The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function
- University of PIttsburgh, United States
- University of Pittsburgh, United States
- University of Florida, United States
- Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
- Boehringer Ingelheim Pharma GmbH & Co. KG, United States
Abstract
Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.
Data availability
Sequencing data has been deposited in GEO accession: GSE156343.
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The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle functionNCBI Gene Expression Omnibus, GSE156343.
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Tabula Muris SenisNCBI Gene Expression Omnibus, GSE132040.
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Skeletal Muscle Transcriptome in Healthy AgingNCBI Gene Expression Omnibus, GSE164471.
Article and author information
Author details
Funding
National Institute on Aging (R01AG052978)
- Fabrisia Ambrosio
National Institute on Aging (R01AG061005)
- Fabrisia Ambrosio
Boehringer Ingelheim
- Fabrisia Ambrosio
J.H., S.K. and M.F. are employees of Boehringer Ingelheim Pharmaceutical Company. They contributed to development, testing and validation of the AAV-Klotho vector, as well as the overall study design.
Reviewing Editor
- Yousin Suh, Columbia University, United States
Ethics
Animal experimentation: All animal experiments were performed with prior approval from the Institutional Animal Care and Use Committee of the University of Pittsburgh. These experiments were conducted in accordance with protocol 17080802 (University of Pittsburgh ARO: IS00017744). All surgeries and invasive procedures were performed under isoflurane anesthesia, with painkillers administered afterwards. Every effort was made to minimize suffering.
Version history
- Received: July 16, 2020
- Accepted: April 6, 2021
- Accepted Manuscript published: April 20, 2021 (version 1)
- Version of Record published: May 13, 2021 (version 2)
Copyright
© 2021, Clemens et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The biphasic and age-dependent impact of Klotho on hallmarks of aging and skeletal muscle function
eLife 10:e61138.
https://doi.org/10.7554/eLife.61138
Further reading
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Accurate prediction of the structurally diverse complementarity determining region heavy chain 3 (CDR-H3) loop structure remains a primary and long-standing challenge for antibody modeling. Here, we present the H3-OPT toolkit for predicting the 3D structures of monoclonal antibodies and nanobodies. H3-OPT combines the strengths of AlphaFold2 with a pre-trained protein language model and provides a 2.24 Å average RMSDCα between predicted and experimentally determined CDR-H3 loops, thus outperforming other current computational methods in our non-redundant high-quality dataset. The model was validated by experimentally solving three structures of anti-VEGF nanobodies predicted by H3-OPT. We examined the potential applications of H3-OPT through analyzing antibody surface properties and antibody–antigen interactions. This structural prediction tool can be used to optimize antibody–antigen binding and engineer therapeutic antibodies with biophysical properties for specialized drug administration route.
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Background:
Preterm birth is the leading cause of neonatal morbidity and mortality worldwide. Most cases of preterm birth occur spontaneously and result from preterm labor with intact (spontaneous preterm labor [sPTL]) or ruptured (preterm prelabor rupture of membranes [PPROM]) membranes. The prediction of spontaneous preterm birth (sPTB) remains underpowered due to its syndromic nature and the dearth of independent analyses of the vaginal host immune response. Thus, we conducted the largest longitudinal investigation targeting vaginal immune mediators, referred to herein as the immunoproteome, in a population at high risk for sPTB.
Methods:
Vaginal swabs were collected across gestation from pregnant women who ultimately underwent term birth, sPTL, or PPROM. Cytokines, chemokines, growth factors, and antimicrobial peptides in the samples were quantified via specific and sensitive immunoassays. Predictive models were constructed from immune mediator concentrations.
Results:
Throughout uncomplicated gestation, the vaginal immunoproteome harbors a cytokine network with a homeostatic profile. Yet, the vaginal immunoproteome is skewed toward a pro-inflammatory state in pregnant women who ultimately experience sPTL and PPROM. Such an inflammatory profile includes increased monocyte chemoattractants, cytokines indicative of macrophage and T-cell activation, and reduced antimicrobial proteins/peptides. The vaginal immunoproteome has improved predictive value over maternal characteristics alone for identifying women at risk for early (<34 weeks) sPTB.
Conclusions:
The vaginal immunoproteome undergoes homeostatic changes throughout gestation and deviations from this shift are associated with sPTB. Furthermore, the vaginal immunoproteome can be leveraged as a potential biomarker for early sPTB, a subset of sPTB associated with extremely adverse neonatal outcomes.
Funding:
This research was conducted by the Perinatology Research Branch, Division of Obstetrics and Maternal-Fetal Medicine, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, U.S. Department of Health and Human Services (NICHD/NIH/DHHS) under contract HHSN275201300006C. ALT, KRT, and NGL were supported by the Wayne State University Perinatal Initiative in Maternal, Perinatal and Child Health.
