No altitude required: differential ventilatory and blood acid-base homeostasis between unacclimatized lowlanders and Tibetan highlanders at 1,400 m

Tibetan highlanders (TH) possess physiological adaptations supporting ventilation, oxygenation, and acid-base regulation with acclimatization to chronic hypobaric hypoxia. Although well-characterized at high altitude, it is unclear whether these traits are evident at low altitude, independent of environmental hypoxic stimuli. To evaluate baseline physiological differences, we compared variables related to ventilatory, blood oxygen, and acid-base balance between unacclimatized ancestral lowlanders (LL; <i>n</i> = 29) and TH (<i>n</i> = 31) residing at 1,400 m, a subthreshold altitude not expected to elicit ventilatory or renal acclimatization. Heated hand capillary blood samples were analyzed for hemoglobin ([Hb]_c), oxygen content (C_cO₂), alveolar ventilation (V̇_A), steady-state chemoreflex drive (SSCD), partial pressure of carbon dioxide (P_cCO₂), bicarbonate ([HCO₃^-]_c), and pH_c. TH demonstrated significantly higher V̇_A (4.6 ± 0.4 vs. 4.8 ± 0.3 L/min; +5.2%; <i>P</i> = 0.0101) and SSCD (11.9 ± 1.9 vs. 13.2 ± 1.9 arbitrary units; +10.3%; <i>P</i> = 0.0127) than LL, despite equivalent [Formula: see text] (<i>P</i> = 0.8882). In addition, TH exhibited lower P_cCO₂ (37.9 ± 2.8 vs. 36.0 ± 2.5 mmHg; -5%; <i>P</i> = 0.0086) and [HCO₃^-]_c (22.9 ± 1.4 vs. 21.5 ± 1.6 mmol/L; -6.1%; <i>P</i> = 0.0007) compared with LL, with no difference in pH_c (<i>P</i> = 0.256). The reduction of [HCO₃^-]_c in TH was greater than expected from passive chemical buffering alone, suggesting differential renal handling while breathing ambient air at low altitude. These findings suggest that TH maintain a distinct ventilatory and acid-base homeostatic set point at low altitude, characterized by augmented resting ventilatory drive and renal excretion of HCO₃^-. These traits, characterized at low altitude, suggest that developmental exposure to hypoxia and/or Tibetan ancestry is associated with developed or evolved physiological traits that optimize respiratory and acid-base homeostasis prior to and/or during high-altitude ascent.<b>NEW & NOTEWORTHY</b> Understanding the role of ancestry in the regulation of ventilatory and renal homeostasis is key to interpreting high-altitude acclimatization and adaptation. We compared unacclimatized lowlanders (LL) and Tibetan highlanders (TH; Sherpa) at 1,400 m. TH had significantly lower Pco₂ and [HCO₃^-], suggesting a distinct respiratory and blood acid-base set point. These results highlight intrinsic respiratory and renal integration in TH, revealing population-level physiological differences independent of hypoxic stress, likely shaped by developmental or genetic adaptation.