Regulation of Oxidative Stress by the Anti-aging Hormone Klotho*♦

Abstract

klotho is an aging suppressor gene and extends life span when overexpressed in mice. Klotho protein was recently demonstrated to function as a hormone that inhibits insulin/insulin-like growth factor-1 (IGF-1) signaling. Here we show that Klotho protein increases resistance to oxidative stress at the cellular and organismal level in mammals. Klotho protein activates the FoxO forkhead transcription factors that are negatively regulated by insulin/IGF-1 signaling, thereby inducing expression of manganese superoxide dismutase. This in turn facilitates removal of reactive oxygen species and confers oxidative stress resistance. Thus, Klotho-induced inhibition of insulin/IGF-1 signaling is associated with increased resistance to oxidative stress, which potentially contributes to the anti-aging properties of klotho.A defect in klotho gene expression in mice leads to a syndrome closely resembling human aging, including shortened life span, infertility, growth arrest, hypoactivity, skin atrophy, premature thymic involution, arteriosclerosis, osteoporosis, and pulmonary emphysema (1). Conversely, overexpression of the klotho gene extends the life span in the mouse (2), indicating that the klotho gene functions as an aging suppressor gene in mammals that delays aging when overexpressed and accelerates the development of aging-like disorders when disrupted. The klotho gene encodes a single-pass transmembrane protein and is expressed only in limited tissues, notably the distal convoluted tubules in the kidney and the choroid plexus in the brain (1). The extracellular domain of Klotho protein is shed and secreted into the blood. It then binds to a high affinity but as yet unidentified cell-surface Klotho receptor and signals suppression of tyrosine phosphorylation of insulin/ IGF-1 2 receptors and insulin receptor substrates (IRS), association of IRS with phosphatidylinositol 3-kinase (PI3K), and serine phosphorylation of Akt/PKB (2). Thus, Klotho protein is a hormone that inhibits the intracellular insulin/IGF-1 signaling cascade. This activity likely contributes to the suppression of aging by Klotho, because inhibition of insulin-like signaling is an evolutionarily conserved mechanism for extending life span (see Ref. 3 for review). Indeed, we observed alleviation of aging-like phenotypes in Klotho deficient mice (KL Ϫ/Ϫ mice) by genetic perturbation of insulin/IGF-1 signaling, indicating that the activity of Klotho that inhibits insulin/IGF-1 signaling accounts for its anti-aging properties, at least in part (2). It remains to be determined whether or not the inhibitory effect of Klotho protein on IRS, PI3K, and Akt is entirely dependent on its ability to inhibit insulin/IGF-1 receptors. Notably, single nucleotide polymorphisms in the human KLOTHO gene are associated with longevity (4) and common age-related diseases including coronary artery disease (5), osteoporosis (6 -8), and stroke (9), strongly arguing that Klotho regulates aging in humans. Increased resistance to oxidative stress is associated with increased longevi...

Single-gene mutations and healthy ageing in mammals

“…Extracellular domain shedding produces a circulating factor (secreted Klotho) which acts on surfaces of cells to modulate function of channels and growth factors including IGF-1, insulin and Wnt [68]. Klotho transgenics are resistant to oxidative stress, likely owing to reduced insulin/IGF-1 signalling, activation of Forkhead box, class O (FOXO) and increased expression of manganese superoxide dismutase [69].…”

Promoter methylation and age-related downregulation of Klotho in rhesus monkey

“…Our findings indicate that KL is among the genes in the brain susceptible to downregulation as a result of age-related promoter methylation. KL is involved in ion homeostasis (Nabeshima 2008) and regulation of signaling pathways (i.e., Insulin/IGF1, FGF23, and Wnt) (Kurosu et al , 2006Liu et al 2007;Utsugi et al 2000;Yamamoto et al 2005). Changes in KL gene expression would, over time, impact normal function of all downstream pathways.…”

Klotho and smoking – An interplay influencing the skeletal muscle function deficits that occur in COPD

“…Yamamoto et al showed that recombinant Klotho protected cells from oxidative stress in vitro and that manganese superoxide dismutase was increased in the muscle of Klotho over-expressing mice -consistent with a protective effect in vivo. However, they did not measure Klotho levels in muscle, indeed the mouse model used over-expressed Klotho in the brain and testis, suggesting that effects on muscle gene expression were mediated by circulating Klotho (35). Oxidative stress is increased in the quadriceps of smokers and COPD patients, in whom it relates to skeletal muscle dysfunction (36).…”