Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

Sara C Sebag; Tate Neff; Qingwen Qian; Arvand Asghari; Zhuozhi Wang; Zeyuan Zhang; Mark Li; Meihua Hao; Vitor Lira; Hongli Sun; Matthew J. Potthoff; Ling Yang

doi:10.1101/2025.07.01.662628

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Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

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Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline

Sara C Sebag, Tate Neff, Qingwen Qian, Arvand Asghari, Zhuozhi Wang, Zeyuan Zhang, Mark Li, Meihua Hao, Vitor Lira, Hongli Sun, …

bioRxiv

Cold Spring Harbor Laboratory, 1.1

07/04/2025

DOI: 10.1101/2025.07.01.662628

PMCID: PMC12236652

PMID: 40631281

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https://doi.org/10.1101/2025.07.01.662628View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Aging-associated decline in brown adipose tissue (BAT) function and mass contributes to energy and metabolic homeostasis disruption. Alcohol dehydrogenase 5 (ADH5) is a major denitrosylase that prevents cellular nitro-thiol redox imbalance, an essential feature of aging. However, the functional significance of BAT ADH5 in the context of aging is largely unknown. Here, we aimed to investigate the role of BAT ADH5 in protecting against age-related metabolic dysfunction. We show that aging promotes aberrant BAT protein S-nitrosylation modification and downregulates ADH5 in mice. Furthermore, BAT ADH5-deletion accelerates BAT senescence and aging-associated declines in metabolic homeostasis and cognition. Mechanistically, we found that aging inactivates BAT Adh5 by suppressing heat shock factor 1 (HSF1), a well-recognized proteostasis regulator. Moreover, pharmacologically enhancing HSF1 improved BAT senescence, metabolic decline, and cognitive dysfunction in aged mice. Together, these findings suggest that the BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline. Ultimately, unraveling the role of thermogenic adipose nitrosative signaling will provide novel insights into the interplay between BAT nitric oxide activity and metabolism in the context of aging.

Physiology

Details

Title: Subtitle: Thermogenic Adipose ADH5 Counteracts Age-related Metabolic Decline
Creators: Sara C Sebag
Tate Neff
Qingwen Qian
Arvand Asghari
Zhuozhi Wang
Zeyuan Zhang
Mark Li
Meihua Hao
Vitor Lira
Hongli Sun
Matthew J. Potthoff
Ling Yang
Resource Type: Preprint
Publication Details: bioRxiv
Edition: 1.1
DOI: 10.1101/2025.07.01.662628
PMID: 40631281
PMCID: PMC12236652
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory
Language: English
Date posted: 07/04/2025
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Craniofacial Anomalies Research Center; Oral and Maxillofacial Surgery; Fraternal Order of Eagles Diabetes Research Center; Dental Research; Health, Sport, and Human Physiology
Record Identifier: 9984845656602771

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