Herbal Medicine Ninjin'yoeito in the Treatment of Sarcopenia and Frailty

Abstract

Frailty and sarcopenia have recently gained considerable attention in terms of preventive care in Japan, which has an ever-increasing aging population. Sarcopenia is defined as atrophy of skeletal muscles caused by the age-related decrease in growth hormone/insulin-like growth factor and sex hormones. The Japanese Ministry of Health, Labor and Welfare reports that frailty can lead to impairment of both mental and physical functioning. Chronic diseases such as diabetes and dementia may underlie frailty. It is important to prevent progression of frailty and extend the healthy lifespan. In herbal medicine practice, including Japanese Kampo medicine, "Mibyo," a presymptomatic state, has long been recognized and may be applicable to frailty. Kampo medicines may include several medicinal plants and are thought to have the potential to improve symptoms of frailty, such as loss of appetite and body weight, fatigue, and sarcopenia, as well as anxiety, depression, and cognitive decline. Ninjin'yoeito (Ren Shen Yang Ying Tang) is the most powerful Kampo medicine and has been widely applied to palliative care of cancer patients. This review includes recent anti-aging studies and describes the effects and mechanisms of Ninjin'yoeito (Ren Shen Yang Ying Tang) when used for frailty or to extend a healthy life expectancy.

Keywords: aging; appetite loss; frailty; ghrelin-neuropeptide Y signals; herbal medicine; kampo medicine; ninjin'yoeito; sarcopenia.

Figure 1

(A) Diagnostic Criteria for Frailty by Fried et al. (4) (a) and Society on Cachexia and Wasting Disorders (b). In both guidelines, frailty is defined as the presence of at least 3 of 5 criteria, with sarcopenia (atrophy of skeletal muscles) as the basis. Frailty may be close to a presymptomatic state Mibyo in Kampo medicine. The Society on Cachexia and Wasting Disorders (a) lists disease aggregation as one of the diagnostic criteria, with frailty cases ranging from mild to severe. Frailty represents a wide range of clinical conditions that encompass emaciation as well as obesity. The appropriate permissions have been obtained from the copyright holders, Sameshima et al. (5). (B) Frailty Cascade/Cycle. Either overnutrition or malnutrition can precipitate frailty, in which both physical and psychological vulnerabilities are likely to be seen. Depression and cognitive impairment are either the causes or results of frailty. The presence of depression, for example, not only has a negative effect on treatment, but also worsens sarcopenia by inducing excessive secretion of adrenal cortical hormones or extreme reduction in physical activity. The appropriate permissions have been obtained from the copyright holders, Kuzuya (2).

Figure 2

(A) Mechanism of Sarcopenia: Positive and Negative Regulators of Skeletal Muscle. Underlying mechanisms of sarcopenia have become increasingly understood through research on brain-gut interactions. Proinflammatory cytokines activate ubiquitin ligases that cause destruction of muscle. The corticotropin-releasing factor (CRF)/glucocorticoid system, insulin resistance, and decreased androgen levels promote sarcopenia, while the hunger hormone, ghrelin, released from the stomach, and insulin-like growth factor (IGF-1) exerts a trophic action on muscle. MuRF1, muscle ring-finger protein 1; MAFbx, muscle atrophy F-box protein (Atrogin-1); IGF-1, insulin-like growth factor 1; Ang II, angiotensin II; NPY, neuropeptide Y; AgRP, agouti-related peptide; POMC, pro-opiomelanocortin; CART, cocaine- and amphetamine-regulated peptide; CRF, corticotrophin-releasing factor; 5-HT, serotonin; PVN, paraventricular hypothalamic nucleus; ARC, arcuate nucleus; LHA, lateral hypothalamic area; HC, glucocorticoids; GH, growth hormone. The appropriate permissions have been obtained from the copyright holders, Amitani et al. (11). (B) Components and Active Ingredients of Ninjin'yoeito and their Effects. Many reports have described the role of ginsenosides/saponins from ginseng root on the efficacy of Ninjin'yoeito. Other reported effects include those of ingredients derived from Atractylodes lancea rhizome and Polygala root on energy metabolism and cognition/emotion. C. unshiu peel, Poria, Glycyrrhiza root, and panaxadiol derived from ginseng root improve ghrelin signaling underlying the mechanism of action of Ninjin'yoeito, leading to appetite stimulation and improvement in sarcopenia. Ninjin'yoeito stimulates bone marrow hematopoietic and mesenchymal stem cells that may be involved in repair and regeneration of organs and tissues. The appropriate permissions have been obtained from the copyright holders, Inui (3) and Sameshima et al. (5). GHSR, growth hormone secretagogue receptor; NPY-R, NPY receptor; 5HT2cR, 5-HT2c receptor; BDNF, Brain-derived neurotrophic factor; GnRH, Gonadotropin releasing hormone; GHRH, Growth hormone releasing hormone.