Cardiopulmonary exercise testing was performed using a stationary bicycle (StrengthErgo 8; Mitsubishi Electric Engineering, Tokyo, Japan) and a breath-by-breath gas analyzer (AE-300S; Minato Ikagaku Co., Tokyo, Japan). Symptomatic maximal exercise was performed using a ramp protocol of 5–30 watts (W)/min according to age and condition after 2–3 min rest and warm-up of 0–10 W lasting 2–3 min. Rating of perceived exertion (RPE) at the end of the exercise was assessed using the Borg scale (Beaver et al., 1986a; Takano, 2000; Dekerle et al., 2003; Balady et al., 2010; Lenti et al., 2011; Wasserman et al., 2012; Yen et al., 2015, 2018; Nishijima et al., 2017, 2019; Keir et al., 2018; Korkmaz Eryılmaz et al., 2018; Carriere et al., 2019; Iannetta et al., 2019; Nakade et al., 2019).

Data are presented as the mean ± standard deviation. Statistical analyses were performed using Statistics for Excel 2012 (Social Survey Research Information Co., Tokyo, Japan). Student’s t-test was used for comparisons between the two groups. Pearson’s correlation coefficient was used to determine the correlation between age and each parameter, and the lowering rate with age was calculated from the regression coefficient of the regression line. The 95% confidence intervals and prediction intervals were also calculated for the relationship between age and RCP/VAT, ΔVO₂/weight RCP-VAT, VAT VO₂/weight, and RCP VO₂/weight. The significance level was set at 5%.

This research was conducted in accordance with the code of ethics of Sapporo Ryokuai Hospital and with due consideration for the protection of the participants’ personal information. Informed consent was obtained from all participants for their participation in the study and for publication of this report. The data obtained were de-linked and anonymized, and this study was conducted using the data for analysis. The authors confirmed that all participants could not be identified and that they were fully anonymized. Furthermore, the authors affirm that all mandatory health and safety procedures were complied within the course of conducting any experimental work reported in this paper.

Each parameter in the CPET is listed in Table 2. Compared with the younger group, the older group showed significantly lower values of VAT and RCP VO₂ (p < 0.001, respectively). Moreover, PetCO₂ was significantly lower in the elderly group, and the VE/VCO₂ slope was significantly higher (p < 0.001, respectively).

Furthermore, both ΔVO₂/weight RCP-VAT and RCP/VAT showed a significant correlation with Peak VO₂ (r = 0.629, p < 0.001 and r = 0.217, p = 0.017, respectively).

There was no significant difference in RCP/VAT between the younger and older groups (Table 2 and Figure 2). The coefficient of the linear regression equation was −0.0031, and the annual rate of decline was 0.185%, indicating that the effect of aging was not significant. ΔVO₂/weight RCP-VAT was significantly lower in the older group, and age-related changes showed moderate negative correlation. The coefficient of the linear regression equation was −0.1303, and the annual rate of decline was 0.914%, indicating a significant effect of age-related changes.

In this study, the decrease in VAT and RCP VO₂/weight was −8.8 and −16.2 ml/min/year (−0.118 and −0.242 ml/kg/min/year, 0.627 and 0.722%/year), respectively, which was comparable to that reported in previous studies (Itoh et al., 2013). Similarly, the ΔVO₂/weight RCP-VAT decreased with age. VAT is detected in CPET by the excretion of carbon dioxide in the exhaled air due to the buffering of lactate, which is produced by increased glycolysis associated with increased exercise intensity. The presence of increased lactate in the blood and carbon dioxide excretion in the exhaled air is well correlated, though there is a time delay. This association is derived from the proportion of slow-twitch fibers in skeletal muscle and CO₂ storage in vivo (Ivy et al., 1980). The RCP is the period from the VAT through the IB phase to the onset of respiratory compensation. The buffering capacity of CO₂/H⁺ produced by lactate is influenced by the fiber type in skeletal muscle; previous studies have shown an association with skeletal muscle composition, particularly type 2 fibers (Nakagawa and Hattori, 2002).

Several mechanisms are believed to allow the organism to rapidly maintain homeostasis in response to dynamic exercise (Bruce et al., 2019). The excretion of carbon dioxide during expiration is related to pulmonary blood flow, that is, cardiac output and ventilatory capacity. In our study, PETCO₂, a measure of cardiac output, was significantly lower in the older group (though cardiac output was not measured directly and may therefore be dissociated from actual measurements). Additionally, the VE/VCO₂ slope was higher in the older group, which may have contributed to the reduced capacity for lactate buffering and carbon dioxide excretion up to RCP, and the higher rate of decline in RCP VO₂ than VAT with age.

In addition, ΔVO₂/ΔWR, which indicates the oxygen utilization capacity of the peripheral motor muscle group, was not affected by age. In patients with specific risk factors, the reduced oxygen availability of the peripheral motor musculature facilitates anaerobic energy production during exercise, leading to the production of lactic acid and the buffering and excretion of CO₂. In patients with heart failure, a decrease in cardiac output and vasodilatory capacity limits blood flow to peripheral exercise muscle groups, leading to a decrease in ΔVO₂/ΔWR. In the present study, ΔVO₂/ΔWR was not affected by aging, suggesting that the effect on energy production was small. However, we were not able to investigate related factors such as circulating blood volume, total body skeletal muscle mass, muscle composition, and plasma bicarbonate ion concentration concerning the accumulation and buffering capacity of CO₂/H⁺ produced in vivo.

The results of this study showed that various indices of exercise (e.g., peak VO₂ and VAT) decreased with age, and the rate of decrease was higher for RCP than for VAT. RCP/VAT, the ratio of RCP VO₂ to VAT VO₂, showed a modest negative correlation over time; however, there was no significant difference in RCP/VAT between the younger and older groups. RCP/VAT is considered a more moderate indicator of the effect of aging than ΔVO₂/weight RCP-VAT. The results suggest that the ability to excrete CO₂ produced in vivo or to accumulate and buffer CO₂ is less affected by aging.

For some IB phases that have been used in the past, the IB phase time can only be used for comparison in the same protocol. In addition, when the IB phase is expressed by ΔVO₂/weight RCP-VAT, it is not possible to determine whether the decrease is only in that part of the whole exercise or the whole exercise, given that it is a cut-off of the oxygen uptake during exercise. In fact, as in a previous study (Carriere et al., 2019), peak VO₂ and ΔVO₂/weight RCP-VAT were correlated; however, since ΔVO₂/weight RCP-VAT decreases with age, it is not suitable for comparison between groups of different ages. Conversely, the ratio of oxygen uptake, such as RCP/VAT, shows that the balance of exercise tolerance indices is maintained, though overall exercise tolerance decreased.

At low exercise intensities, oxidative phosphorylation is the main source of ATP production. As the exercise intensity increases, glycolysis increases, leading to lactate production and buffering. When the RCP is exceeded, lactic acidosis occurs. Since mitochondrial function including oxidative phosphorylation is not affected by aging or is only mildly affected (Lanza et al., 2005), VAT is considered to be less susceptible to the decline in mitochondrial function, except in certain diseases.

For a practical recommendation, by combining data with VAT and RCP VO₂ and ΔVO₂/weight RCP-VAT, we believe that RCP/VAT can possibly be used as a concise indicator for lactate buffering capacity and skeletal muscle composition ratio.

This study had several limitations. First, because the analysis was based on only exhaled gas analysis, hematological parameters such as blood levels of lactate and bicarbonate ions, as well as hemodynamics, could not be evaluated in parallel. RCP is associated with maximal lactate steady state, and exercise therapy improves skeletal muscle function (oxidative capacity); however, in this study, it was difficult to clarify what led to the increase and improvement in RCP/VAT with exercise therapy. Second, RCP/VAT is an index that can be influenced by either an increase or decrease in one of the indices; a decrease in VAT may result in an increase in RCP/VAT. Third, the relationship with prognosis, as shown by IB phase time and ΔVO₂/weight RCP-VAT, is unclear. Fourth, the effect of the degree of training on the lactate buffering capacity is unknown because we did not investigate the activity level or the degree of training in all participants. Finally, due to the small number of cases in the 30–60 age range, there is insufficient analysis of trends by age and by age group.