- The C-terminal of SIRT1 can be cleaved by cathepsin B at amino acid H533 to generate a lower-functioning, N-terminally intact 75 kDa polypeptide (75SIRT1) that may be involved in age-related pathologies. However, mechanisms underlying cathepsin B docking to and cleavage of SIRT1 are unclear. Here, we first identify several 75SIRT1 variants that are augmented with aging correlatively with increased cathepsin B levels in various mouse tissues, highlighting the possible role of this cleavage event in age-related pathologies. Then, based on H533 point mutation and structural modeling, we generated a functionally intact ΔSIRT1 mutant, lacking the internal amino acids 528-543 (a predicted C-terminus loop domain), which exhibits resistance to cathepsin B cleavage in vitro and in cell cultures. Finally, we show that cells expressing ΔSIRT1 under pro-inflammatory stress, are more likely to undergo caspase 9-dependent apoptosis than those expressing 75SIRT1. Thus, our data suggest that the 15-amino acid predicted loop motif embedded in the C-terminus of SIRT1 is susceptible to proteolytic cleavage by cathepsin B, leading to the formation of several N-terminally intact SIRT1 truncated variants in various aging mouse tissues.