Frailty impairs a healthy lifespan, and the core element of frailty is a decline in physical function, such as muscular strength and walking ability [1
]. Furthermore, frailty has come to be recognized as a broad health problem that involves not only physical but also psychological aspects, such as diminished cognitive function and depression, and social problems, such as withdrawal and isolating behaviors [2
]. Although frailty is a problem mainly in older age, studies have also found relationships between hypertension and cerebrovascular dementia [3
], and between diabetes and Alzheimer’s disease [4
]. Lifestyle-related diseases in middle age can also increase the risk of frailty; hence, starting prevention of frailty is critical in middle age as well as for older adults.
It is widely known that physical activity (PA) positively contributes to health, and an inactive lifestyle can lead to health problems [5
]. PA controls obesity and other lifestyle-related diseases during middle age, and also lessens the risk of muscle weakness, decreased balancing capacity, falls, and fractures in the elderly [8
]. A previous study indicates that physical activity level and activity energy expenditure are negatively associated with age after 52 years old, although they are not associated with age between 18 and 52 years old [10
]. Numerous reports have examined the relationship between health and time spent sedentary (time spent sitting, watching television, driving, performing office work, etc.), and many of these reports have identified correlations between sedentary time and the onset of pathologies including diabetes and cardiovascular disease, as well as mortality risk [11
]. PA can help in improving not only physical problems but also psychological problems such as Alzheimer’s disease and depression, as well as overall improved quality of life (QOL) [12
]. As such, increasing one’s amount of PA is believed to be essential for maintaining good health, particularly from middle age onward.
Capsiate, dihydrocapsiate, and nordihydrocapsiate (referred to as capsinoids) are analog compounds of capsacin, a physiologically active heat compound, and were discovered from non-pungent chili pepper cultivar, CH-19 sweet, by Yazawa and his colleagues [14
]. Physiological actions of capsinoids reported to date include an energy-metabolism-promoting effect, a body-heat-production-promoting effect and a body-fat-mass-reducing effect that has been confirmed in mice and humans [16
]. For this reason, the ingestion of capsinoids is believed to reduce body fat mass in overweight individuals and reduce the risk of onset of lifestyle-related diseases.
The aging process has been shown to be associated with an increase in the proinflammatory status of organisms, and it is proposed that age-associated increase in chronic inflammation is a highly significant risk factor for age-associated disorders (called the inflamm-aging theory) [20
]. The brain is not an exception; chronic inflammation is found in the human aging brain, and it is considered to be responsible for age-associated neurodegenerative disease [21
]. Artificially induced brain inflammation was also found to suppress spontaneous activity in rats and mice; therefore, age-related chronic inflammation in the brain is supposed to lead to decreased physical activity in middle-aged and older adults [22
]. Nevertheless, inflammation-mitigating agent recovered the locomotor activity impaired by artificially induced inflammation [22
]. There are some findings that capsinoids have anti-inflammation pharmacological effect in vivo; mice treated with nordihydrocapsiate and dihydrocapsiate showed less peripheral inflammation [24
]. Although there are no reports which elucidate whether capsinoids reduce inflammation in the central nervous system, considering these, we presumed that capsinoids alleviate age-related brain inflammation and increase PA in middle-aged and older adults. Cumulating research shows that brain inflammation is also a possible factor for geriatric depression [26
]. Assuming that capsinoids have an anti-inflammation effect in the human brain, it may be expressed as a positive change of mood states.
In addition, women who often complain of feeling cold (chills or cold hypersensitivity) have been reported to suffer from swelling in the lower extremities, dizziness when standing up, stiff shoulders, and fatigue [28
]. However, some improvement was observed following ingestion of capsinoids with respect to subjective complaints concerning chills by young women, and they were also shown to improve accompanying indefinite complaints such as dull head pain and shoulder stiffness [29
We therefore hypothesized that (1) continuous oral intake of capsinoids for three months would increase PA in middle-aged and older adults, and the effect would be more pronounced in participants with sedentary lifestyles, (2) capsinoids would reduce visceral fat accumulation that would cause lifestyle-related diseases, especially in overweight participants, (3) capsinoids would alleviate the age-related brain inflammation and lead to improved PA, and (4) capsinoids would also attenuate cold hypersensitivity. For these aims, we conducted human and mice research.
In this study, we investigated our hypothesis that continuous ingestion of capsinoids for 3 months would increase PA in middle-aged and elderly people as measured using an activity meter. We especially focused on LMPA because it covers almost all the daily PA in older adults [32
]. However, we failed to find a significant effect of capsinoids on LMPA among our participants. Individual differences in the physical activity levels of the subjects were large; for example, the mean value of time attributable to baseline LMPA per day varied from 233 min to 606 min across all participants. It is possible that this variation may have obscured the effects of capsinoids ingestion. Thus, we focused our analysis on participants found to spend long periods in sedentary positions, that is, inactive participants. As a result of this subgroup analysis, we found that subjects from the CP exhibited significantly higher times and amounts of LMPA than subjects from the PL. We calculated and checked the energy expended in physical activity in both groups and confirmed that the increased LMPA was related to increased energy expenditure in CP from inactive participants.
Several reports from past studies using activity monitors on Japanese older adults stated that physical activities of 6 METs or more are observed scarcely in daily life. In our study, VPA with 6.0 METs or more was not observed at all in 33 subjects, and the mean activity period per day at this level was just 0.5 min. It can be inferred based on this observation that LMPA, which is the sum of all light- and moderate-intensity activity, comprises nearly the total amount of daily physical activity of the subjects in this study. Stated differently, the above results indicate that the total amount of physical activity per day increased in CP subjects who exhibited an inactive tendency.
Numerous papers have agreed on the importance of moderate physical activity (3.0 METs or more and less than 6.0 METs) to maintaining physical functions, preventing diseases, and reducing mortality rates [5
]. Meanwhile, the value of the contribution of light physical activity to health has become recognized in recent years [32
]. As a result of a several studies conducted by categorizing low-intensity physical activity of less than 3.0 METs into either low-intensity light physical activity (LLPA) of 1.6 METs or more and less than 2.0 METs, or high-intensity light physical activity (HLPA) of 2.0 METs or more and less than 3.0 METs, HLPA has been reported to improve insulin resistance, activity as mild as walking has been reported to have led to reduced severity of stroke events, and these activities have been partially correlated with physical functions in elderly Japanese women [38
]. Furthermore, a study by Buman et al. [41
] demonstrated that HLPA contributes to health to the same degree as moderate physical activity and also contributes greatly to subjective life satisfaction. Even more interestingly, this study also found that replacing just 30 min of sedentary time with light physical activity can lead to improvements in both overall health and subjective lifestyle assessment. Although no reduction in sedentary time was observed in the CP subjects in this study who exhibited inactive tendencies, the significant increase in the time and amount of LMPA in these same subjects suggested that continuous ingestion of capsinoids led to improvements in physical functions, overall health, and thus subjective lifestyle satisfaction.
In our animal research to elucidate the relation between brain inflammation and PA, we found that old mice were less active than young mice, whereas capsinoids supplementation improved age-related reduction of PA in animals as well as humans (Figure 4
Capsinoids are reported as a potent anti-inflammatory compound that targets specific immune pathways and reduces the extensive damage of inflammation in mice [25
]. In our animal study, as shown in Figure 4
A–C, old mice with ND indicated less activity and aging-induced increase of mRNA levels related to inflammation in the brain, whereas old mice with DHCte were as active as young mice, and inflammation-related mRNA levels were suppressed. The anti-inflammatory effect of DHCte in the brain, not only in peripheral tissues, can at least partly contribute to improving physical activity in older mice, and it may also explain the increased LMPA in inactive older adults. We hypothesized that the alleviation of brain inflammation would appear as positive change of mood state; however, it was unclear. The inflammation in the brain is presumed to be responsible for age-related brain deteriorations; therefore, the possible function of capsinoids as an anti-inflammation ligand needs further investigation.
Another possible interpretation is that the capsinoids were responsible for the change in energy production. Both one-time ingestion and 2 week continuous ingestion of capsinoids suppressed glucose use by increasing oxidative phosphorylation in muscles and facilitating lipid use [42
]. Additionally, mice that ingested capsinoids exhibited longer endurance swimming capacity, implying that capsinoids-induced change in energy production increases endurance exercise capacity [44
]. To relate these findings to the present study, capsinoids ingestion may have supported sustained physical exercise in the elderly subjects, thereby reducing their reluctance to physical activity and their sense of fatigue.
Based on the results of analysis of the body-composition-related evaluation items, significant decreases were observed in CP subjects with respect to waist circumference, visceral fat index, and body fat percentage. Moreover, our subgroup analysis focusing on overweight subjects (excluding obese subjects) also found significant decreases in body fat percentage. These findings are consistent with previous studies and are considered to be the result of the lipid-oxidation-enhancing physiological effect of capsinoids [18
Continuous ingestion of capsinoids has been reported to promote the formation of brown adipose tissue and thereby to accelerate thermogenesis, which may lead to alleviation of complaints of chills [19
]. Chills are a common complaint in Japanese people: 53.1% of men and 81.6% of women aged 65 or older, as well as 71.0% of men and 95.2% of women aged 75 or older, have complained of cold hands and feet (Japanese Ministry of Health, Labour and Welfare, 2010). Takagi et al. [47
] conducted a study focused on thermogenesis and reported that women who chronically felt cold had lower basal energy consumption and sympathetic nervous activity related to body temperature regulation and heat production. Additionally, another study found that young men and women who ingested the CH-19 sweet pepper directly exhibited increased sympathetic nervous activity and elevated tympanic membrane temperature, so capsinoids ingestion may relieve these causes of chills [48
]. In the present study, subjects over 80 years of age tended to feel reduced chilly sensation. In another study, following an intravenous injection of physiological saline cooled to 4 °C, middle-aged and elderly subjects exhibited lower concentrations of norepinephrine in the blood, less oxygen intake increase, and less blood flow decrease to the fingertips compared to younger subjects, resulting in lower body core temperatures than the younger subjects [49
]. This result suggests that age-related deterioration in the capacity of homeostasis may be responsible for the chilly sensation, and this is consistent with the observation of more frequent complaints of chills in older people. The results of our study suggest that enhancement of sympathetic nervous activity and subsequent thermogenic effects due to capsinoids ingestion were especially noticeable in subjects aged 80 years or older who experienced particularly lowered homeostatic capacity. This study investigated the effects of capsinoids on cold sensitivity in middle-aged and elderly subjects for the first time; however, further study will be necessary in the future.
We have considered that our sample size of the human study was adequate, but there were many deficiencies in the data. It possibly caused the results of all participants to not be very clear. Further investigations with subjects of sufficient number and similar properties would be needed.