A new mouse mutant, termed klotho, was discovered that exhibits a syndrome resembling human aging, including a reduced life span, decreased activity, infertility, osteoporosis, arteriosclerosis, atrophy of the skin, etc. All these phenotypes were caused by the disruption of a single gene, klotho (Figs. 1 and 3).
The klotho gene encodes a novel protein that appears to function outside of the cells (secreted protein), and thus it is very different from that involved in previously described prematureaging syndromes and cell senescence, which function in the nucleus. In addition, the klotho gene exhibited a homology to b-glucosidase enzymes of both bacteria and plants. Evidence is accumulating that Klotho protein functions through a signaling pathway involving a circulating humoral factor(s) (Fig. 3).
Despite the fact that klotho mutant mice show systemic aging phenotypes, only limited organs express the klotho gene endogenously.
Klotho protein administered into limited organs rescued all of the systemic aging phenotypes of the klotho mutant. Thus, the possibility is raised that the Klotho protein functions as a humoral factor or "anti-aging hormone" (Fig. 3).
The klotho mutant mouse, the first laboratory animal model established, is expected to bring new insights into human aging mechanisms and also to validate the novel concept that a humoral factor(s) can regulate aging.