HIV, pathology and epigenetic age acceleration in different human tissues

Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlate with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals. We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen and pituitary gland) from 133 clinically characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history. Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multiorgan impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that amyotrophic lateral sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues. Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.

Automated summary

Epigenetic clocks based on DNA methylation patterns are important for understanding aging and disease, but there are basic questions to be resolved in their application. This study investigates the correlation of epigenetic age acceleration (EAA) between different tissues within an individual, the association of tissue pathology and clinical illness with EAA in the target organ, and the differences in EAA variability across tissues according to sex. The findings indicate that epigenetic age is moderately correlated across tissues, with blood showing the strongest correlation with spleen and bone marrow. However, blood does not correlate with liver epigenetic age. Clinically, hypertension and HIV infection are associated with EAA in different tissues, and male sex is associated with increased epigenetic acceleration in several tissues. Furthermore, greater multimorbidity is associated with higher EAA across all tissues.