Stress increases cardiac function, ventilation, and body temperature and induces analgesia. These changes, which result in an increase in metabolic rate, oxygen supply, and the conduction velocity of nerve impulses, prepare the body for a fight-or-flight response and collectively called as the defense response. A part of the hypothalamus called the defense area has long been known to play a key role in these responses, but the precise mechanisms are largely unknown. Our recent findings suggest that orexin (hypocretin) neurons act as a master switch of the defense response. In addition, our results, as well as those from other researchers, suggest that orexin neurons do not regulate specific behaviors such as the fight-or-flight responses, but rather integrate the autonomic functions and behaviors in a broad sense or in a vigilance state-dependent manner. The orexin system seems to be a pivotal link in the psychosomatic interaction.

Herbal medicine has not been fully accepted by mainstream medicine because of the complex nature of the formulae. However, the stringent quality control, such as that in Japan, and reproducibility of preclinical and clinical findings, together with few adverse events in aged patients, have made herbal medicine such as Ninjin’yoeito (NYT) more and more attractive for the treatment of frailty and related conditions. Klotho, originally identified as a putative aging-suppressor gene, extends lifespan and accelerates aging when disrupted. Klotho-deficient mice display multiple pathologies resembling human aging, including calcified atherosclerosis and shortened lifespan. We have recently found that NYT extends the lifespan of Klotho-deficient mice nearly 30% and improves many of the aging-related pathologies. An important action of NYT is the activation of ghrelin-neuropeptide Y (NPY) hunger system that triggers the adaptive response to starvation. The ghrelin-NPY system is dysfunctional in aging and frailty which could be improved by NYT. This review is the summary of the recent work by us and others focusing on anorexia-cachexia syndrome, frailty and herbal medicine.

It is well known that impaired glucose tolerance neuropathy is characterized by early selective involvement of small nerve fibers. We adopted compound method （laser-Doppler flowmetry and urinary myoinositol measurement） for detecting the onset of small-fiber neuropathy in impaired glucose tolerance. Moreover, we also found the existence of “pre-borderline neuropathy”. We are currently working on elucidating its pathogenesis and devising a very early diagnosis method.

We described the current concept of ‘Lewy body constipation’, i.e., constipation due to Lewy body diseases (LBD), with minimal neurologic symptoms. Epidemiology and pathology studies showed that LBD can start with constipation alone, mostly due to neuronal loss and appearance of Lewy bodies in the myenteric plexus. Since LBD significantly increases with age, ‘Lewy body constipation’ may also increase with age. Neuroimaging such as metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DAT) scan provides a way to detect ‘Lewy body constipation’. Key for ‘Lewy body constipation’ includes minimal non-motor features such as REM sleep behavior disorder (night talking). Add-on therapy may be needed to ameliorate constipation in the patients. Arriving at a diagnosis is not always easy. Therefore, collaboration of gastroenterologists and neurologists are highly recommended in order to maximize patients’ quality of life. In conclusion, ‘Lewy body constipation’ might become a distinct category among geriatric constipation, regarding patients follow-up and their management.

Multiple system atrophy is a neurodegenerative disorder characterized clinically by the combination of autonomic, cerebellar and extrapyramidal dysfunctions. The presence of autonomic dysfunctions is mandatory for the diagnosis of multiple system atrophy. However, it is usually difficult to make a diagnosis of multiple system atrophy in the early stage because some patients show moderate motor dysfunctions with slight autonomic dysfunctions, whereas other patients show moderate autonomic dysfunctions with slight motor dysfunctions. Recent studies including our reports suggested that motor dysfunctions and lower urinary dysfunctions (the most prevalent autonomic dysfunctions) are not necessarily correlated. We aimed to discuss the relationships between the severities of motor dysfunctions and lower urinary tract dysfunctions in multiple system atrophy in this mini-review.

The responses of blood pressure to stroking stimulation of the back were compared under the conditions of elevated blood pressure and normal blood pressure. The elevated blood pressure was achieved by the immersion of one hand in cold water. The subjects immersed their right hand up to the wrist level in 8-10°C water (cold immersion) or 30-32°C water (control immersion) for 3 min. Blood pressure was recorded using an automated sphygmomanometer. Stroking stimulation was manually applied to the back for 2 min at a frequency of 1 Hz, 1 min after the onset of cold or control immersion. Both systolic and diastolic blood pressures were elevated during the 3 min of cold immersion, and the elevation was significantly attenuated by the stroking stimulation. The control immersion had no effect on the systolic or diastolic blood pressure, but the diastolic (not systolic) blood pressure was significantly decreased by stroking stimulation. The present study shows that stroking stimulation lowers blood pressure, and that the effects are larger under the condition of elevated blood pressure. These results suggest that stroking stimulation is useful for normalizing the pressor responses.