Re: “Decreased Levels of Anti-Aging Klotho in Obstructive Sleep Apnea” by Pákó et al. (Rejuvenation Res 2019 [Epub ahead of print];DOI: 10.1089/rej.2019.2183)

We read with keen interest the recent article of Pákó et al. “Decreased levels of anti-aging klotho in obstructive sleep apnoea” published in the Rejuvenation Research journal. ¹ We would like to congratulate the authors for the elegant work and to stress the great implication of such a study in the understanding of the relationship between obstructive sleep apnea (OSA) and premature aging. The authors examined the association of OSA with klotho levels, a protein with significant antiaging effects. It was reported that the levels of plasma klotho were decreased in OSA in comparison with controls, and also reduced klotho concentrations were associated with markers of overnight hypoxemia and hypertension. The authors concluded that chronic intermittent hypoxia reduces the levels of klotho in OSA that may contribute to the development of hypertension. In addition, decreased klotho levels may play a role in enhanced systemic inflammation in OSA. Considering these findings, we would like to add some comments and open for future discussion regarding the relationship between OSA and aging. ¹

Substantial literature suggests that the frequency of OSA increases with aging, with a number of studies reporting a remarkable prevalence of sleep-disordered breathing in older individuals. ² The mechanism proposed is generally attributed to impaired respiratory control with aging. They might also have a more easily collapsible airway caused by loss of collagen or a reduced arousal threshold caused by poorer quality of sleep. ³ However, the relationship between OSA and premature aging has only recently gained more attention.

The core features of OSA contribute to the exacerbation of inflammation and oxidative stress pathways. ⁴ The accumulation of damage caused by proinflammatory and reactive oxygen species (ROS) has an impact on critical aspects of aging process and contributes to physiological function impairment, increased incidence of disease, and reduction in life span. ⁵ In this sense, quantitative biomarkers of aging are valuable tools to measure physiological age, potentially predict health span, and assess the extent of the contribution of OSA in the aging process. A review conducted by Gaspar et al. gathered the literature on the association between OSA and nine hallmarks of aging, among them is telomere length. ⁶

Telomeres consist of repeated noncoding DNA TTAGG(n) sequence, located in terminal region of chromosomes. In human aging, because of the cumulative cell replication throughout lifespan, telomere length tends to diminish and to be strongly correlated with mortality risk. ⁷ However, in proliferative cells, telomeric DNA is replicated by the actions of telomerase, a specialized reverse transcriptase. The association between OSA and short telomere length in cross-sectional studies is well described in the literature. ⁸ As a speculative hypothesis, the underlying mechanism would involve the cascade of events related to intermittent hypoxia, with subsequent increased production of ROS and proinflammatory cytokines. Faced with this evidence, it is plausible to hypothesize that modulation of klotho may have a direct impact on the effect of OSA on telomere maintenance.

As mentioned by Pákó et al., klotho reduction can contribute to accelerated systemic inflammation and oxidative stress. Also, prior studies have shown that decreased levels of klotho are implicated in shortened life span, and drive much of its capacities from regulation of the telomerase activity. ⁹ Specifically, klotho deficiency diminishes telomerase activity by altering the expression of telomeric repeat-binding factor 1 (TERF1), a protein from the telomere nucleoprotein complex and telomerase reverse transcriptase, the catalytic subunit of telomerase, causing impaired differentiation potential, pluripotency, cellular senescence, and apoptosis in stem cells. ¹⁰ In this sense, it is possible that the mediation between OSA and short telomere is through klotho action.

Klotho opens a new venue in OSA research. It is a promising diagnostic marker, a prognostic marker, and a therapeutic agent. Preventing its downregulation by targeting the factors that decrease its expression, upregulation of its endogenous production or its external repletion would be applicable to prevent the consequences of short telomeres in individuals with OSA.