Response of Circulating Inflammatory Markers to Intermittent Hypoxia-Hyperoxia Training in Healthy Elderly People and Patients with Mild Cognitive Impairment

Abstract

Intermittent hypoxia-hyperoxia training (IHHT) is a non-pharmacological therapeutic modality for management of some chronic- and age-related pathologies, such as Alzheimer’s disease (AD). Our previous studies demonstrated significant improvement of cognitive function after IHHT in the patients with mild cognitive impairment (MCI). The present study further investigated the effects of IHHT on pro-inflammatory factors in healthy elderly individuals and patients with early signs of AD. Twenty-nine subjects (13 healthy subjects without signs of cognitive impairment syndrome and 16 patients diagnosed with MCI; age 52 to 76 years) were divided into four groups: Healthy+Sham (n = 7), Healthy+IHHT (n = 6), MCI+Sham (n = 6), and MCI+IHHT (n = 10). IHHT was carried out 5 days per week for 3 weeks (total 15 sessions), and each daily session included 4 cycles of 5-min hypoxia (12% FIO2) and 3-min hyperoxia (33% FIO2). Decline in cognitive function indices was observed initially in both MCI+Sham and MCI+IHHT groups. The sham training did not alter any of the parameters, whereas IHHT resulted in improvement in latency of cognitive evoked potentials, along with elevation in APP110, GDF15 expression, and MMP9 activity in both healthy subjects and those with MCI. Increased MMP2 activity, HMGB1, and P-selectin expression and decreased NETs formation and Aβ expression were also observed in the MCI+IHHT group. There was a negative correlation between MoCA score and the plasma GDF15 expression (R = −0.5799, p < 0.05) before the initiation of IHHT. The enhanced expression of GDF15 was also associated with longer latency of the event-related potentials P330 and N200 (R = 0.6263, p < 0.05 and R = 0.5715, p < 0.05, respectively). In conclusion, IHHT upregulated circulating levels of some inflammatory markers, which may represent potential triggers for cellular adaptive reprogramming, leading to therapeutic effects against cognitive dysfunction and neuropathological changes during progression of AD. Further investigation is needed to clarify if there is a causative relationship between the improved cognitive function and the elevated inflammatory markers following IHHT.

Effects of Intermittent Normobaric Hypoxia on Health-Related Outcomes in Healthy Older Adults: A Systematic Review

“…However, in another study [ 36 ] included in this review, no change in C-reactive protein levels was observed after an 8-week intervention of passive hypoxia. Previous studies have suggested that IH protocols could exert an anti-inflammatory and tissue-protective effects [ 68 , 69 ], notably via the suppression of pro-inflammatory mediators such as TNF-α and IL-4 [ 70 ] and contribution to the production of anti-inflammatory interleukins by B cells [ 71 ]. However, when using active IH, such as resistance training with elastic bands during a 24-week intervention [ 34 ], no additive effect on inflammatory biomarkers was observed.…”

Intermittent hypoxia conditioning as a potential prevention and treatment strategy for ischemic stroke: Current evidence and future directions

“…Intermittent hypoxia-hyperoxia (IHH) is a modified IH protocol. The normoxia period is replaced by a moderate hyperoxia period (FiO 2 = 30-40%), resulting in a faster recovery from deoxygenation (Bayer et al, 2017;Glazachev et al, 2017;Dudnik et al, 2018;Serebrovska et al, 2019cSerebrovska et al, , 2022Afina et al, 2021;Behrendt et al, 2022;Bestavashvili et al, 2022). Compared with IH, IHH offers a more obvious improvement in the clinical parameters and is considered to offer more beneficial effects (Serebrovska et al, 2019a).…”

“…Serebrovska et al (2019c) showed that IHH conditioning can improve the cognitive function of patients with mild cognitive impairment and reduces the biomarkers for Alzheimer's disease in the peripheral blood while increasing the levels of some inflammatory markers. The upregulation of inflammatory markers may be a potential trigger for cellular adaptation (Serebrovska et al, 2022), but whether these proinflammatory factors mediate the neuroprotective effects is unclear and needs to be further explored.…”

Influence of acute and chronic intermittent hypoxic-hyperoxic exposure prior to aerobic exercise on cardiovascular risk factors in geriatric patients—a randomized controlled trial

“…In order to enhance the activity of transcription factors (e.g., nuclear factor kappa B, hypoxia induced factor 1α), which augments the expression of signalling proteins (e.g., VEGF, NOs, and PGC-1α) and thus the beneficial adaptive effects of the intermittent hypoxic stimulus, it is hypothesized that normoxic periods should be replaced by moderate hyperoxia (fraction of inspired oxygen [F i O 2 ] = 0.30–0.40, termed intermittent hypoxic-hyperoxic exposure [IHHE]) ( Sazontova et al, 2012 ; Mallet et al, 2020 ; Burtscher et al, 2022 ). Previous studies have shown that IHHE is safe and well-tolerated in various clinical populations such as patients with coronary artery disease ( Glazachev et al, 2017 ), ischemic heart disease ( Tuter et al, 2018 ), mild cognitive impairment ( Serebrovska et al, 2022 ), prediabetes ( Serebrovska et al, 2019 ), comorbidities ( Dudnik et al, 2018 ), and in geriatric patients ( Bayer et al, 2017b ; Behrendt et al, 2022a ). Hence, intermittent exposure to hypoxia and hyperoxia is expected to have beneficial effects on two of the most common age-related risk factors/comorbidities (i.e., hypertension and dyslipidemia) and is well applicable in geriatric patients.…”