Adherence and Factors Affecting Adherence
We found that adherence to the approximately 5-month and the 22-month IWT programs was comparatively higher than adherence to other previously reported exercise programs that required greater personnel support conducted in a Japanese population (23) and an American population (12,22) and was accompanied by significant improvements in LSD risk factors and physical fitness in middle-aged and older individuals (17).
We speculate that the high adherence to our training system may be explained by the following three reasons. 1) Recognition of progress. Instructions for IWT based on individual walking and health records are returned to each individual by trainers every 2 wk via the Internet. Therefore, participants recognize their increased physical fitness from energy expenditure and time for fast walking because the IWT advances together with their improved health records, which encourages them to continue IWT with the confidence that their efforts are being rewarded. 2) Comparison with others. If a participant recognizes how hard his/her competitor performs IWT, then this knowledge stimulates the competitive spirit. 3) Community-based intervention. If a friend is considering dropping out, other friends in the community encourage him/her, and if a friend performs IWT very hard, other friends admire his/her achievements. Therefore, our training system may fulfill these basic conditions to motivate individuals to continue the training, which is performed at a low cost with minimum requirements of staff support.
This system likely improved adherence rates to the IWT program as a whole, but we found that the adherence rate also exhibited great interindividual variation. Because higher adherence was critical for improvements in LSD risk factors and physical fitness (Figs. 3, 4), we attempted to identify factors that affect interindividual variations in adherence to the long-term IWT program. It has been suggested that sex, physical characteristics, physical activity, and other acquired factors affect adherence (3,35). However, no studies have yet investigated genetic factors affecting adherence. This oversight may be because previously, there were neither uniformly and broadly available exercise training regimens nor systems for precisely tracking daily training achievements. However, the IWT program is remotely and uniformly supervised via the Internet throughout the training period and requires minimal staff support, enabling us to identify factors without any bias from a varied training regimen and with less support from staff.
We recently reported that middle-aged and older Japanese men carrying the TT genotype of the rs1042615 single nucleotide polymorphism in the vasopressin receptor 1a gene (AVPR1A) had a significantly higher body mass index (BMI) and diastolic blood pressure than those who did not (16). However, these values decreased to levels comparable with those of men with other genotypes after 5 months of IWT, suggesting that men with the TT genotype may have been physically inactive before IWT (16). In addition, the AVPR1A microsatellite polymorphism RS3 (40) may be linked to lower physical activity in TT men. We therefore assessed whether adherence to the 22-month IWT program was affected by the RS3 and rs1042615 polymorphisms of the AVPR1A in addition to previously reported factors (3,35).
We found that the major determinants of higher adherence were a lower baseline BMI and male sex. In addition to BMI, smoking and the AVPR1A polymorphisms were independent determinants of adherence in men (17). As shown in Figure 5, monthly adherence rates to the exercise program (4 d·wk−1) gradually decreased after the first 5 months of IWT in all subjects; however, this effect was enhanced in men carrying the RS3 [one or two 334 alleles] in combination with the rs1042615 [TT] of AVPR1A polymorphisms (group 4) compared with other carriers. These results suggested that men carrying the [334 alleles–TT] of AVPR1A polymorphisms exhibited lower adherence to the long-term IWT program (17). Although the detailed mechanism for this finding remains unknown, the impaired pressor response at the onset of exercise may be involved, as described subsequently, although this is one of many possibilities.
POSSIBLE MECHANISMS OF LOWER EXERCISE ADHERENCE VIA V1a RECEPTORS: ANIMAL STUDIES
Arterial blood pressure rises at the onset of voluntary exercise, which is likely advantageous for increasing blood flow to contracting muscles and facilitating exercise. Therefore, we speculated that arterial pressure may not increase at the onset of exercise in men carrying the [334 alleles–TT], perhaps due to impaired V1a receptor function.
V1a Receptors and Pressor Response at the Onset of Voluntary Exercise
Arterial pressure regulation is achieved through the baroreflexes. In the cardiovascular center of the medulla, the feedback gain of the baroreflexes is further modulated by signals from higher brain regions (36). Because vasopressin V1a receptors have been reported to be richly expressed in the nucleus tractus solitarii (NTS) of the medulla (13) and to regulate the activity of NTS neurons receiving baroreceptor input (2), we postulated that central vasopressin may play an important role as a neurotransmitter in the pressor response at the onset of voluntary locomotion (21).
In wild-type mice, increased cerebral activity suppressed baroreflex control of heart rate (HR), which was associated with the start of voluntary locomotion with a rapid increase in arterial pressure (Fig. 6, left panel) (20). In contrast, in vasopressin V1a receptor knockout (V1a KO) mice, the probability of locomotion after cerebral activation was reduced, with no suppression of baroreflex control of HR and no increase in arterial pressure (Fig. 6, right panel). Moreover, these findings in V1a KO mice were confirmed after local infusion of the V1a receptor antagonist into the NTS of wild-type mice (21). Therefore, lower exercise adherence in men carrying the [334 alleles–TT] of AVPR1A polymorphisms may be associated with impaired pressor response at the onset of exercise, although we need to provide more direct evidence in humans.
EFFECTS OF IWT AND NUTRITIONAL SUPPLEMENTATION
Because the IWT program is a consistent, simple intervention for longer durations that precisely tracks daily walking intensity and energy expenditure, several food companies have used our research field to assess the effects of their products.
It has been reported that inactivity triggers persistent, low-grade, systemic inflammation that is linked to the development of many chronic diseases (8). However, we have reported that approximately 5 months of IWT induced suppression of chronic inflammation, as well as increases in muscle strength (28,42). In addition, we found that IWT and milk protein intake enhanced increases in thigh muscle mass and strength (34); therefore, we assessed whether IWT and milk product intake enhanced suppression of chronic inflammation more than IWT alone (19).
Subjects (~66 yr of age) who had been performing IWT for more than 6 months participated in this study. They randomly were divided into the following three groups: IWT alone (CNT, n = 12) or IWT and a low (n = 12) or high dose (HD, n = 13) of postexercise milk product. IWT achievements were similar among the groups; however, pyrosequencing analysis of whole blood showed that methylation of the NFKB1 and NFKB2 genes after IWT was enhanced more in the HD group than in the CNT group. Genome-wide DNA methylation analysis showed that several inflammation-related genes were hypermethylated in the HD group compared with the CNT group. Moreover, thigh muscle strength increased in the HD group more than in the CNT group. These results suggest that milk product intake during IWT enhanced proinflammatory cytokine gene suppression with increased muscle strength in middle-aged and older individuals (19).
In addition to these protective effects against chronic inflammation, we also found that milk protein intake during exercise training enhanced plasma volume expansion (39), which would facilitate thermoregulatory adaptation (11,32,33) through cardiopulmonary baroreflexes (9,30) to protect against heat illness in older people.
Aging is associated with reduced mitochondrial function. Experimentally, the function of the mitochondrial electron transport chain, especially complex IV (cytochrome c oxidase) activity, was reported to decline with aging in human (26) and animal muscles (6). Mitochondrial dysfunction has been suggested not only to decrease exercise efficiency (5) but also to enhance the generation of reactive oxygen species that injure the tissues (6). These changes may evoke chronic inflammatory responses in the body and thereby cause LSD (8). Thus, mitochondrial dysfunction may be one of the key mechanisms limiting daily physical activity and evoking LSD in middle-aged and older individuals (8). In contrast, it has been reported that the oral ingestion of 5-aminolevulinic acid (ALA) increases complex IV activity and raises the adenosine triphosphate production rate in the liver of mice (31). However, no studies have evaluated how ALA affects respiratory response during exercise and the voluntary achievement of exercise training in humans.
A study was conducted using a placebo-controlled, double-blind crossover design (18). All subjects (n = 10, ~65 yr) underwent two trials for 7 d each in which they performed IWT in combination with either an ALA or placebo supplement intake (CNT). Before and after each trial, subjects underwent a graded cycling test. As a result, in the ALA trial, V˙O2 during graded cycling decreased by 12% at every workload, accompanied by a 16% reduction in plasma lactate concentrations. Furthermore, the training days, training volume, and time at fast walking were all higher in the ALA intake period compared with the CNT intake period. These results suggest that ALA supplementation augmented exercise efficiency and thereby improved IWT achievement in older people (18).
Thus, using our research field, we successfully evaluated the effects of IWT and several nutritional supplements.
IWT FOR REHABILITATION
In Japan, exercise training for rehabilitation is performed immediately after orthopedic and other related surgeries under the supervision of medical staff; however, for hospital management reasons, patients can stay in the hospital under financial support from national insurance for up to 2 wk, a period that is too short to recover their muscle strength. Therefore, the development of a home-based exercise training regimen is needed.
Total Hip Arthroplasty
Total hip arthroplasty (THA) is a broadly prescribed surgical treatment for patients with advanced arthritic joint disorders. Although THA patients are thought to experience muscle atrophy and weakness for several years after surgery, there were previously no home-based exercise training regimens for preventing these issues. We therefore examined whether IWT could prevent muscle atrophy and aerobic capacity impairment in these patients. We found that all THA patients performed fast walking for an average of greater than 60 min·wk−1 during the 12-week training period, leading to increases in muscle strength and aerobic capacity, which were accompanied by a lack of hip pain. Thus, IWT may be an effective home-based training regimen for the rehabilitation of THA patients (25).
IWT in Water
It has been reported in Japan that approximately 70% of women and approximately 50% of men older than 65 yr experience knee osteoarthritis. Half of these cases experience difficulty performing exercise training, especially at higher intensities, due to knee pain (27). To address this problem, we developed an IWT regimen in water in which reduced pressure on the knee joints and increased venous return to the heart were expected. We found that walking in water elevated V˙O2 at the gas exchange threshold and decreased HR at a given exercise intensity in middle-aged and older women. This enabled the subjects to perform exercise at a higher metabolic rate than on land because of improved subjective feelings, which resulted in greater gains in physical fitness for these subjects (7).
We have developed a broadly available, remotely supervised exercise training system for middle-aged and older people. The key observations are as follows: 1) adherence to the program for up to 22 months was high, 2) participation increased physical fitness and decreased LSD risk factors, 3) the high adherence may be explained by the feedback provided to individual participants based on their achievements, 4) genetic factors, such as AVPR1A polymorphisms, affect adherence to the program, which may be associated with impaired pressor responses at the onset of exercise as suggested in the animal studies, 5) the effects of IWT were enhanced by nutritional supplements, 6) our findings were supported by epigenetic as well as clinical evidence, and 7) the IWT program was also applicable to rehabilitation medicine. Thus, our exercise training system, composed of IWT and an IT network, may protect against age-associated declines in physical fitness and LSD over an extended duration. Moreover, by incorporating factors that enhance adherence and effectiveness into the program, the regimen can be used by a larger population throughout their lifespan.
This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18689009 and 21790224), the Japan Society for the Promotion of Science (17209007, 21650168, 24689014, 25670117, 15H01830, and 15H04680), and the Ministry of Health, Labor and Welfare of Japan (H17-Chohju-Ippan-016). This study was also supported 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. No conflicts of interests, financial or otherwise, are declared by the authors.
1. American College of Sports Medicine. General principles of exercise prescription. In: Pescatello LS, editor. ACSM’s Guidelines for Exercise Testing and Prescription
. 9th ed. Baltimore (MD): Lippincott Williams & Wilkins; 2014. p. 162–93.
2. Bailey TW, Jin YH, Doyle MW, Smith SM, Andresen MC. Vasopressin
inhibits glutamate release via two distinct modes in the brainstem. J. Neurosci
. 2006; 26:6131–42.
3. Bauman AE, Reis RS, Sallis JF, Wells JC, Loos RJ, Martin BW. Correlates of physical activity: why are some people physically active and others not? Lancet
. 2012; 380:258–71.
4. Blair SN, Kohl HW 3rd, Paffenbarger RS Jr, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA
. 1989; 262(17):2395–401.
5. Conley KE, Jubrias SA, Cress ME, Esselman P. Exercise efficiency is reduced by mitochondrial uncoupling in the elderly. Exp. Physiol
. 2013; 98(3):768–77.
6. Ferguson M, Mockett RJ, Shen Y, Orr WC, Sohal RS. Age-associated decline in mitochondrial respiration and electron transport in Drosophila melanogaster. Biochem. J
. 2005; 390(Pt 2):501–11.
7. Handa S, Masuki S, Ohshio T, Kamijo Y, Takamata A, Nose H. Target intensity and interval walking training in water to enhance physical fitness in middle-aged and older women: a randomised controlled study. Eur. J. Appl. Physiol
. 2016; 116(1):203–15.
8. Handschin C, Spiegelman BM. The role of exercise and PGC1alpha in inflammation and chronic disease. Nature
. 2008; 454(7203):463–9.
9. Kamijo Y, Okada Y, Ikegawa S, Okazaki K, Goto M, Nose H. Skin sympathetic nerve activity component synchronizing with cardiac cycle is involved in hypovolaemic suppression of cutaneous vasodilatation in hyperthermia. J. Physiol
. 2011; 589(Pt 24):6231–42.
10. Karstoft K, Winding K, Knudsen SH, et al. The effects of free-living interval-walking training on glycemic control, body composition, and physical fitness in type 2 diabetic patients: a randomized, controlled trial. Diabetes Care
. 2013; 36(2):228–36.
11. Kataoka Y, Kamijo Y, Ogawa Y, et al. Effects of hypervolemia by protein and glucose supplementation during aerobic training on thermal and arterial pressure regulations in hypertensive older men. J. Appl. Physiol
. 2016; 121(4):1021–31.
12. King AC, Haskell WL, Young DR, Oka RK, Stefanick ML. Long-term effects of varying intensities and formats of physical activity on participation rates, fitness, and lipoproteins in men and women aged 50 to 65 years. Circulation
. 1995; 91(10):2596–604.
13. Koshimizu TA, Nasa Y, Tanoue A, et al. V1a vasopressin
receptors maintain normal blood pressure by regulating circulating blood volume and baroreflex sensitivity. Proc. Natl. Acad. Sci. U. S. A
. 2006; 103(20):7807–12.
14. Lalande S, Okazaki K, Yamazaki T, Nose H, Joyner MJ, Johnson BD. Effects of interval walking on physical fitness in middle-aged individuals. J. Prim. Care Community Health
. 2010; 1(2):104–10.
15. Manson JE, Greenland P, LaCroix AZ, et al. Walking compared with vigorous exercise for the prevention of cardiovascular events in women. N. Engl. J. Med
. 2002; 347(10):716–25.
16. Masuki S, Mori M, Tabara Y, et al. Vasopressin
V1a receptor polymorphism and interval walking training effects in middle-aged and older people. Hypertension
. 2010; 55(3):747–54.
17. Masuki S, Mori M, Tabara Y, et al. The factors affecting adherence to a long-term interval walking training program in middle-aged and older people. J. Appl. Physiol
. 2015; 118(5):595–603.
18. Masuki S, Morita A, Kamijo Y, et al. Impact of 5-aminolevulinic acid with iron supplementation on exercise efficiency and home-based walking training achievement in older women. J. Appl. Physiol
. 2016; 120(1):87–96.
19. Masuki S, Nishida K, Hashimoto S, et al. Effects of milk product intake on thigh muscle strength and NFKB
gene methylation during home-based interval walking training in older women: a randomized, controlled pilot study. PLOS ONE
. in press
. doi: 10.1371/journal.pone.0176757.
20. Masuki S, Nose H. Increased cerebral activity suppresses baroreflex control of heart rate in freely moving mice. J. Physiol
. 2009; 587(Pt 23):5783–94.
21. Masuki S, Sumiyoshi E, Koshimizu TA, et al. Voluntary locomotion linked with cerebral activation is mediated by vasopressin
V1a receptors in free-moving mice. J. Physiol
. 2013; 591(14):3651–65.
22. Messier SP, Loeser RF, Miller GD, et al. Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: the arthritis, diet, and activity promotion trial. Arthritis Rheum
. 2004; 50:1501–10.
23. Mori Y, Tobina T, Shirasaya K, Kiyonaga A, Shindo M, Tanaka H. Long-term effects of home-based bench-stepping exercise training
on healthcare expenditure for elderly Japanese. J. Epidemiol
. 2011; 21(5):363–9.
24. Morikawa M, Okazaki K, Masuki S, et al. Physical fitness and indices of lifestyle-related diseases before and after interval walking training in middle-aged and older males and females. Br. J. Sports Med
. 2011; 45(3):216–24.
25. Morishima Y, Mizushima T, Yamauchi K, Morikawa M, Masuki S, Nose H. Effects of home-based interval walking training on thigh muscle strength and aerobic capacity in female total hip arthroplasty patients: a randomized, controlled pilot study. PLoS One
. 2014; 9(9):e108690.
26. Muller-Hocker J. Cytochrome c oxidase deficient fibres in the limb muscle and diaphragm of man without muscular disease: an age-related alteration. J. Neurol. Sci
. 1990; 100(1–2):14–21.
27. Muraki S, Oka H, Akune T, et al. Prevalence of radiographic knee osteoarthritis and its association with knee pain in the elderly of Japanese population-based cohorts: the ROAD study. Osteoarthritis Cartilage
. 2009; 17(9):1137–43.
28. Nemoto K, Gen-no H, Masuki S, Okazaki K, Nose H. Effects of high-intensity interval walking training on physical fitness and blood pressure in middle-aged and older people. Mayo Clin. Proc
. 2007; 82(7):803–11.
29. Nose H, Morikawa M, Yamazaki T, et al. Beyond epidemiology: field studies and the physiology laboratory as the whole world. J. Physiol
. 2009; 587(Pt 23):5569–75.
30. Ogawa Y, Kamijo YI, Ikegawa S, Masuki S, Nose H. Effects of postural change from supine to head-up tilt on the skin sympathetic nerve activity component synchronised with the cardiac cycle in warmed men. J. Physiol
. 2017; 595(4):1185–200.
31. Ogura S, Maruyama K, Hagiya Y, et al. The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver. BMC. Res. Notes
. 2011; 4:66.
32. Okazaki K, Hayase H, Ichinose T, Mitono H, Doi T, Nose H. Protein and carbohydrate supplementation after exercise increases plasma volume and albumin content in older and young men. J. Appl. Physiol
. 2009; 107:770–9.
33. Okazaki K, Ichinose T, Mitono H, et al. Impact of protein and carbohydrate supplementation on plasma volume expansion and thermoregulatory adaptation by aerobic training in older men. J. Appl. Physiol
. 2009; 107(3):725–33.
34. Okazaki K, Yazawa D, Goto M, et al. Effects of macronutrient intake on thigh muscle mass during home-based walking training in middle-aged and older women. Scand. J. Med. Sci. Sports
. 2013; 23(5):e286–92.
35. Rhodes RE, Martin AD, Taunton JE, Rhodes EC, Donnelly M, Elliot J. Factors associated with exercise adherence among older adults. An individual perspective. Sports Med
. 1999; 28(6):397–411.
36. Rowell LB, O'Leary DS, Kellogg DL Jr. Integration of cardiovascular control systems in dynamic exercise. In: Rowell LB, Shepherd JT, editors. Handbook of Physiology: Section 12: Exercise: Regulation and Integration of Multiple Systems
. Bethesda (MD): American Physiological Society; 1996. p. 770–838.
37. Sakai A, Terasawa K, Inaki M, et al. Physical effects of the “Jukunen Taiikudaigaku Project” [article in Japanese]. Shinshu Med. J
. 2000; 48:89–96.
38. Swain DP. Exercise prescription for healthy populations. In: Swain DP, editor. ACSM’s Resource Manual for Guidelines for Exercise Testing and Prescription
. 7th Edition. Baltimore (MD): Lippincott Williams & Wilkins; 2014. p. 465–595.
39. Uchida K, Kamijo Y, Ikegawa S, Masuki S, Nose H. Effects of whey-protein and carbohydrate supplementation on plasma volume and plasma albumin content during home-based interval walking training in middle-aged and older people [abstract in Japanese]. Jpn. J. Phys. Fitness Sports Med
. 2015; 64:683.
40. Walum H, Westberg L, Henningsson S, et al. Genetic variation in the vasopressin
receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans. Proc. Natl. Acad. Sci. U. S. A
. 2008; 105(37):14153–6.
41. Yamazaki T, Gen-No H, Kamijo Y, Okazaki K, Masuki S, Nose H. A new device to estimate V˙O2 during incline walking by accelerometry and barometry. Med. Sci. Sports Exerc
. 2009; 41(12):2213–9.
42. Zhang Y, Hashimoto S, Fujii C, et al. NFκB2 gene as a novel candidate that epigenetically responds to interval walking training. Int. J. Sports Med
. 2015; 36(9):769–75.
Keywords:© 2017 American College of Sports Medicine
aging; exercise training; genetics; lifestyle-related disease; remotely supervised system; vasopressin