Potential Ameliorative Effects of Kampo Medicines Ninjin’yoeito and Kamikihito on Frailty-Like Behavior in Naturally Aged C57BL/6J Mice

Abstract

Frailty is defined as an age-related decline in physiological reserve and increased vulnerability to stress. As frailty is a multifaceted condition, there is no effective pharmacotherapy for it yet. Ninjin'yoeito (NYT) and Kamikihito (KKT), traditional Japanese medicines (Kampo medicines), are promising in treating multifaceted conditions of frailty including fatigue and mental anxiety. However, their effects are still unclear. In this study, the effects of NYT and KKT on different types of frailty in naturally aged mice were explored by survival, physical aspects (Frailty Assessment Scores and muscle strength measurements), psychological aspects (sucrose splash test for motivation-related behavior), and social aspects (rescue-like behavior test for prosocial behavior). Mice aged 22-months were fed a diet containing 3% NYT or 3%KKT for 13 weeks until the age of 25 months. Behavioral alterations in old mice were compared with those in adult mice (five months old). Throughout the study period, Old-control mice showed frailty-like symptoms, including elevation of frailty assessment score, reduction of muscle strength and motivation for self-care, and rescue-like behavior compared to adult mice. NYT increased the survival rate of old mice and suppressed the declines in their frailty assessment score, muscle strength, and motivation for self-care. KKT reduced decreases in the frailty assessment score, motivation for self-care, and rescue-like behavior in old mice. These results suggest that NYT and KKT alleviate general frailty-like symptoms in old mice. Additionally, NYT may extend lifespan. These findings suggest that NYT and KKT may be helpful for improving the multifaceted symptoms of frailty.

Review of frequently used Kampo prescriptions: Part 4, Ninjin'yoeito

“…Previous studies indicated that NYT exerted ghrelinneuropeptide Y (NPY) pathway-mediated appetiteenhancing effects [81][82][83] and increased blood albumin levels [84], thereby improving the nutritional state. Experiments using older mice and mouse aging models revealed that NYT inhibited muscle strength [85][86][87] and volume loss [85,88], and also prevented muscular telomere shortening [85]. Muscle protein synthesis was promoted and degradation was inhibited.…”

“…Previous studies indicated that NYT ameliorated dementia or depression/anxiety [94][95][96] by increasing the levels of neurotrophic factors [94,97], attenuating the inhibition of neurogenesis [95,98], suppressing microglial overactivity [99], increasing cerebral blood flow [100], and enhancing cerebral glucose metabolism [92]. Furthermore, NYT improved diminished motivation [86,87,101,102] and suppressed the hypothalamic-pituitary-adrenal (HPA) axis by downregulating the sympathetic-adrenal-medullary (SAM) axis and GABA neurons to improve sociability [103].…”

“…On the basis of these findings, NYT may be an effective treatment for frailty and various steps of the frailty cycle (Figure 4). Furthermore, NYT was shown to inhibit aging-related reductions in body temperature [86], body weight [85,90], hearing [104], memory [84], cardiopulmonary function [85], bone mass [85], thymus/spleen weights [85], and prolonged the lifespan as well [85,87,105].…”