Targeting SIRT1 Rescues Age- and Obesity-Induced Microvascular Dysfunction in Ex Vivo Human Vessels

Area of Science:

• Vascular Biology
• Aging Research
• Metabolic Syndrome

Background:

• Experimental evidence implicates silent information regulator 1 (SIRT1) in age- and metabolic-related vascular dysfunction.
• The role of SIRT1 in the human microvasculature, particularly in early-stage dysfunction, remains largely unknown.
• This study investigates SIRT1's role in the earliest microvascular changes associated with aging and obesity in humans.

Purpose of the Study:

• To investigate the role of silent information regulator 1 (SIRT1) in early human microvascular dysfunction.
• To determine if SIRT1 modulation can ameliorate age- and obesity-induced endothelial dysfunction.
• To explore the epigenetic mechanisms underlying SIRT1's influence on microvascular health.

Main Methods:

• Recruited 95 subjects stratified by age and BMI into four groups: Young Nonobese, Young Obese, Old Nonobese, and Old Obese.
• Assessed endothelial function using pressurized micromyography, measuring responses to a SIRT1 agonist (SRT1720) and a mitochondria reactive oxygen species (mtROS) scavenger (MitoTEMPO).
• Quantified vascular mtROS, nitric oxide (NO) availability, and gene expression of SIRT1 and mitochondrial proteins; investigated SIRT1-dependent epigenetic regulation via chromatin immunoprecipitation.

Main Results:

• Obese and older individuals exhibited lower vascular SIRT1 and antioxidant protein (FOXO3, SOD2) expression, alongside increased pro-oxidant proteins (p66Shc, Arginase II).
• Endothelial dysfunction in Old Obese, Young Obese, and Old Nonobese groups was significantly improved by SRT1720, comparable to MitoTEMPO treatment.
• SIRT1-dependent epigenetic changes reduced p66Shc and increased mitochondrial respiratory chain protein expression, explaining the functional improvements.

Conclusions:

• Silent information regulator 1 (SIRT1) is a critical regulator of early microvascular damage caused by aging and obesity.
• SIRT1 influences mtROS levels and NO availability through epigenetic control of p66Shc, Arginase II, and mitochondrial proteins.
• Therapeutic targeting of SIRT1 shows promise for preventing and treating age- and obesity-related microvascular dysfunction.