Menopause Hormone Replacement Therapy and Lifestyle Factors affect Metabolism and Immune System in the Serum Proteome of Aging Individuals

Aging is a fundamental risk factor for a wide array of diseases. The Berlin Aging Study II (BASE-II) is a cohort study designed to investigate the physical, mental, and social determinants of successful aging. We utilized high-throughput mass spectrometry to measure the proteomes of 1890 BASE-II participants, divided into two age groups: 27-37 years and 60-85 years. We employed multiple linear regression analyses to explore the effects of demographic factors such as age, sex, and BMI, along with hormonal treatments and lifestyle factors, on the serum proteome. We identify new associations and confirm previously described proteins linked to age, sex, BMI and hormonal contraceptive use (HCU). Notably, we observed that the abundance of nutrient transport proteins, particularly apolipoproteins, is linked to metabolic diseases in aged individuals, including metabolic syndrome and type 2 diabetes. Additionally, we identified specific alterations explained by lifestyle factors, such as smoking and alcohol consumption. We further report a significant proteome signature in female study participants corresponding to menopause hormone replacement therapy (MHT). We successfully classified these participants based on MHT status with an AUROC of 0.82 using two proteins, Complement Component 9 and Plasminogen, slightly outperforming estradiol (AUROC: 0.80), the active ingredient in most MHT preparations. Overall, our study underscores the impact of lifestyle and hormonal therapies on the serum proteome during aging, primarily affecting components of the immune system and metabolism.