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other·ophthalmology, dry eye, endocrinology, preclinical research, biomedical research·PMC10154200

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

Nature Aging · 25 authors, 12 centres

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TL;DR

This study used mouse models and human imaging to show that age-related decline in the intracrine enzyme 3β-HSD causes meibomian gland atrophy. Reactivating this enzyme with an NAD+ precursor eye drop improved gland structure in aged mice.

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The study investigated the molecular mechanism of age-associated meibomian gland dysfunction (MGD), a common cause of dry eye. Using mouse models, including genetic deletion of the 3β-HSD enzyme, the authors demonstrated that local intracrine steroidogenesis, dependent on NAD+ and circadian activity, governs meibomian gland health. Aged mice and human subjects showed meibomian gland atrophy. The study establishes a causal link between declining intracrine 3β-HSD activity and age-related MGD, proposing a potential mechanism-based therapeutic strategy. Limitations include the use of animal models and the need for further clinical evaluation in humans.

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other

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ophthalmology

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ORIGINAL PAPER

PMC10154200

Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction

Nature Aging

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ABSTRACT

Abstract Canonically, hormones are produced in the endocrine organs and delivered to target tissues. However, for steroids, the concept of tissue intracrinology, whereby hormones are produced in the tissues where they exert their effect without release into circulation, has been proposed, but its role in physiology/disease remains unclear. The meibomian glands in the eyelids produce oil to prevent tear evaporation, which reduces with aging. Here, we demonstrate that (re)activation of local intracrine activity through nicotinamide adenine dinucleotide (NAD + )-dependent circadian 3β-hydroxyl-steroid dehydrogenase (3β-HSD) activity ameliorates age-associated meibomian gland dysfunction and accompanying evaporative dry eye disease. Genetic ablation of 3β-HSD nullified local steroidogenesis and led to atrophy of the meibomian gland. Conversely, reactivation of 3β-HSD activity by boosting its coenzyme NAD + availability improved glandular cell proliferation and alleviated the dry eye disease phenotype. Both women and men express 3β-HSD in the meibomian gland. Enhancing local steroidogenesis may help combat age-associated meibomian gland dysfunction. Subject terms: Ageing, Endocrine system and metabolic diseases

CITATION EXPORT

Lena Sasaki, Yuki Hamada, Daisuke Yarimizu et al.. Intracrine activity involving NAD-dependent circadian steroidogenic activity governs age-associated meibomian gland dysfunction. Nature Aging. (2022). https://doi.org/10.1038/s43587-021-00167-8

AUTHORS

25 · 12 CENTRES

Lena Sasaki, Yuki Hamada, Daisuke Yarimizu, Tomo Suzuki, Hiroki Nakamura, Aya Shimada, Khanh Tien Nguyen Pham, Xinyan Shao, Koki Yamamura, Tsutomu Inatomi, Hironobu Morinaga, Emi K Nishimura, Fujimi Kudo, Ichiro Manabe, Shogo Haraguchi, Yuki Sugiura, Makoto Suematsu, Shigeru Kinoshita, Mamiko Machida, Takeshi Nakajima, Hiroshi Kiyonari, Hitoshi Okamura, Yoshiaki Yamaguchi, Takahito Miyake, Masao Doi

1Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan
2Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
3Department of Ophthalmology, Kyoto City Hospital, Kyoto, Japan
4Department of Ophthalmology, National Center for Geriatrics and Gerontology, Aichi, Japan
5Dpartment of Stem Cell Biology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
6Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan
7Department of Biochemistry, Showa University School of Medicine, Tokyo, Japan
8Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan
9Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan
10Senju Laboratory of Ocular Sciences, Senju Pharmaceutical Co., Kobe, Japan
11Laboratory for Animal Resources and Genetic Engineering, RIKEN Center for Biosystems Dynamics Research, Kobe, Japan
12Division of Physiology and Neurobiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan