An Innovative Treatment Using Calcium Hydroxyapatite for Non-Surgical Facial Rejuvenation: The Vectorial-Lift Technique

Virginia Marcia Amaral1  iD• Helena Hotz Arroyo Ramos2 • Fernanda Aquino Cavallieri3 • Mariana Muniz4 • Guilherme Muzy5 • Ada Trindade de Almeida6

1 IVA Medical Institute, Av. dos Bandeirantes 1518, Belo Horizonte CEP: 30.315-032, Brazil

2 Vito´ria, Brazil

3  Rio de Janeiro, Brazil

4 Sa˜o Paulo, Brazil

5 Sa˜o Paulo, Brazil

6 Hospital do Servidor Pu´blico Municipal de Sa˜o Paulo, Sa˜o Paulo, Brazil

Received: 13 January 2024 / Accepted: 9 April 2024 / Published online: 7 May 2024

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© The Authors 2024, corrected publication 2024

Abstract  Background The facial aging process entails alterations in the volume, shape, and texture of all skin layers over time. Calcium hydroxyapatite (CaHA) is a well-established safe skin filler with unique properties to resolve some skin alterations by stimulating neocollagenesis. The vectoral-lift (V-lift) technique targets the global repositioning of facial structures by addressing distinct anatomical injection planes. It includes deep facial augmentation with Radiesse PlusTM to retain ligament restructuring and superficial subcutaneous enhancement with diluted Radiesse DuoTM. Herein, we present cases that illustrate the use of this approach.

Methods This pilot study enrolled 36 participants (33 women and three men; ages 37–68 years) in a Brazilian clinical setting, and all patients underwent a single treatment. Photographs were taken at rest, in frontal and oblique views, before injection, and 90 days after treatment.

Results Treatment resulted in elevation of the upper and middle face, notable improvements in the infraorbital hollow, and adjustment of the mean facial volume.

Conclusions The V-lift technique is a three-dimensional pan-facial treatment that relies on ligament support and face vectoring to obtain a lifting effect and facial contour restoration. It encompasses deep facial augmentation involving the use of Radiesse PlusTM for restructuring and retaining ligaments and Radiesse DuoTM for superficial subcutaneous enhancement. This approach targets a global repositioning of the facial structures by addressing distinct anatomical injection planes. It achieves a repositioning of the overall facial anatomy without requiring a substantial volumetric expansion.

Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Keywords Skin aging   Collagen  Plastic surgery  Dermatology  Aesthetics  Calcium hydroxyapatite  Biostimulation

The efcacy of hyaluronic acid fragments with amino acid in combating facial skin aging: an ultrasound and histological study

Antonio Scarano1  · E. Qorri2  · A. Sbarbati3  · S. A. Gehrke4  · Alessio Frisone1  · D. Amuso3  · Sergio Rexhep Tari1

Received: 30 March 2024 / Accepted: 17 May 2024 / Published online: 24 June 2024

© The Author(s) 2024

Antonio Scarano

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E. Qorri

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A. Sbarbati

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S. A. Gehrke

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D. Amuso

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Sergio Rexhep Tari

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1 Department of Medical, Oral and Biotechnological Sciences, University of Chieti-Pescara, Strada Marcello Mucci 38/B, 66100 Chieti, Italy

2 Department of Dentistry, Faculty of Medical Sciences, Albanian University, 1001 Tirana, Albania

3 Department of Neurosciences, Biomedicine and Movement Sciences, Anatomy and Histology Section, School of Medicine, University of Verona, Verona, Italy

4 Department of Research, Bioface/PgO/UCAM, Montevideo, Uruguay

Abstract

Background Various techniques have been employed in aesthetic medicine to combat skin aging, in particular that of the facial region. Hyaluronic acid is utilized to enhance moisture levels and extracellular matrix molecules. This study aims to histologically assess the efects of low molecular weight hyaluronic acid fragments combined with amino acids (HAAM) on facial skin rejuvenation through intradermal microinjections.

Methods A total of twenty women, with an average age of 45 and ranging from 35 to 64 years old, participated in the study, including 8 in menopause and 12 in the childbearing age group. Mesotherapy was used to administer HAAM to the patients. Prior to and three months after the treatment, each patient underwent small circular punch biopsies. Ultrasound examinations were conducted using B-mode, capturing 2D images in longitudinal or transverse orientations with frequencies ranging from 5 to 13 Mega-hertz (MY LAB X8, ESAOTE, Genova, Italy). A total of 60 ultrasound examinations were taken, with 30 collected before treatment and 30 after treatment.

Results The histological analysis demonstrates an increase in fbroblast activity resulting in the production of Type III reticular collagen, as well as an increased number of blood vessels and epidermal thickness. However, the analysis of ultrasound data before and after treatment showed no statistical diference in skin thickness in malar area, chin and mandibular angle.

Conclusions Histological assessments indicate that subcutaneous infltration of HAAM has a substantial impact on the dermis of facial skin.

Keywords Hyaluronic acid · Hyaluronic acid fragments · Amino acid · Fibroblast · Skin aging · Ultrasound

GLP1R Gene Expression and Kidney Disease Progression

Jefferson L. Triozzi, MD, MSCI; Zhihong Yu, MS, PhD; Ayush Giri, MS, PhD; Hua-Chang Chen, PhD; Otis D. Wilson, BBA; Brian Ferolito, MS; T. Alp Ikizler, MD; Elvis A. Akwo, MD, MS; Cassianne Robinson-Cohen, PhD; John Michael Gaziano, MD, MPH; Kelly Cho, PhD, MPH; Lawrence S. Phillips, MD; Ran Tao, PhD; Alexandre C. Pereira, MD, PhD; Adriana M. Hung, MD, MPH; for the VA Million Veteran Program

Key Points

Question Are glucagon-like peptide 1 receptor agonists (GLP-1RAs) associated with kidney disease progression?

Findings In this genetic association study of 353 153 adults, higher genetic GLP1R gene expression as a proxy for GLP-1RAs was associated with a small reduction in the risk of kidney disease progression, even after adjusting for obesity and diabetes.

Meaning These findings support a nephroprotective role of GLP-1RAs.

Abstract

IMPORTANCE Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control.

OBJECTIVE To investigate the association of genetically proxied GLP-1RAs with kidney disease

DESIGN, SETTING, AND PARTICIPANTS This genetic association study assembled a national retrospective cohort of veterans aged 18 years or older from the US Department of Veterans Affairs Million Veteran Program between January 10, 2011, and December 31, 2021. Data were analyzed from November 2023 to February 2024.

EXPOSURES Genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels across all tissue samples within the Genotype-Tissue Expression project.

MAIN OUTCOMES AND MEASURES The primary composite outcome was incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate. Cox proportional hazards regression survival analysis assessed the association between genetically proxied GLP-1RAs and kidney disease progression.

RESULTS Among 353 153 individuals (92.5% men), median age was 66 years (IQR, 58.0-72.0 years) and median follow-up was 5.1 years (IQR, 3.1-7.2 years). Overall, 25.7% had diabetes, and 45.0% had obesity. A total of 4.6% experienced kidney disease progression. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted model (hazard ratio [HR], 0.96; 95% CI, 0.92-0.99; P = .02) and in the fully adjusted model accounting for baseline patient characteristics, body mass index, and the presence or absence of diabetes (HR, 0.96; 95% CI, 0.92-1.00; P = .04). The results were similar in sensitivity analyses stratified by diabetes or obesity status.

CONCLUSIONS AND RELEVANCE In this genetic association study, higher GLP1R gene expression was associated with a small reduction in risk of kidney disease progression. These findings support pleiotropic nephroprotective mechanisms of GLP-1RAs independent of their effects on body weight and glycemic control.

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

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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

Use of Retinoids in Topical Antiaging Treatments: A Focused Review of Clinical Evidence for Conventional and Nanoformulations

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

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:

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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