Key result
HSF1 activation alleviates aging-related metabolic and cognitive decline driven by brown fat ADH5 loss.
Why the study?
The functional significance of brown adipose tissue ADH5 in protecting against age-related metabolic dysfunction in the context of aging was largely unknown.
Does BAT ADH5 deletion or HSF1 enhancement affect age-related metabolic decline and cognitive dysfunction in mice?
Does BAT ADH5 deletion or HSF1 enhancement affect age-related metabolic decline and cognitive dysfunction in mice?
The BAT HSF1-ADH5 signaling cascade plays a key role in protecting against age-related systemic functional decline, highlighting a potential therapeutic target for metabolic and cognitive aging.
BAT ADH5-HSF1 signaling protects against murine aging phenotypes; leaves open translation to human metabolic or cognitive therapies.
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 elevates 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 age-related BAT senescence, metabolic decline, and cognitive dysfunction. 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 bioactivity and metabolism in the context of aging.
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Sebag et al. (2025) studied Age-related metabolic decline. BAT ADH5 deletion and HSF1 activation vs. Wild-type littermates or vehicle was evaluated on BAT senescence and metabolic homeostasis. Loss of thermogenic adipose tissue ADH5 accelerates brown adipose tissue senescence and exacerbates aging-associated metabolic and cognitive dysfunctions, which can be alleviated by HSF1 activation.
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