Introduction: aging research comes of age.
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Aging↗
Biomedical subjects
M Kuroo
Publications and source records attributed to M Kuroo.
Cellular and molecular mechanism of low-turnover osteopenia in the klotho-deficient mouse.
The mouse homozygous for a disruption of the klotho locus (KL-/- or klotho mouse) exhibited multiple pathological conditions resembling human aging. We observed osteopenia in KL-/- mice with a low bone turnover, in which the decrease in bone formation exceeded the decrease in bone resorption and resulted in net bone loss. This pathophysiology resembles closely that of senile osteoporosis in humans. Osteoblastic cells from KL-/- mice proliferated normally in vitro; however, they showed much lower alkaline phosphatase activity and mineralized matrix formation than those from control mice. Cultured osteoclastic cells from KL-/- mice had normal resorbing activity and survival rate, but the differentiation of osteoclastic cells from their precursors was significantly disturbed: in the co-culture of osteoblastic cells and osteoclast precursor cells, the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclastic cells was extremely poor only when osteoclast precursor cells originated from KL-/- mice independently of the origin of the osteoblastic cells. In addition, we found that osteoprotegerin a secreted factor which inhibits osteoclastogenesis, was up-regulated in KL-/- mice. We conclude that a defect in klotho gene expression leads to the independent impairment of osteoblast and osteoclast differentiation, which can be a cause of low-turnover osteoporosis.
Aging↗
Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases.
The human aging process is associated with vascular endothelial dysfunction. However, humoral factors which might protect against endothelial dysfunction during aging have not yet been identified. We recently identified the klotho gene as a possible regulator of human aging. In the present study using the klotho-deficient heterozygous mouse, we examined whether the Klotho protein is a humoral factor protecting against endothelial dysfunction. We further cloned rat klotho cDNA and investigated whether klotho mRNA expression in rat kidney is altered under pathological conditions such as hypertension, hyperlipidemia, renal failure, and inflammatory stress. The Klotho protein itself, or its metabolites, promotes endothelial NO production in aorta as well as arterioles, and klotho mRNA in kidney is downregulated under sustained circulatory stress.
Acetylcholine↗
[The protective role of Klotho gene on vascular endothelium].
Arteriosclerosis caused by aging is recognized to be a crucial risk factor of cardiovascular disease. We recently established Klotho mouse that causes age-related disorders including arteriosclerosis. The Klotho gene encodes a novel cell surface protein of 1014 amino acids. In humans, a secretory form of Klotho cDNA has been isolated, but the pathophysiological role of Klotho protein remains to be elucidated. We demonstrate that the vasodilator response of aorta to acetylcholine is significantly attenuated in and homozygous Klotho mice as compared with wild-type mice. Parabiosis between wild-type and heterozygous Klotho mice results in restoration of endothelial function in heterozygous Klotho mice. These results suggest that the Klotho protein protects the cardiovascular system through endothelium-derived NO production by humoral pathways.
Aging↗
[Development of a novel mouse model for human aging].
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Aging↗
[Vascular smooth muscle cells and arteriosclerosis].
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Arteriosclerosis↗
Cardiovascular disease in the aged: overview of an autopsy series.
As an overview of cardiovascular disease in the aged, 3657 autopsy cases were analyzed for the frequency and age-wise incidence of cardiovascular disease. The three major categories, ischemic heart disease, valvular heart disease, and aortic aneurysm and dissection were described. 1. The incidence of overall cardiovascular disease increases sharply between the ages of 60 and 75. Prevention and treatment could be effectively directed at this age group. 2. The incidence of organic cardiovascular disease was: myocardial infarction 19.8 percent; valvular disease 10.0 percent; arteriosclerosis obliterans 3.5 percent; aortic aneurysm and dissection 3.3 percent; pericarditis 2.1 percent; cardiomyopathy 1.6 percent; cor pulmonale 1.4 percent; congenital heart disease 0.7 percent; and others 0.8 percent. 3. As coronary sclerosis progresses, death from ischemic heart disease increases; however, 7 out of 10 patients with 3 vessel disease still die of causes other than ischemic heart disease (pneumonia, malignancy etc.). The general management of infection and malignant neoplasms is important in addition to treatment of cardiovascular disease. 4. Except for mitral stenosis, valvular heart disease, the etiology of which is mostly non-rheumatic, increases with advancing age. 5. In aortic aneurysm, the rupture rate is relatively high in the thoracic aorta; however, this may be caused by the successful surgical repair of abdominal aneurysms. An aneurysm below 6 cm in diameter is not absolutely safe from rupture. 6. In aortic dissection, the interval from onset to the death of the patient is often too short to consider surgery.
Age Factors↗