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Updated: May 7, 2025
A Simplified and Efficient Method to Isolate Primary Human Keratinocytes from Adult Skin Tissue
Published on: August 25, 2018
The aldose reductase inhibitors AT-001, AT-003 and AT-007 attenuate human keratinocyte senescence
Gautham Yepuri1, Kushie Kancharla1, Riccardo Perfetti2
1Diabetes Research Program, Holman Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, New York University School of Medicine, New York, NY, United States.
Abstract:
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: high glucose (HG), hydrogen peroxide (H2O2) 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.
Insights
Novel aldose reductase inhibitors (ARIs) effectively reduce skin cell senescence markers. These findings suggest ARIs could be potential treatments for aging skin and related diseases.
Area of Science:
- Dermatology and Cellular Biology
- Biochemistry and Molecular Biology
Background:
- Skin aging involves the accumulation of senescent keratinocytes, contributing to chronological aging.
- Cellular senescence can occur independently of chronological aging and be accelerated by pathological conditions.
- Oxidative stress-induced keratinocyte senescence is linked to aldose reductase (AR), a key polyol pathway enzyme.
Purpose of the Study:
- To investigate the efficacy of three novel synthetic aldose reductase inhibitors (ARIs): AT-001, AT-003, and AT-007.
- To determine if these ARIs can attenuate induced skin cell senescence in primary normal human keratinocytes (NHK cells).
Main Methods:
- Senescence was induced in NHK cells using high glucose (HG), hydrogen peroxide (H2O2), and mitomycin-c (MMC).
- The effects of ARIs were assessed by measuring senescence markers: SA-β-galactosidase activity, γ-H2AX foci, gene expression (CDKN1A, TP53, SERPINE1), reactive oxygen species (ROS), and senescence-associated secretory phenotypes (SASP).
Main Results:
- All three novel ARIs (AT-001, AT-003, AT-007) significantly inhibited key markers of induced senescence in NHK cells.
- The ARIs demonstrated efficacy in reducing SA-β-galactosidase activity, γ-H2AX foci, specific gene expression, ROS generation, and SASP.
Conclusions:
- The study confirms the potential role of aldose reductase inhibitors in mitigating keratinocyte senescence.
- These findings support the preclinical and clinical investigation of ARIs for attenuating skin aging and associated diseases.
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