Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

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01 11月 2024

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Author : 伤口世界

Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging

Gérald J. Prud’homme 1,2,* and Qinghua Wang 3,4

1 Department of Laboratory Medicine and Pathobiology, University of Toronto, 220 Walmer Rd, Toronto, ON M5R 3R7, Canada

2 Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON M5B 1W8, Canada

3 Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai 200030, China

4 Shanghai Innogen Pharmaceutical Co., Ltd., Shanghai 201318, China

* Correspondence: 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

Citation: Prud’homme, G.J.; Wang, Q. Anti-Inflammatory Role of the Klotho Protein and Relevance to Aging. Cells 2024, 13, 1413. https://doi.org/ 10.3390/cells13171413

Academic Editors: Fabrizio

Montecucco and

Nickolay Brustovetsky

Received: 1 August 2024

Revised: 17 August 2024

Accepted: 23 August 2024

Published: 24 August 2024

Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Abstract: The α-Klotho protein (hereafter Klotho) is an obligate coreceptor for fibroblast growth factor 23 (FGF23). It is produced in the kidneys, brain and other sites. Klotho insufficiency causes hyperphosphatemia and other anomalies. Importantly, it is associated with chronic pathologies (often age-related) that have an inflammatory component. This includes atherosclerosis, diabetes and Alzheimer’s disease. Its mode of action in these diseases is not well understood, but it inhibits or regulates multiple major pathways. Klotho has a membrane form and a soluble form (s-Klotho). Cytosolic Klotho is postulated but not well characterized. s-Klotho has endocrine properties that are incompletely elucidated. It binds to the FGF receptor 1c (FGFR1c) that is widely expressed (including endothelial cells). It also attaches to soluble FGF23, and FGF23/Klotho binds to FGFRs. Thus, sKlotho might be a roaming FGF23 coreceptor, but it has other functions. Notably, Klotho (cell-bound or soluble) counteracts inflammation and appears to mitigate related aging (inflammaging). It inhibits NF-κB and the NLRP3 inflammasome. This inflammasome requires priming by NF-κB and produces active IL-1β, membrane pores and cell death (pyroptosis). In accord, Klotho countered inflammation and cell injury induced by toxins, damage-associated molecular patterns (DAMPs), cytokines, and reactive oxygen species (ROS). s-Klotho also blocks the TGF-β receptor and Wnt ligands, which lessens fibrotic disease. Low Klotho is associated with loss of muscle mass (sarcopenia), as occurs in aging and chronic diseases. s-Klotho counters the inhibitory effects of myostatin and TGF-β on muscle, reduces inflammation, and improves muscle repair following injury. The inhibition of TGF-β and other factors may also be protective in diabetic retinopathy and age-related macular degeneration (AMD). This review examines Klotho functions especially as related to inflammation and potential applications.

Keywords: aging; Alzheimer; atherosclerosis; inflammasome; FGF23; fibrosis; Klotho; NF-κB; sarcopenia; TGF-β

This article is excerpted from the Cells 2024, 13, 1413. https://doi.org/10.3390/cells13171413 by Wound World.

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Use of Retinoids in Topical Antiaging Treatments: A Focused Review of Clinical Evidence for Conventional and Nanoformulations 2024-10-31 00:00

Daniela Milosheska . Robert Roskar

Received: August 17, 2022 / Accepted: September 6, 2022 / Published online: October 11, 2022

©The Author(s) 2022

ABSTRACT

Nowadays, numerous skincare routines are used to rejuvenate aging skin. Retinoids are one of the most popular ingredients used in antiaging treatments. Among the representatives of retinoids, tretinoin is considered the most effective agent with proven antiaging effects on the skin and can be found in formulations approved as medicines for topical treatment of acne, facial wrinkles, and hyperpigmentation. Other retinoids present in topical medicines are used for various indications, but only tazarotene is also approved as adjunctive agent for treatment of facial fine wrinkling and pigmentation. The most commonly used retinoids such as retinol, retinaldehyde, and retinyl palmitate are contained in cosmeceuticals regulated as cosmetics. Since clinical efficacy studies are not required for marketing cosmetic formulations, there are concerns about the efficacy of these retinoids.

From a formulation perspective, retinoids pose a challenge to researchers as a result of their proven instability, low penetration, and potential for skin irritation. Therefore, novel delivery systems based on nanotechnology are being developed to overcome the limitations of conventional formulations and improve user compliance. In this review, the clinical evidence for retinoids in conventional and nanoformulations for topical antiaging treatments was evaluated. In addition, an overview of the comparison clinical trials between tretinoin and other retinoids is presented. In general, there is a lack of evidence from properly designed clinical trials to support the claimed efficacy of the most commonly used retinoids as antiaging agents in cosmeceuticals. Of the other retinoids contained in medicines, tazarotene and adapalene have clinically evaluated antiaging effects compared to tretinoin and may be considered as potential alternatives for antiaging treatments. The promising potential of retinoid nanoformulations requires a more comprehensive evaluation with additional studies to support the preliminary findings.

Keywords: Antiaging; Clinical evidence; Cosmeceuticals; Nanoformulations; Retinoids; Retinol; Tretinoin

Key Summary Points

Tretinoin is the retinoid present in medicines for topical application with the strongest clinical evidence of antiaging Tazarotene and adapalene may be considered as tretinoin alternatives for antiaging treatments.

Clinical evidence is lacking for retinoids contained in cosmeceuticals for topical antiaging treatments.

Novel formulations based on nanotechnology are being developed to overcome the major drawbacks of retinoid Further evaluation with in vivo testing and clinical trials are needed to support the preclinical results for the developed nanoformulations containing retinoids.

D. Milosheska INSLAB, Maribor, Slovenia

R. Roskar (&)

University of Ljubljana, Faculty of Pharmacy, Askerceva cesta 7, 1000 Ljubljana, Slovenia

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations 2024-10-30 00:00

Gérald J. Prud’homme1,2 *, Mervé Kurt 2 and Qinghua Wang3,4

1 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada,

2 Department of Laboratory Medicine, Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, ON, Canada,

3 Department of Endocrinology and Metabolism, Huashan Hospital, Shanghai Medical School, Fudan University, Shanghai, China,

4 Shanghai Yinuo Pharmaceutical Co., Ltd., Shanghai, China

Edited by:

Cátia F. Lourenço, University of Coimbra, Portugal

Reviewed by:

Mujib Ullah, Stanford University, United States Taylor Landry, East Carolina University, United States

*Correspondence:

Gérald J. Prud’homme 该Email地址已收到反垃圾邮件插件保护。要显示它您需要在浏览器中启用JavaScript。

Specialty section:

This article was submitted to Molecular Mechanisms of Aging, a section of the journal Frontiers in Aging

Received: 28 April 2022

Accepted: 06 June 2022

Published: 12 July 2022

Citation:

Prud’homme GJ, Kurt M and Wang Q (2022) Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations. Front. Aging 3:931331.

doi: 10.3389/fragi.2022.931331

The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

Keywords: aging, FGF23, hyperphosphatemia, klotho, IGF-1, NF-KappaB, TGF-beta, Wnt
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