Suppression of Aging

A spontaneous homozygous loss-of-function mutation in KLOTHO (KL) gene (OMIM 604824, chromosome 13q12) was initially described in a strain of mice with accelerated aging and premature death.¹ Its human homolog was later identified. KL encodes a transmembrane protein expressed in renal distal convoluted tubules and neural choroid plexus. Kurosu et al developed 2 strains of transgenic mice that overexpressed Kl under the control of the promoter of human elongation factor 1α. Both male and female animals overexpressing Kl lived 20% to 30% longer than did wild-type (WT) control mice. They did so without restricting caloric intake or impeding somatic growth; however, fecundity was reduced in like-breeding pairs. Mice overexpressing Kl were euglycemic, but males had higher serum insulin concentrations than did WT controls, and both genders had attenuated hypoglycemic responses to exogenous insulin and/or insulin-like growth factor (IGF)-I. The serum concentration of the extracellular domain of Klotho was twice as high in transgenic as in WT mice. Intraperitoneal administration of Klotho protein increased blood glucose concentrations and depressed the hypoglycemic effect of co-injected insulin. In vitro in cultured cells, Klotho peptide did not inhibit binding of insulin or IGF-I to their specific receptors, but specifically suppressed autophosphorylation of these receptors and impaired insulin-stimulated glucose uptake. Furthermore, Klotho down-regulated intracellular signaling transmitted through insulin receptor substrate (IRS)-1 and -2 and phosphoinositide 3-kinase p85. In Kl^-/- mice who die prematurely, life could be substantially prolonged and signs of aging halted (ie, arteriosclerosis, renal calcification, testicular atrophy) by decreasing a generation of IRS-1. The authors concluded that Klotho was a secreted protein (ie, a hormone) that extended life and suppressed aging by antagonizing the cellular effects of insulin and IGF-I.

Klotho overexpression extends life span in the mouse. Kaplan-Meier analysis of survival in males [P = 0.006 in EFmKL46 versus WT mice, and P<0.0001 in EFmKL48 versus wild type by log-rank test).

Editor’s Comment: Klotho may be the long sought after elixir from the “fountain of youth.” KLOTHO is named after the mythological Greek Fate who spun the “thread of life.” By alternative RNA splicing, KL generates 2 transcripts: a 1012 amino acid protein with extracellular, transmembrane, and intracellular domains and a 549 amino acid peptide, the amino terminal sequence of the extracellular domain that is secreted and is the predominant form produced. In man, single-nucleotide polymorphisms in KL have been associated with altered life span and risk for atherosclerosis and osteoporosis.² That increased generation of Klotho extended life span without impairing growth emphasizes the distinctive difference between the effects of this gene and that related to caloric deprivation, another experimental mechanism to prolong life. Although both processes act by impeding insulin and IGF-I action, Klotho apparently enhances their production but antagonizes their function, while caloric deprivation depresses their production and impairs growth and fertility. These studies reinforce the concept that decreased secretion of growth hormone, insulin, and IGF-I extends life and suppresses aging,³ a concept that is the opposite of that voiced by many lay “anti-aging authorities.” Although excess Klotho decreased fecundity between like-breeding pairs of mice, the effect of this protein on the fertility of a mouse with a high level of Klotho when mated with a WT animal remains to be explored. Conceptually, there appears to be a “trade-off” between life span and reproduction. It will be of great interest to measure serum concentrations of Kotho at various stages of life and in various hormonal and metabolic disorders, particularly those involving energy utilization, as well as to determine its physiologic (and potentially therapeutic and anti-aging) effects in humans of all ages.


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Current GGH - Vol. 24 No. 1 View table of contents Download PDF
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