins revealed numerous genes well established in immune aging (fig.1). Therefor, using 118 proteins, we calculated a recently published and validated comprehensive plasma protein-derived biological immune age estimate, which was shown to be a robust indicator of organ age, health and mortality risk beyond gold standard clinical aging biomarkers. mLOY as continuous variable was correlated with a significantly (p<0.009) increased immune age gap. In men with mLOY > 13%, 9.8% were classified as extreme immune agers compared to 3.7% in men with mLOY < 13% (p<0.001). mLOY and immune age gap independently predicted mortality.
Conclusions: mLOY associates with proteomic and transcriptomic signatures linked to fibrosis, inflammation, and accelerated immune aging indicating that mLOY may contribute to ‘inflammaging’ and organ fibrosis, thereby playing a causal or mediating role in the increased incidence and worse prognosis of heart failure in aging men.