Epigenetic factors and inflammaging. FOXO3A as a potential biomarker of sarcopenia and upregulation of DNMT3A and SIRT3 in older adults

Diana Bogucka ^1* Anna Wajda ¹ Barbara Stypińska ¹ Marcin Jerzy Radkowski ² Tomasz Targowski ² Ewa Modzelewska ¹ Tomasz Kmiołek ¹ Adam Ejma-Multański ¹ Gabriela Filipowicz ¹ Yana Kaliberda ¹ Ewa Dudek ¹ Agnieszka Paradowska-Gorycka ¹

• ¹ Department of Molecular Biology, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
• ² Department of Geriatrics, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland

Background: Epigenetics factors influence inflammaging and geriatrics disorders such as sarcopenia and frailty. It is necessary to develop a biomarker/ panel of biomarkers for fast and easy diagnostics. Currently, hard-to-reach equipment is required to diagnose sarcopenia. The development of a biomarker/ panel of biomarkers will prevent many older adults from being excluded from the diagnostic process. Methods: In this project, we analyzed selected gene expression profiles: SIRT1, SIRT3, SIRT6, DNMT3A, FOXO1, FOXO3A and ELAVL1 in whole blood. The study included 168 subjects divided into 5 groups: patients hospitalized at the Geriatrics Clinic and Polyclinic with sarcopenia, frailty syndrome, or without those disorders (geriatric control) and non-hospitalized healthy controls (HC) in age 25-30 and over 50.Results: We revealed a lower mRNA level of FOXO3A (p<0.001) in sarcopenic patients compared to geriatric controls. Furthermore, we detected upregulation of DNMT3A (p=0.003) and SIRT3 (p=0.015) in HC over 50 years old compared to HC 25-30. Interestingly, we observed 2 clusters formation during gene expression correlation analysis (SIRT1, SIRT3, DNMT3A and FOXO1, ELAVL1). We also noted correlations of clinical parameters with mRNA levels in the sarcopenic patients group, such as vitamin D level with SIRT1 (r=0.64, p=0.010), creatine kinase with SIRT3 (r=–0.58, p=0.032) and DNMT3A (r=–0.59, p=0.026), creatinine with DNMT3A (r=0.57, p=0.026), erythrocyte sedimentation rate (ESR) with FOXO3A (r=0.69, p=0.004), lactate dehydrogenase (LDH) with FOXO3A (r=–0.86, p=0.007). In the frailty syndrome group, we noted a correlation of appendicular skeletal muscle mass (ASMM) with ELAVL1 (r=0.59, p=0.026) mRNA level. In geriatric control, we observed a correlation of serum iron with FOXO3A mRNA level (r=–0.79, p=0.036).Conclusions: Our study revealed FOXO3A as a potential biomarker of sarcopenia. Furthermore, we observed high expression of epigenetic factors (DNMT3A and SIRT3) in older adults.