Age-Dependent Systemic Effects of a Systemic Intermittent Hypoxic Therapy <i>In Vivo</i>

Introduction: The adaptive response to systemic intermittent hypoxic therapy (SIHT) may be used for therapeutic advances due to the activation of multiple pathways involved in angiogenesis, immunomodulation, and tissue homeostasis. The aim of this study was to investigate the early age-dependent systemic response of different exposures of SIHT in mice.

Materials and Methods: Sixty-four C57BL/6NRj female mice in three different age groups, young (4–5 weeks), adolescent (8–10 weeks), and adults (23–32 weeks), were exposed to SIHT. Different algorithms for equal hypoxic challenges (oxygen-decrease*time) were investigated to allow examination of the role of absolute hypoxia (oxygen-decrease) compared with relative hypoxia (total oxygen depletion over time). The systemic effects of angiogenetic regulation were investigated using blood samples analyzed by ELISA, proteome profiles, and proximity extension immunoassay. One-way analysis of variance with post hoc Bonferroni analyses was performed.

Results: The early systemic response to SIHT was dependent on the absolute hypoxia rather than relative hypoxia over time. Serum erythropoietin (EPO) levels were increased significantly in young mice receiving low-oxygen SIHT treatments (10% and 15% oxygen). The expression of angiogenic proteins differed between the different age groups indicating an age-dependent response to SIHT. Focusing on hypoxia-inducible factor-1 (HIF-1) signaling, there was a trend toward upregulated angiogenetic response with younger age. Furthermore, clustering of protein expression in low-oxygen SIHT algorithms were found between young and adolescent mice. In adult mice, the majority of the proteins were downregulated as a response to SIHT. The systemic response of metabolites expressions was most pronounced in young mice. Systemic levels of cardiac troponin I (Tnni3) was unaffected by SIHT independent of age groups.

Conclusions: The systemic response to SIHT is dependent on the absolute hypoxic exposure rather than the relative hypoxic depletion over time. Age-dependent effects of a short-term SIHT were associated with an increase in EPO, upregulation of angiogenetic pathways, and select metabolic and cell-surface proteins.