Increased ghrelin signaling prolongs survival in mouse models of human aging through activation of sirtuin1.

Caloric restriction (CR) is known to retard aging and delay functional decline as well as the onset of diseases in most organisms. Ghrelin is secreted from the stomach in response to CR and regulates energy metabolism. We hypothesized that in CR ghrelin has a role in protecting aging-related diseases. We examined the physiological mechanisms underlying the ghrelin system during the aging process in three mouse strains with different genetic and biochemical backgrounds as animal models of accelerated or normal human aging. The elevated plasma ghrelin concentration was observed in both klotho-deficient and senescence-accelerated mouse prone/8 (SAMP8) mice. Ghrelin treatment failed to stimulate appetite and prolong survival in klotho-deficient mice, suggesting the existence of ghrelin resistance in the process of aging. However, ghrelin antagonist hastened death and ghrelin signaling potentiators rikkunshito and atractylodin ameliorated several age-related diseases with decreased microglial activation in the brain and prolonged survival in klotho-deficient, SAMP8 and aged ICR mice. In vitro experiments, the elevated sirtuin1 (SIRT1) activity and protein expression through the cAMP-CREB pathway was observed after ghrelin and ghrelin potentiator treatment in ghrelin receptor 1a-expressing cells and human umbilical vein endothelial cells. Furthermore, rikkunshito increased hypothalamic SIRT1 activity and SIRT1 protein expression of the heart in the all three mouse models of aging. Pericarditis, myocardial calcification and atrophy of myocardial and muscle fiber were improved by treatment with rikkunshito. Ghrelin signaling may represent one of the mechanisms activated by CR, and potentiating ghrelin signaling may be useful to extend health and lifespan.

[The effect of body respirator on the desaturation during the night in Duchenne muscular dystrophy].

Recently body respirator (BR) has been used to control respiratory failure in patients with late stage Duchenne muscular dystrophy (DMD). We examined the effect of BR using a pulse oximeter. Arterial oxygen saturation (SaO2) for the night (21:00-7:00) was monitored in 15 DMD patients (5 cases without BR, 3 cases with BR partially for the night and 6 cases with BR all night long) and the desaturation (SaO2 less than 90%) time was followed three times (Jan. '87, Nov. '87, Apr. '88) in each patient. Desaturation time did not increase in 4 cases without BR. But in one case without BR it increased so much that we decided to put the patient on BR. In 3 cases with BR partially for the night, desaturation was well controlled when they used BR. No marked increase of desaturation was found in 4 cases with BR all night long. 2 of these cases were changed from cuirass type BR to jacket type BR and were getting on satisfactorily. Thoracic cage expansion of jacket type was larger than that of cuirass type, and it was found that jacket type was valuable. Also, we investigated the cause of desaturation by recording SaO2, nasal flow, thoracic cage motion and abdominal motion at the same time by making use of a polygraphy. The result showed that the main cause of desaturation was the resistance of thoracic cage motion against BR. And we think research and development is needed.

Chronic progressive myelopathy associated with elevated antibodies to human T-lymphotropic virus type I and adult T-cell leukemialike cells.

Six adult patients had a chronic progressive myelopathy that possessed the following features: high antibody titers to human T-lymphotropic virus type I (HTLV-I) in serum and cerebrospinal fluid (CSF); predominantly upper motor neuron disorder, symmetrical, with mild sensory and bladder disturbances; and presence of adult T-cell leukemia-like cells in both peripheral blood and CSF. We refer to this entity as HTLV-I-associated myelopathy (HAM). Electrophoretic studies of immunoglobulin G in CSF using Western blot analysis characteristically demonstrated p24 and p32 bands. Rates of intra-blood-brain barrier synthesis were determined and found increased in the patients with HAM. Corticosteroid treatment produced clinical improvement in all of 4 patients. A retrospective survey of CSF samples was carried out in 287 patients with neurological disorders, and 6 additional patients with HAM were identified.