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BRIEF RESEARCH REPORT article

Front. Aging
Sec. Interventions in Aging
Volume 5 - 2024 | doi: 10.3389/fragi.2024.1466281
This article is part of the Research Topic Aging and Small Molecules: Mechanisms and Molecular Signaling Controlling Aging Phenotype View all articles

The Aldose Reductase Inhibitors AT-001, AT-003 and AT-007 Attenuate Human

Provisionally accepted
Gautham Yepuri Gautham Yepuri 1Kushie Kancharla Kushie Kancharla 1Riccardo Perfetti Riccardo Perfetti 2Shoshana Shendelman Perfetti Shoshana Shendelman Perfetti 2Andrew Wasmuth Andrew Wasmuth 2Ravichandran Ramasamy Ravichandran Ramasamy 1*
  • 1 Diabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, New York 10016., New York, United States
  • 2 Applied Therapeutics,Inc, New York, New York, United States

The final, formatted version of the article will be published soon.

    Human skin plays an important role protecting the body from both extrinsic and intrinsic factors.Skin aging at cellular level, which is a consequence of accumulation of irreparable senescent keratinocytes is associated with chronological aging. However, cell senescence may occur independent of chronological aging and it may be accelerated by various pathological conditions.Recent studies have shown that oxidative stress driven keratinocyte senescence is linked to the rate limiting polyol pathway enzyme aldose reductase (AR). Here we investigated the role of three novel synthetic AR inhibitors (ARIs) AT-001, AT-003 and AT-007 in attenuating induced skin cell senescence, in primary normal human keratinocytes (NHK cells), using three different senescence inducing agents: hyperglycemia (HG), hydrogen peroxide (H 2 O 2 ) and mitomycin-c (MMC). To understand the efficacy of ARIs in reducing senescence, we have assessed markers of senescence, including SA-β-galactosidase activity, γ-H2AX foci, gene expression of CDKN1A, TP53 and SERPINE1, reactive oxygen species generation and senescence associated secretory phenotypes (SASP). Strikingly, all three ARIs significantly inhibited the assessed senescent markers, after senescence induction. Our data confirms the potential role of ARIs in reducing NHK cell senescence and paves the way for preclinical and clinical testing of these ARIs in attenuating cell aging and aging associated diseases.

    Keywords: aldose reductase, Aldose reductase inhibitors, Skin cell aging, senescence, Oxidative Stress

    Received: 17 Jul 2024; Accepted: 28 Nov 2024.

    Copyright: © 2024 Yepuri, Kancharla, Perfetti, Perfetti, Wasmuth and Ramasamy. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Ravichandran Ramasamy, Diabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, New York 10016., New York, United States

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