High-Intensity Walking Time Is a Key Determinant to Increase Physical Fitness and Improve Health Outcomes After Interval Walking Training in Middle-Aged and Older People

ORIGINAL ARTICLE

High-Intensity Walking Time Is a Key Determinant to Increase Physical Fitness and Improve Health Outcomes After Interval Walking Training in Middle-Aged and Older People Shizue Masuki, PhD; Mayuko Morikawa, PhD; and Hiroshi Nose, MD, PhD Abstract Objective: To examine the effects of interval walking training (IWT) on the estimated peak aerobic _ 2peak ) and lifestyle-related disease (LSD) score while focusing on exercise intensity and capacity (eVO volume in middle-aged and older people. Participants and Methods: Men and women (N¼679; mean age, 657 SD years) completed 5-month IWT. Participants were instructed to repeat 5 or more sets of fast and slow walking for 3 minutes each _ 2peak for walking, respectively, per day for 4 or more d/wk. This study at 70% or more and 40% eVO was conducted from April 1, 2005, through February 29, 2008. _ 2peak by 14% and decreased LSD score by 17% on Results: Interval walking training increased eVO average (P<.001). During 5-month IWT, fast and slow walking times were 8865 SD and 10086 min/wk, respectively, but varied among participants. We divided participants into approximately 10 bins for 6 minutes each of fast and slow walking times per week up to 60 min/wk, and above this time, approximately 8 bins for 30 or 60 minutes each of fast and slow walking up to the maximal time. We _ 2peak and LSD score improved as fast walking time per week increased up to 50 found that both eVO 2 _ 2peak ; R2¼0.51; P¼.03 for LSDS) but plateaued above this time. In min/wk (R ¼0.94; P<.001 for eVO _ 2peak nor LSDS was positively correlated with slow or total contrast, improvement in neither eVO walking time per week. Multiple regression analyses confirmed that fast walking time per week was _ 2peak (P<.001) and LSD score (P¼.001). the major determinant of improvements in eVO _ 2peak and decrease Conclusion: High-intensity walking time during IWT is a key factor to increase eVO LSD score in middle-aged and older people. ª 2019 Mayo Foundation for Medical Education and Research

T

he rapid growth in the elderly population in many countries has highlighted the importance of exercise training in _ 2peak ), improving peak aerobic capacity (VO which can not only promote independence and enhance quality of life but also decrease the likelihood of lifestyle-related diseases _ 2peak is a powerful (LSDs).1,2 Indeed, lower VO risk factor for LSDs and all-cause mortality3,4 and has been associated with higher health care costs.5 Based on these findings, any types of exercise that meet the physical activity _ 2peak , such as guidelines6,7 to increase VO

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walking, running, or cycling, have been recommended.4,8-10 However, a substantial proportion of participants in an exercise training program reported that there was little effect _ 2peak and therefore on LSD risk factors, on VO even after those participants completed the same period of training as those who reported improvements.11 This might be caused by lack of evidence distinguishing exercise intensity from training volume as factors contributing to training-induced improvements. For example, walking 10,000 steps/d, which focuses on training volume, has been

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From the Department of Sports Medical Sciences, Shinshu University Graduate School of Medicine, Matsumoto, Japan (S.M., M.M.); Institute for Biomedical Sciences, Shinshu University, Matsumoto, Japan (S.M., M.M.); and Jukunen Taiikudaigaku Research Center, Matsumoto, Japan (M.M., H.N.).

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widely recommended to middle-aged and older people in Japan12 on the basis of studies reporting a dose-response relationship between the volume of physical activity and health outcomes.13,14 Because walking steps can be easily monitored using a pedometer, this simplicity has facilitated accumulation of evidence related to exercise volume in a large population of middle-aged and older people. In contrast, American College of Sports Medicine’s guidelines suggest that exercise training should be performed above a _ 2peak given intensity relative to individual VO to obtain particular effects.15 Accordingly, such exercise training has been mainly conducted at gymnasiums using machines, such as bicycles and treadmills, with the requirement of staff support. However, these exercise programs are costly and have limited availability, which prevented exercise training _ 2peak from calibrated to individual VO becoming widespread and being implemented long-term. Moreover, different trainers with different abilities might induce variability in exercise training responses. For these reasons, it has been difficult to simultaneously assess how exercise intensity and volume during training affected the im_ 2peak and risk factors for provements in VO LSDs in a large population of middle-aged and older people. In contrast, we recently developed an exercise training system that is broadly applicable for middle-aged and older people.16 The system comprises interval walking training (IWT) that is designed according _ 2peak (eVO _ 2peak ) in each indito estimated VO vidual and an Internet of Things system that tracks exercise intensity and energy expenditure during training.17-19 Because the IWT regimen is so simple and participants can perform training at their favorite time and place without going to exercise facilities, this approach enabled us to determine the respective contributions of exercise intensity and volume to exercise trainingeinduced improvements in a large population of middle-aged and older people. Using this system, we examined the hypothesis that high-intensity walking time during IWT would be a key determinant for 2

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_ 2peak and improving LSD risk increasing eVO factors in middle-aged and older people. PARTICIPANTS AND METHODS Study Participants The study protocol was approved by the Institutional Review Board on Human Experiments, Shinshu University School of Medicine; 696 middle-aged and older adults provided written informed consent and were enrolled in the study. Effects of IWT over 5 months in the present study were derived from some of the data from our previously published 22-month study.20 Because 17 subjects lacked 1 or more of the measurements at the fifth month assessment of IWT, we analyzed only the remaining 679 subjects in the present study (Table 1). Subjects were recruited from the participants of a government-supported IWT program in Matsumoto, Japan. For these subjects, the past incidence of certain disorders was as follows: 27% for hypertension, 20% for dyslipidemia, and 9% for diabetes mellitus. Protocol Physical characteristics, blood pressure, blood lipid level, and glucose level as well _ 2peak were measured at baseline and as eVO at the fifth month of IWT. The assessment at “the fifth month” was called the “posttraining” assessment in the present study. _ 2peak , All measurements, except for eVO were performed after fasting overnight. _ 2peak As reported previously,17 after eVO was measured using a graded walking test as described below, participants were invited to a community office near their homes before training and were instructed to repeat 5 or more sets of 3-minute low-intensity walking at approximately 40% of the pre_ 2peak for walking (see below training eVO for details) followed by 3-minute highintensity walking at 70% or more but less _ 2peak per day for 4 d/wk or than 85% eVO more. Energy expenditure during daily walking at their favorite time and place was monitored with a triaxial accelerometer (Jukudai Mate, Kissei Comtec Co., Ltd.) on the right or left side of the waist in the XXX 2019;nn(n):1-12

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HIGH-INTENSITY WALKING TIME TO INCREASE FITNESS

TABLE 1. Physical Characteristics Before IWTa,b,c Characteristic

Total (N¼679)

Age (y)

Men (n¼196)

Women (n¼483)

657

696

637

Height (cm)

1567

1655

1535

Body weight (kg)

58.79.4

66.38.4

55.77.9

BMI (kg/m2)

23.93.1

24.42.6

23.83.2

SBP (mm Hg)

13416

13916

13216

DBP (mm Hg)

7910

8110

7810

10551

11053

10250

Triglyceride level (mg/dL) HDL cholesterol level (mg/dL)

6716

6015

7016

LDL cholesterol level (mg/dL)

13731

12831

14030

Glucose level (mg/dL)

10619

11016

10420

LSD score _ 2peak (mL/kg per minute) eVO

1.91.0

2.11.0

1.81.0

21.43.9

20.34.0

21.93.8

HRpeak (beats/min)

12917

12319

13115

1.80.7

2.00.8

1.70.7

179 (26%)

41 (21%)

138 (29%)

25 (4%)

23 (12%)

2 (0.4%)

Physical activity Knee or lower-back pain Smokers

_ 2peak ¼ estimated peak aerobic capacity for walking; HDL ¼ high-density BMI ¼ body mass index; DBP ¼ diastolic blood pressure; eVO lipoprotein; HRpeak ¼ peak heart rate; IWT ¼ interval walking training; LDL ¼ low-density lipoprotein; LSD ¼ lifestyle-related disease; SBP ¼ systolic blood pressure. b _ 2peak determination. Heart rate was measured with a near-infrared ear pickup probe during eVO c Data are presented as mean  SD or as no. (%). a

midclavicular line. A beeping signal alerted the participants when a change in intensity was scheduled, and another signal informed them when their walking intensity reached _ 2peak . 70% eVO Every 2 weeks, participants visited a local office to download their walking records from the accelerometer via the Internet to a central server at the administrative center for automatic analysis and reporting, which was supported by trainers. Trainers used

these reports to track daily walking intensity, energy expenditure, and other parameters given in Table 217,21 and to instruct the participants on how best to achieve their target levels. Each local office was located near the participants’ homes so that they all had easy access to the office without limitations due to transportation. The training program was initiated on April or October in 2005, 2006, or 2007. During the 5-month training period, the

TABLE 2. Training Achievements Over 5 Moa Total (N¼679) Variable

Fast walking

Walking days per week

Slow walking 3.71.5

Time (min/walking day)

2311

2719

Energy expenditure (mL O2/kg per walking day)b

328180

199107

Intensity (mL O2/kg per minute)b

14.53.1

7.82.4

Data are presented as mean  SD. b Resting oxygen consumption is not included. a

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6 *

*

4 2 *

0

. ΔeVO2peak (mL/kg per minute)

200 –2

4

0 0

2

100 200 300 400 500 Slow walking time (min/wk)

No. of participants

6

*

8 6

*

4 0

0

200

200

–2

–2 0

100 200 Fast walking time (min/wk)

A

300

0

0 550

0

200 400 600 800 1000 Total walking time (min/wk)

No. of participants

2

0.4 0 0.4 –0.4 –0.8

ΔLSD score

0

* * * * * 0 100 200 300 400 500 Slow walking time (min/wk)

0.4 0

–0.4 *

*

* –0.4

* *

*

* –0.8

**

–0.8 0

B

*

*

200 100 Fast walking time (min/wk)

300

550

0

200 400 600 800 1000 Total walking time (min/wk)

_ 2peak ) FIGURE 1. Fast, slow, and total walking times over 5 months vs changes in estimated peak aerobic capacity for walking (DeVO (A) and in lifestyle-related disease (DLSD) score (B) after training in 679 middle-aged and older adults. Data are presented as mean  SE. The number of participants who were included in each bin of training achievements was also presented in panel A. *Significant differences from pretraining values, P<.05.

average atmospheric temperature ranged from 1.6 C to 25.8 C and the average relative humidity ranged from 54% to 75%. 4

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Measurements _ 2peak . We determined eVO _ 2peak Estimated VO by measuring energy expenditure with an XXX 2019;nn(n):1-12

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HIGH-INTENSITY WALKING TIME TO INCREASE FITNESS

accelerometer during graded-intensity walking on a flat floor at a slow, moderate, and fast pace for 3 minutes each, as reported previously.19 We used this approach because it was likely to be in much better agreement with a graded cycling test17 than with other _ 2peak algorithms.22 eVO Body Mass Index. Body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. Blood Pressure. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by auscultation after 10 minutes of sitting in a room at approximately 25 C and approximately 50% relative humidity. Exercise, caffeine, and smoking were not permitted for more than 30 minutes before measurement according to American Heart Association guidelines.23 Blood Samples. Blood samples were collected from the antecubital vein to measure blood lipid and glucose levels before and after training. Serum concentrations of cholesterol and triglycerides as well as the plasma concentration of glucose were determined using standard enzymatic methods. Medical Survey. participants were interviewed by medical staff and asked to answer questionnaires about their anamnesis, knee or lower back pain, and their baseline physical activity. Physical activity level was scored as 1¼light, 2¼moderate, or 3¼high according to physical activity and energy requirement guidelines.24 Analyses Determination of LSD Score. To determine improvements in risk factors for LSDs from training, we calculated LSD scores with reference to Japanese25 and US26 health care guidelines, as previously described.21 We added 1 point when a value met 1 of the following 4 criteria: (1) BMI 25 kg/m2 or greater; (2) SBP 130 mm Hg or greater or DBP 85 mm Hg or greater; (3) triglyceride level 150 mg/dL or greater, high-density lipoprotein cholesterol level less than 40 mg/dL, or Mayo Clin Proc. n XXX 2019;nn(n):1-12 www.mayoclinicproceedings.org

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low-density lipoprotein cholesterol level 130 mg/dL or greater; and (4) blood glucose level 110 mg/dL or greater (to convert to mg/dL values to mmol/L, multiply by 0.0555). Therefore, the maximum total score was 4 points when all criteria were met. _ 2peak and LSD Score Estimated VO Responses in Individuals With Different IWT Achievements. The slow walking time (in min/wk) over the 5-month training period _ 2peak and the corresponding changes in eVO _ 2peak ) and LSD score (DLSD score) after (DeVO 5-month IWT were grouped into bins of a 6min/wk increment up to 60 min/wk, an approximately 30-min/wk increment up to 180 min/wk, and an approximately 60-min/wk increment up to 400 min/wk, and the values above this time were pooled. Similarly, the fast walking time (in min/wk) and the corre_ 2peak and DLSD scores were sponding DeVO grouped, and values above 240 min/wk were pooled. The total walking time (in min/wk) _ 2peak and DLSD and the corresponding DeVO scores were grouped into bins of a 10-min/wk increment up to 200 min/wk, a 50-min/wk increment up to 500 min/wk, and a 100-min/ wk increment up to 600 min/wk, and values above this time were pooled. The mean and SE for each bin were presented together with the number of participants in Figure 1. Nonresponders to IWT. We defined those _ 2peak after IWT less who reported DeVO than 2.0 mL/kg per minute as nonresponders to IWT. The reasons for adopting the threshold _ 2peak in particiwere that the average DeVO pants (n¼23) who belonged to the lowest bin for fast walking time was 1.20.8 (SE) mL/kg per minute and the average value could vary from 2.0 to 0.4 mL/kg per minute, _ 2peak could decrease by at suggesting that eVO most 2.0 mL/kg per minute with aging for 5 months of sedentary lifestyle. The percentage of nonresponders was calculated as the num_ 2peak less ber of participants who had DeVO than 2.0 mL/kg per minute divided by the total number of participants in each bin for fast walking time (Figure 2). Each bin was constructed in a similar way as mentioned above.

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constant in individual participants. Therefore, in addition to the direct effects of fast and slow walking times, the interaction between fast and slow walking times was considered in the regression analysis. Multicollinearity among independent variables was evaluated using the variance inflation factors, and variables were removed from the equation if they were above 10. Consequently, total walking time was removed from the models throughout.

40

%Nonresponders

30

20

10

0 0

100 200 Fast walking time (min/wk)

300

RESULTS

FIGURE 2. Fast walking time over 5 months vs the percentage of nonresponders to interval walking training. The percentage of nonresponders was calculated as the number of participants who had change in estimated peak aerobic capacity <2.0 mL/kg per minute divided by the total number of participants in each bin for fast walking time.

Statistics The standard least-squares method was used to determine the regression equation between slow, fast, or total walking time during IWT _ 2peak and DLSD over 5 months versus DeVO scores (Figure 1) as well as between fast walking time during IWT over 5 months versus the percentage of nonresponders (Figure 2). One-way analysis of variance for repeated measures was used to examine any substantial _ 2peak after training (Figure. changes in eVO 1A). The Wilcoxon signed-rank test was used to examine any substantial changes in LSD scores after training (Figure 1B). The independent determinants of _ DeVO2peak and DLSD score were examined using multiple regression analysis. In the model, IWT achievements and previously re_ 2peak ported factors that could affect DeVO 20,27,28 and DLSD score, such as sex, age, _ 2peak and LSD score, BMI, and baseline eVO were considered (Table 3). In addition, we found that the ratio of fast to total walking time decreased as slow walking time increased (R2¼0.18; P<.001), suggesting that total walking time per day was almost 6

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_ 2peak and LSD Score Estimated VO Responses in Individuals With Different IWT Achievements Table 2 presents the training achievements over 5 months. The fast walking time that was prescribed was 60 min/wk, whereas the average fast walking time completed in the 679 participants was 88 min/wk, which indicated that the adherence to IWT was high. However, the fast walking time varied from 0 to 338 min/wk among participants and the slow walking time varied from 0 to 674 min/wk. _ 2peak plotted Figure 1A depicts DeVO against each bin for fast, slow, and total walking times over 5 months. Overall, the IWT program significantly increased _ 2peak from baseline to 5 months by eVO 2.83.9 SD mL/kg per minute (N¼679; _ 2peak varied among parP<.001), but DeVO ticipants. As depicted in the figure, as fast walking time increased over a range of 0 to _ 2peak increased proportion50 min/wk, DeVO ally (R2¼0.94; P<.001) and plateaued thereafter. In contrast, as slow walking time _ 2peak rather decreased increased, DeVO 2 (R ¼0.24; P¼.03) whereas total walking time was not significantly correlated with _ 2peak (R2¼0.063; P¼.20). These reDeVO sponses were not influenced by sex. Figure 1B depicts the DLSD score plotted against each bin for fast, slow, and total walking times over 5 months. Overall, the IWT program significantly decreased the LSD score from baseline to 5 months by 0.320.86 SD (N¼679; P<.001), but the DLSD score varied among participants. As XXX 2019;nn(n):1-12

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_ 2peak and LSD Score Responses to 5-mo IWTa,b,c,d TABLE 3. Multiple Linear Regression Analysis for eVO _ 2peak DeVO b (95% CI)

Characteristic

0.088 (0.73 to 0.55)

Sex

0.11 (0.15 to 0.07)

Age, y

0.032 (0.12 to 0.06)

P value

b (95% CI)

Std b

P value

0.010

.79

0.17 (0.32 to 0.03)

0.092

.02

0.20

<.001

0.007 (0.003 to 0.016)

0.054

.16 

0.025

.49





0.23

<.001













0.35

<.001

0.031 (0.024 to 0.038) 0.001 (0.004 to 0.007) 6.9  105 (0.000 to 0.000)

0.48 0.031 0.27

<.001 .62 .001

0.19 0.009 0.15

.001 .89 .09

BMI, kg/m2e _ 2peak , mL/kg per min Baseline eVO

0.23 (0.30 to 0.15)

Baseline LSD score IWT achievements over 5 mo Fast walking time, min/week Slow walking time, min/week Fast  Slow walking time interaction

DLSD score Std b

0.29 (0.34 to 0.23) 0.003 (0.004 to 0.001) 8.5  105 (0.001 to 0.001) 8.1  106 (0.000 to 0.000)

_ 2peak ¼ estimated peak aerobic capacity; IWT ¼ interval walking training; LSD ¼ lifestyle-related disease; Std b ¼ unstandardized coefficient; BMI ¼ body mass index; eVO b ¼ standardized coefficient. b Sex was introduced into the regression equation as men ¼ 1 and women ¼ 0. c _ 2peak and DLSD score refer to changes in estimated peak aerobic capacity and lifestyle-related disease score after 5-mo IWT, respectively. DeVO d Because BMI was used to calculate the LSD score, it was not included in the model of multiple linear regression analysis for the DLSD score. e Values in boldface indicate significant determinants. a

depicted in the figure, as fast walking time increased over a range of 0 to 50 min/wk, the DLSD score decreased proportionally (R2¼0.51; P¼.03) and plateaued thereafter whereas neither slow nor total walking time was significantly correlated with the DLSD score (R2¼0.088; P¼.20 for slow walking time; R2¼0.032; P¼.36 for total walking time). In additional analyses stratified by sex, we reconfirmed similar responses between sexes. However, the DLSD score in response to a given fast walking time was shifted downward in men compared with women: the DLSD score was significantly lower (more negative) in men than in women at the fast walking times of 9, 33, and 75 min/wk (P<.05 for all). Multiple Regression Analysis of the Associations of IWT Achievements With Im_ 2peak and LSD Score provements in eVO To investigate factors independently associ_ 2peak and LSD ated with improvements in eVO score, we performed a multiple regression analysis considering IWT achievements over 5 months and previously reported factors _ 2peak and the DLSD that could affect DeVO score. We found that the independent determi_ 2peak were fast walking time nants of DeVO Mayo Clin Proc. n XXX 2019;nn(n):1-12 www.mayoclinicproceedings.org

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_ 2peak (P<.001) followed by baseline eVO (P<.001) and age (P<.001) (Table 3, left column). As presented in the table, fast walking time had a positive effect on the increase in _ 2peak . In addition, there was a significant eVO interaction between fast and slow walking times (P¼.001), which had a negative effect _ 2peak . This might reflect on the increase in eVO the fact that the ratio of fast to total walking time decreased as slow walking time increased. In contrast, the independent determinants of the DLSD score were the baseline LSD score (P<.001) followed by fast walking time (P¼.001) and sex (P¼.02) (Table 3, right column). As presented in the table, fast walking time had a positive effect on the reduction in LSD score, which was _ 2peak . consistent with its effect on DeVO Because sex was another determinant of the DLSD score, we tried to identify individual risk factors contributing to the difference. Overall, the percentage of participants who met each criterion was higher in the order of blood pressure (66%), blood lipid level (64%), BMI (33%), and blood glucose level (25%) before training, which decreased to 55%, 58%, 24%, and 19%, respectively, after training. In contrast, when we focused on the interactive effects of the (Sex  Training)

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on the LSD score, we found that the effect on blood glucose was significant (P<.001), suggesting that the sex difference in the total _ 2peak LSD score at a given increase in eVO was caused by the greater reduction in blood glucose levels in men than in women. _ 2peak Nonresponders With Estimated VO Different IWT Achievements Figure 2 depicts the percentage of nonresponders plotted against each bin for fast walking time over 5 months. As depicted in the figure, as fast walking time increased over a range of 0 to 50 min/wk, the percentage of nonresponders decreased proportionally (R2¼0.90; P<.001) and gradually decreased to 0 thereafter. DISCUSSION The major findings in the present study are as follows: (1) In 679 middle-aged and older Japanese, the average fast walking time completed during the 5-month IWT program was higher than the prescribed time but the individual fast walking time varied among participants. (2) The variability in fast walking time was positively correlated _ 2peak and with improvements in both eVO LSD score after training. (3) Multiple regression analyses after adjustment for possible covariates indicated that fast walking time was the key determinant for improvements _ 2peak and LSD score. in both eVO Study Participants _ 2peak , Body mass index, blood pressure, eVO and physical activity (Table 1) were almost equal to the values previously reported in age-matched Japanese populations,24,29,30 as were the incidence of orthopedic and other diseases.30,31 Thus, the characteristics of the participants in this study reflected this age group of the Japanese population well. Exercise Intensity Assessment System in the Field To our knowledge, this study is the first to monitor exercise intensity at every training session during a 5-month training period in the field to simultaneously assess how exercise intensity and volume affected the improvements 8

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_ 2peak and risk factors for LSDs in middlein VO aged and older people. Although the importance of exercise intensity has recently been highlighted32-34 and exercise training regimens above a given _ 2peak have intensity relative to individual VO been broadly recommended to increase _ 2peak and to prevent LSDs in middle-aged VO and older people,15 the field training systems available for these purposes are limited. For example, Coleman et al35 conducted a brisk walking training program for 16 weeks in adults aged approximately 40 years. However, target exercise intensity was not determined _ 2peak , and moreon the basis of individual VO over, actual exercise intensity was verified using a Polar heart rate (HR) monitor at only 2 points during the training period. In contrast, King et al36 conducted a homebased exercise training program according to individual fitness level for 12 months in adults aged approximately 56 years; however, actual exercise intensity was verified only in half of the participants using a portable HR monitor at only 3 points during the training period. Therefore, in these studies, it was unclear whether participants adhered to the prescribed exercise intensity at every training session. In the present study, using a portable device (Jukudai Mate) equipped with a triaxial accelerometer and a barometer that we have developed to estimate VO2,19 we determined _ 2peak for walking and conindividual eVO ducted the IWT regimen according to indi_ 2peak in the field. Because vidual eVO exercise intensity and duration during daily IWT was precisely monitored with the Jukudai Mate throughout the training period, this enabled us to assess how exercise intensity and volume affected the improvements in _ 2peak and risk factors for LSDs. eVO _ 2peak Fast Walking Time vs Increases in VO As shown in Figure 1A, as fast walking time increased over a range of 0 to 50 min/wk, _ 2peak increased proportionally and plaDeVO teaued thereafter, which is consistent with a classical principle of physiological adaptation.37 For example, Gettman et al38 assessed _ 2peak responses to 1, 3, and 5 d/wk of the VO treadmill running at 85% to 90% of maximal XXX 2019;nn(n):1-12

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HR for 30 min/session for 20 weeks in adults aged approximately 24 years and reported _ 2peak occurred that significant increases in VO in direct proportion to the frequency of training but there was no difference in _ 2peak improvements between the 3-day VO and 5-day groups. Although their protocol was not conducted to identify any minimum training time per week that would induce a _ 2peak response, their results of plateau VO facility-based training in a younger population are consistent with those from our field-based training in older participants. _ 2peak However, in our participants, DeVO plateaued after approximately 50 min/wk of fast walking, slightly less than the 75 min/wk of vigorous-intensity physical activity recommended by the American Heart Association and other physical activity guidelines.6,7 This might be because our participants performed interval training, not traditional continuous training.39 For example, Nybo et al40 compared the effects of high-intensity interval running (high-intensity time 20 min/wk) with those of moderate-intensity continuous running (w150 min/wk) for 12 weeks in adults aged approximately 31 years, and their data sug_ 2peak after training gested that the increase in VO was greater in the former than the latter. These results suggest that high-intensity interval training can greatly save training time compared with moderate-intensity continuous training. Another reason for the discrepancy in the minimal fast walking time per week _ 2peak between the needed to increase VO 6,7 guidelines and the present study (Figure 1A) might be the higher precision with which we measured exercise intensity and duration. Our system tracked exercise intensity continuously at every training session during a 5-month training period in all the middle-aged and older participants and calculated precise fast walking time _ 2peak ) in each individual. Consis(70% eVO tent with our findings, a recent review41 suggests substantial benefits even from exercise training doses much lower than that recommended by the guidelines.6,7 Therefore, based on these results, it seems reasonable to suggest that at least 50 min/wk of fast Mayo Clin Proc. n XXX 2019;nn(n):1-12 www.mayoclinicproceedings.org

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_ 2peak is neceswalking at 70% or more eVO sary to receive the greatest benefit in terms _ 2peak in middle-aged and older people. of eVO _ 2peak did not increase as In contrast, eVO slow walking time increased (Figure 1A). Because participants performed both slow and fast walking during daily IWT, the combined effect of fast and slow walking might make it difficult to see a clear relationship _ 2peak . between slow walking time vs DeVO However, even after considering the interaction between slow and fast walking times in multiple regression analyses, slow walking _ 2peak time was not the determinant of DeVO (Table 3), which suggests that the effect of _ 2peak slow walking on the increase in eVO was minimal. Indeed, Nemoto et al17 reported that in middle-aged and older people, the IWT program for 5 months increased _ 2peak by approximately 10% whereas VO moderate-intensity continuous walking at _ 2peak for 60 min/d 4 approximately 50% VO d/wk for 5 months produced no increase in _ 2peak . Taken together, these results sugVO gest that there is a key relationship between _ 2peak increase, fast walking time and eVO which was independent of the slow or total amount of walking time. Fast Walking Time vs Improvements in LSD Risk Factors We could not find any previous intervention studies that documented how exercise intensity affected improvements in LSD risk factors after training in a large number of older people. This outcome might have been observed because although the prevalence of LSDs increases with age, it is more challenging to conduct facility- or field-based interventions while monitoring exercise intensity continuously in older populations compared with younger populations.35,36,38 Using our system, in the present study, we found that as fast walking time increased over a range of 0 to 50 min/wk, the DLSD score decreased proportionally and plateaued thereafter (Figure 1B), which was the mirror image _ 2peak response. Consistent with this of the eVO observation, the aforementioned study17 also _ 2peak by the reported that the increase in VO IWT program was accompanied by

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approximately 9 and approximately 5 mm Hg reductions in SBP and DBP, respectively, _ 2peak by moderatewhereas no increase in VO intensity continuous walking produced only minimal effects on blood pressure. Moreover, Morikawa et al21 assessed the effects of IWT _ 2peak and LSD risk factors in 198 men on eVO and 468 women aged approximately 65 years and reported that the LSD score (calculated similarly to the present study) before training was higher in individuals with a lower _ 2peak and that the magnitude of the score eVO decrease was correlated with the magnitude _ 2peak after 4-month of the increase in eVO IWT. These results suggest that an exercise _ 2peak is closely training-induced increase in VO associated with improvements in LSD risk factors in middle-aged and older people, consistent with recent evidence.4 Regarding the possible mechanism, mitochondrial dysfunction due to muscle atrophy with aging causes persistent, low-grade, systemic inflammation that is linked to the development of many chronic diseases.42 This concept might be supported by the results of Zhang et al,43 which suggests that a 6-month IWT facilitated inactivation of one of the master proinflammatory response genes, the NFKB2 gene (for expansion of gene symbols, use search tool at www.genenames.org). These results suggest that IWT suppressed chronic inflammation to improve LSD symptoms _ 2peak . with increased VO

Other Factors Influencing Improvements in _ 2peak and LSD Risk Factors eVO In general, the results of multiple regression analysis (Table 3) confirmed the results of simple regression analysis (Figure 1). In addition, _ 2peak the analysis revealed that baseline eVO and age were other determinants of _ 2peak , which is consistent with results of DeVO previous studies.21,28,44 In contrast, the HERITAGE Family Study reported that baseline _ 2peak and age had little or only a small influVO _ 2peak .27,45 Although the precise ence on DVO reasons for this discrepancy were unknown, it might be because our participants were much older (w65 years) than those in the HERITAGE Family Study (w35 years). 10

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Other determinants of the DLSD score were baseline LSD score and sex (Table 3, right column), which is consistent with the results of a previous study in middle-aged and older people,21 suggesting that a greater reduction in LSD score after training was observed in in_ 2peak and consedividuals who had a lower eVO quently had a higher LSD score before training. Thus, the results of the present study might _ 2peak and LSD risk represent responses of VO factors in middle-aged and older people. _ 2peak Fast Walking Time vs eVO Nonresponders As fast walking time increased over a range of 0 to 50 min/wk, the percentage of nonresponders decreased proportionally and it gradually dropped to 0 thereafter (Figure 2). This suggests that every middle-aged and older person is trainable if they perform training for long enough at a higher intensity.46 Experimental Considerations _ 2peak with the acceleromWe estimated VO eter during the graded walking test. However, because peak HR was approximately 130 beats/min, which is approximately 25 beats/ min lower than the age-predicted maximal _ 2peak estimated in the present HR, the VO study was approximately 10% lower than the maximal VO2 determined by the standard methods of treadmill running. Howev_ 2peak er, we previously confirmed that VO values (y) (in mL/min) estimated by accelerometry in graded walking exercise were _ 2peak values (x) (in almost identical to VO mL/min) measured using respiratory gas analysis in a graded cycling exercise test with a regression equation of y¼0.81xþ247 (n¼278; R2¼0.83; P<.001). Therefore, it is _ 2peak for walking approprilikely that eVO ately reflected the physical fitness of each individual. CONCLUSION We developed a field training system to perform IWT according to individual _ 2peak while monitoring exercise intensity eVO continuously. Using this system, our findings suggest that high-intensity walking XXX 2019;nn(n):1-12

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time during IWT is a key determinant for _ 2peak and improving LSD increasing eVO risk factors in middle-aged and older people. Abbreviations and Acronyms: BMI = body mass index; _ = estimated DBP = diastolic blood pressure; eVO 2peak peak aerobic capacity; HR = heart rate; IWT = interval walking training; LSD = lifestyle-related disease; SBP = _ systolic blood pressure; VO = peak aerobic capacity 2peak Grant Support: The work was supported in part by the Shinshu University Partnership Project between Shinshu University; Jukunen Taiikudaigaku Research Center; the Ministry of Education, Culture, Sports, Science, and Technology of Japan; and Matsumoto City. This research was also supported by the Ministry of Health, Labour and Welfare of Japan (H17-Chohju-Ippan-016) and the Japan Society for the Promotion of Science (18H04083). Potential Competing Interests: The authors report no competing interests. Correspondence: Address to Shizue Masuki, PhD, Department of Sports Medical Sciences, Shinshu University Graduate School of Medicine, 3-1-1 Asahi Matsumoto 3908621, Japan ([email protected]).

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