Sirtuin Expression in Age-Associated Hepatic Response to Burn Trauma: Translational and Clinical Insights From a Murine Model

Background Burn injuries can lead to substantial liver damage, and this response appears to worsen with age. Although clinical patterns suggest that older individuals are more susceptible to poor outcomes, the biological mechanisms contributing to this increased vulnerability are poorly understood. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD⁺)-dependent enzymes involved in cellular stress regulation, metabolism, and aging, may play a key role in modulating the hepatic response to burn injury. This study explores the potential mechanistic involvement of sirtuins in age-related liver damage following thermal injury. Methods Female C57BL/6 mice (young: four months; aged: 20-22 months) underwent sham or 15% total body surface area scald burn. Liver tissue was collected at 24- and 48-hours post-injury for quantitative polymerase chain reaction (qPCR) analysis of all seven sirtuin family members. Results Burn injury significantly altered hepatic sirtuin expression in an age- and time-dependent manner. Inflammatory regulators, <i>Sirt1</i> and <i>Sirt2</i>, showed immediate downregulation in young mice with partial recovery at 48 hours, while aged mice exhibited delayed, more profound, and persistent suppression. In contrast, mitochondrial sirtuins (<i>Sirt3-5</i>) were downregulated in both age groups, and only young burned mice showed recovery of <i>Sirt3</i> and <i>Sirt4</i> expression at 48 hours. The most pronounced age-dependent difference occurred with <i>Sirt4</i>. At this time point, the expression of <i>Sirt4</i> was 71% higher in young burned mice compared to aged injured counterparts (p < 0.05). Genome stability regulating <i>Sirt6</i> and <i>Sirt7</i> exhibited age-specific responses, with <i>Sirt6</i> remaining stable in young injured mice, while <i>Sirt7</i> was lower in aged mice at 48 hours (p < 0.05). Conclusion This study reveals for the first time that burn injury triggers age-dependent alterations in the pattern of hepatic sirtuin expression, with delayed and/or more severe and persistent suppression across all sirtuin family members. These findings provide new mechanistic insights into the dysregulation of critical cellular homeostatic mechanisms in aged livers following burn injury and identify sirtuins as potential therapeutic targets for mitigating age-associated hepatic damage in elderly burn patients.