Klotho: An Elephant in Aging Research - PubMed (original) (raw)

Review

Klotho: An Elephant in Aging Research

Amin Cheikhi et al. J Gerontol A Biol Sci Med Sci. 2019.

Abstract

The year 2017 marked the 20th anniversary of the first publication describing Klotho. This single protein was and is remarkable in that its absence in mice conferred an accelerated aging, or progeroid, phenotype with a dramatically shortened life span. On the other hand, genetic overexpression extended both health span and life span by an impressive 30%. Not only has Klotho deficiency been linked to a number of debilitating age-related illnesses but many subsequent reports have lent credence to the idea that Klotho can compress the period of morbidity and extend the life span of both model organisms and humans. This suggests that Klotho functions as an integrator of organ systems, making it both a promising tool for advancing our understanding of the biology of aging and an intriguing target for interventional studies. In this review, we highlight advances in our understanding of Klotho as well as key challenges that have somewhat limited our view, and thus translational potential, of this potent protein.

Keywords: Biomarker; Geroscience; Health span; Klotho; Longevity.

© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Figures

Figure 1.

Figure 1.

The Klotho gene consists of five exons and four introns with several hundreds of genomic variants in both coding and non-coding sequences that are predicted to affect the splicing of the gene transcript. Two Klotho messenger RNAs (mRNAs) messages are produced: a canonical transcript encoding the full-length membrane Klotho protein or a processed transcript harboring premature termination codons that undergo nonsense mRNA decay in processing bodies. Klotho possesses two homologous domains KL1 and KL2. Shedding α-cut (after the membrane portion of Klotho) generates a “full-length” soluble Klotho, whereas shedding at both β-cut and α-cut (between KL1 and KL2) results in KL1 and KL2, respectively. NMD = nonsense-mediated decay; TM = transmembrane.

Figure 2.

Figure 2.

Annotated Klotho variants (n = 1,090) using Gencode, version 19 with variant effect prediction, version 85 from the Genome Aggregation Database (gnomAD). This database spans 123,136 exomes and 15,496 genomes from unrelated individuals sequenced as part of various international disease-specific and population genetic projects, including the 1,000 genomes, Alzheimer’s Disease Sequencing Project, Atrial Fibrillation Genetics Consortium, T2D-SEARCH, and the Cancer Genome Atlas.

Figure 3.

Figure 3.

Aged animals (22–24 mo old) received intraperitoneal injections of recombinant mouse α-Klotho (1.05 μg/200 μL injection; R&D Systems, 1819-KL, aa 35-982) or isotonic saline for 6 consecutive days immediately after injury. (A) Force-frequency curves obtained via in situ contractile testing of anterior compartment strength (n = 5–6/group; two-way repeated measures analysis of variance, *p < .05; one animal removed from the saline group for analysis due to electrode misplacement). (B) Hang impulse (calculated as hanging time (s) × mouse bodyweight [g]) at 14 d post-injury (n = 5–6/group; *p < .05, one-tailed Student’s _t_-test).

Figure 4.

Figure 4.

Recombinant human Klotho (SFN23) stability after thawing was evaluated over 3 d. Enzyme-linked immunosorbent assay (ELISA) was performed at 1 hr, 1, 2, and 3 d after Klotho was stored at +4°C from a –80°C freezer. The recombinant human Klotho ELISA optical density (OD) values were compared with the provided kit standard reference OD values. Results reveal that the activity of recombinant human Klotho rapidly decreases when stored at +4°C.

Figure 5.

Figure 5.

Immunohistochemistry staining validation of two commercially available Klotho antibodies from two different vendors (Antibody #1 and Antibody #2). Each of the antibodies were diluted at 1:400 in an antibody solution (3% bovine serum albumin + 0.1% Triton-X + 5% goat serum) made in phosphate-buffered saline. Tibialis anterior muscle of Klotho wild-type (Kl+/+) and hypomorphs (Kl-/-) 7 d post-injury were incubated with one of the two antibodies overnight at 4°C, and images obtained were thresholded to negative control images.

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