Administration of NMN restores the glucose-responsive phenotypes in aged BESTO female mice
An alternative explanation for the absence of glucose-responsive phenotypes in the aged BESTO mice is that Sirt1 activity decreases with advanced age. Because Sirt1 requires NAD for its enzymatic activity, a decline in NAD biosynthesis with age could result in reduced Sirt1 activity and subsequent loss of the glucose-responsive phenotypes in BESTO mice. To address this possibility, we initially assessed the NAD biosynthetic capability of pancreatic islets from young (5-month-old) and old (19-month-old) BESTO mice. Because the NAD biosynthetic machinery quickly adapts to culture conditions, we cultured isolated islets in RPMI media containing a physiological concentration (1 μM) of nicotinamide, a major precursor to NAD, for ~24 h prior to measuring the NAD content per 100 islets. No difference was detected in NAD content between young and old BESTO islets in vitro (Fig. 6A), suggesting that the NAD biosynthetic capability of the BESTO islets does not alter during aging.