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.
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.
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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Accumulating evidence to make decisions is a core cognitive function. Previous studies have tended to estimate accumulation using either neural or behavioral data alone. Here, we develop a unified framework for modeling stimulus-driven behavior and multi-neuron activity simultaneously. We applied our method to choices and neural recordings from three rat brain regions—the posterior parietal cortex (PPC), the frontal orienting fields (FOF), and the anterior-dorsal striatum (ADS)—while subjects performed a pulse-based accumulation task. Each region was best described by a distinct accumulation model, which all differed from the model that best described the animal’s choices. FOF activity was consistent with an accumulator where early evidence was favored while the ADS reflected near perfect accumulation. Neural responses within an accumulation framework unveiled a distinct association between each brain region and choice. Choices were better predicted from all regions using a comprehensive, accumulation-based framework and different brain regions were found to differentially reflect choice-related accumulation signals: FOF and ADS both reflected choice but ADS showed more instances of decision vacillation. Previous studies relating neural data to behaviorally inferred accumulation dynamics have implicitly assumed that individual brain regions reflect the whole-animal level accumulator. Our results suggest that different brain regions represent accumulated evidence in dramatically different ways and that accumulation at the whole-animal level may be constructed from a variety of neural-level accumulators.
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