Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging

doi:10.1016/j.tem.2006.01.002

Trends in Endocrinology & Metabolism

Volume 17, Issue 2, March 2006, Pages 33-35

https://doi.org/10.1016/j.tem.2006.01.002 Get rights and content

It was recently reported by Kurosu et al. that overexpression of Klotho, a newly discovered hormone, extends longevity of mice. Because Klotho induces IGF-1 and insulin resistance, these findings appear to contradict previous evidence for increased life span of dwarf mice with reduced IGF-1 and insulin levels and enhanced insulin sensitivity. However, activation of signaling molecules downstream from IGF-1 and insulin receptors is reduced in both Klotho and dwarf mice, suggesting common mechanisms of delayed aging.

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Acknowledgements

Studies in our laboratory related to this topic are supported by the National Institute on Aging and by the Ellison Medical Foundation.

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Cited by (83)

Serum klotho protein levels and their correlations with the progression of type 2 diabetes mellitus
2017, Journal of Diabetes and its Complications
To investigate the associations of serum α-Klotho and β-Klotho levels with type 2 diabetes mellitus (T2DM) progression.
We evaluated 106 healthy controls and 261 cases of T2DM with or without diabetic complications (range: 45–84 years). Serum α-Klotho and β-Klotho levels were analyzed using enzyme-linked immunosorbent assays.
Compared to the healthy controls, α-Klotho and β-Klotho levels were significantly lower among patients with T2DM and with or without diabetic complications (P < 0.05). Furthermore, α-Klotho levels were lower in the microalbuminuric and macroalbuminuric groups, compared to the normoalbuminuric group. However, β-Klotho levels were only lower in the macroalbuminuric group (P < 0.05). Multiple linear regression analyses revealed that α-Klotho and β-Klotho levels were positively correlated with the creatinine clearance rate, and negatively correlated with the urinary albumin to creatinine ratio and randomly sampled serum levels of creatinine, blood urea nitrogen, and blood glucose. Moreover, α-Klotho and β-Klotho levels were positively correlated among patients with T2DM (r = 0.693, P < 0.001).
Serum levels of α-Klotho and β-Klotho are down-regulated in patients with T2DM. Thus, these proteins may participate in the pathological mechanism of diabetes, and the positive correlation of α-Klotho and β-Klotho levels indicates that they might have similar mechanisms in T2DM.
Tetrahydroxystilbene glucoside extends mouse life span via upregulating neural klotho and downregulating neural insulin or insulin-like growth factor 1
2015, Neurobiology of Aging
Citation Excerpt :
Reduced level of Klotho has also been observed in the brains of aged mammals (Duce et al., 2008). Klotho ablates the effect of the insulin/IGF-1 signaling pathway's signals with aging process and can be mutually regulatory (Bartke, 2006). Consistent with the theory, TSG delays aging by increasing the levels of klotho in aged mice (Xu et al., 2009).
A Chinese herb, Polygonatum multiflorum, has been reported to prolong animal life span, but the relevant molecular mechanism remains unclear. Tetrahydroxystilbene glucoside (TSG) is one main component of P. multiflorum and may contribute to extending life span of mammals. On the other hand, neuronal insulin signaling mediates the life span of mammals. Therefore, we investigated the effects of TSG on memory ability, life span, and the neural insulin signaling in the senescence-accelerated prone mouse (SAMP8). TSG improved the memory ability significantly (p < 0.01, compared with a control group). TSG prolonged the life span of SAMP8 by 17% at the most (p < 0.01, compared with a control group). TSG increased the protein level of neural klotho and reduced the levels of neural insulin, insulin-receptor, insulin-like growth factor-1, and insulin-like growth factor-1 receptor in the brain of SAMP8 (p < 0.01, compared with a control group). All these proteins are key factors of the pathways related to neural insulin/IGF-1 signaling. These findings suggest that TSG has anti-aging effects on mammals. From these results, TSG from P. multiflorum should be developed as a potential anti-age drug.
Fibroblast growth factor 23 and Klotho serum levels in healthy children
2014, Bone
Citation Excerpt :
Thus, the higher Klotho levels in girls and pubertal children we found, in the presence also of higher IGF-I levels in the same groups, could reflect a counterregulatory action on the IGF-I sparing effect on phosphate in order to maintain an appropriate phosphate homeostasis. In addition, we cannot exclude that Klotho increases secondary to increased IGF-I levels in order to inhibit the augmented IGF-I signaling according to in vitro studies [50–54]. To our knowledge, this is so far the largest study in healthy children where FGF23 and Klotho were measured simultaneously.
Data for fibroblast growth factor 23 (FGF23) and particularly for Klotho in healthy children are limited. We aimed to investigate the relationship between FGF23 and Klotho with age and TmP/GFR and to evaluate parameters that might affect FGF23 and Klotho. In 159 healthy children (82 boys) with a mean ± SD age of 8.78 ± 3.47 years we measured FGF23 (intact FGF23/iFGF23 and C-terminal FGF23/cFGF23) and soluble aKlotho serum levels by ELISA. Mean ± SD value for cFGF23, was 51.14 ± 12.79 RU/ml whereas median (range) values for iFGF23 and Klotho were 35 (8.8, 120) pg/ml and 1945 (372, 5866) pg/ml respectively. Neither FGF23 nor Klotho were significantly associated with age. Pubertal children had higher Klotho than prepubertal (p < 0.05), and girls had higher levels of cFGF23 (p < 0.05) and Klotho (p < 0.001) than boys. Serum phosphate and TmP/GFR were positively associated with cFGF23 (p < 0.01 and p < 0.001), iFGF23 (p < 0.05 and p < 0.001) and Klotho (p < 0.05 and p < 0.01). Klotho was positively correlated with IGF-I (p < 0.0001) and 1,25 (OH)₂ vitamin D (p < 0.05).
In this study we provide data on cFGF23, iFGF23, and Klotho measured simultaneously in healthy children. The positive association of serum phosphate and TmP/GFR with FGF23 and Klotho suggests that they have a counterregulatory effect on phosphate homeostasis. The strong association of Klotho with IGF-I could indicate a role of Klotho in linear growth through phosphate regulation, but further studies are required.
Overexpression of α-Klotho isoforms promotes distinct Effects on BDNF-Induced Alterations in Dendritic Morphology
2024, Molecular Neurobiology
The Role of the FGF19 Family in the Pathogenesis of Gestational Diabetes: A Narrative Review
2023, International Journal of Molecular Sciences
Renal Function Mediates the Association Between Klotho and Congestive Heart Failure Among Middle-Aged and Older Individuals
2022, Frontiers in Cardiovascular Medicine

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Trends in Endocrinology & Metabolism

Research FocusLong-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging

Section snippets

Acknowledgements

Mech. Ageing Dev.

The endocrine regulation of aging by insulin-like signals

Science

Evolutionary medicine: from dwarf model systems to healthy centenarians?

Science

Dwarf mice and the ageing process

Nature

Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production

Proc. Natl. Acad. Sci. U. S. A.

Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span

Endocrinology

Research Focus
Long-lived Klotho mice: new insights into the roles of IGF-1 and insulin in aging