Proper Control of Inflammatory Cell Death during Aging of Brown Adipose Tissue (BAT)
Human studies suggest that loss of brown adipose tissue (BAT) is associated with decreased energy expenditure during aging, but the exact mechanism of BAT loss is not fully understood. This project focuses on determining the basic mechanisms responsible for BAT during aging. In a mouse model of premature aging, Dr. Shinoda found that caspase-1-dependent inflammatory cell death ("pyroptosis") of brown adipocytes is significantly increased, although the activation mechanism is unclear. BAT function and mass decline during chronological aging, and during BAT aging there is a concomitant increase in progenitor markers, indicating loss of brown adipocyte identity. BAT regression can be reversed by the caspase-1 inhibitor VX-765. Based on these findings, Dr. Shinoda formulated the central hypothesis that aging causes brown adipocyte involution via the inflammasome-Casp1 axis and that inhibition of a specific inflammasome protein or Casp1 ameliorates age-related metabolic diseases by preserving BAT.
