Protein Controls Aging by Controlling Insulin

Researchers have demonstrated that overexpression of a gene, called Klotho, in mice extends their life span by between 19% to 31% longer than normal mice.

The gene expresses a protein that works by repressing intracellular signals of insulin and insulin-like growth factor-1 (IGF1), and may function as an anti-aging hormone in mammals, they say.

The study, published online in Science Express, was conducted by researchers at the University of Texas Southwestern Medical Center, Dallas.

Therapies based on this hormone could prove to be a way to extend life or slow its effects, said Makoto Kuro-o, MD, PhD, assistant professor, pathology, and senior author of the study.

Kuro-o and colleagues originally discovered the Klotho gene in 1997, naming it after one of the mythical Greek fates who controlled the length of human life.

Their previous studies have shown that mutant mice lacking the Klotho gene appear normal until about three to four weeks old, and then begin showing signs of age, such as skin atrophy, osteoporosis, arteriosclerosis, and emphysema. The mice died prematurely at about two months.

However, they say, little is known about Klotho protein function and the molecular mechanism by which it suppresses the development of aging-like phenotypes.

“Many genetic data demonstrate that inhibited insulin/IGF1 signaling extends life span in animals from C. elegans [and] Drosophila to mice,” the researchers write.

“Because Klotho must mediate aging through effects of a systemic hormone, we investigated whether the Klotho gene is involved in the inhibition of insulin or IGF1 signaling.”

For the current study, using a second strain of mutant mice overexpressing Klotho, they demonstrated that Klotho is an aging suppressor gene whose product functions as a hormone that inhibits intracellular insulin/IGF1 signaling. These mice outlived wild type controls by 19% to 31%.

The researchers also identified an extracellular Klotho peptide detected in the transgenic mice at twice the normal level.

They then generated a soluble form of recombinant Klotho protein comprising the peptide domain and injected it into normal mice to see if it promoted insulin resistance.

They found that the peptide modulates the insulin/IGF1 signaling pathway, which some recent research shows may be the mechanism that extends longevity in animals that are fed an ultra-low-calorie diet.

“Extended life span upon negative regulation of insulin/IGF1 signaling is an evolutionarily conserved mechanism to suppress aging. Klotho appears to be a peptide hormone to modulate such signaling and thereby mediate insulin metabolism and aging,” the researchers conclude.

The influence on insulin may make it difficult to develop the protein itself as a therapy against aging but other substances that mimic the protein’s anti-aging effects could be more practical, Kuro-o says