Key result
Pharmacological HSF1 activation mitigates aging-associated metabolic and cognitive decline driven by BAT senescence.
Why the study?
The functional significance of brown adipose tissue ADH5 in the context of aging is largely unknown.
p-value: p=<0.05
The BAT HSF1-ADH5 signaling cascade protects against age-related systemic functional decline, suggesting a potential therapeutic target for age-related metabolic dysfunction.
Mouse data link ADH5 loss to BAT senescence and aging decline; hypothesis-generating for HSF1 activation in humans.
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 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. Age-matched littermate controls or vehicle was evaluated on Metabolic and cognitive function (e.g., glucose tolerance, energy expenditure, Barnes maze performance) (p=<0.05). Loss of thermogenic adipose tissue ADH5 accelerates brown adipose tissue senescence and exacerbates aging-associated metabolic and cognitive dysfunctions, which can be alleviated by pharmacological activation of HSF1.
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