Previously, we showed that thyroid hormone (TH) triiodothyronine (T₃) enhanced β-cell functional maturation through induction of Mafa High levels of T₃ have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T₃ increased p16^Ink4a (a β-cell senescence marker and effector) mRNA in rodent and human β-cells. The kinetics of Mafa and p16^Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16^Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16^Ink4a , whereas THRB1 bound to Mafa but not to p16^Ink4a On a cellular level, T₃ treatment accelerated cell senescence as shown by increased number of β-cells with acidic β-galactosidase activity. Our data show that T₃ can simultaneously induce both maturation (Mafa) and aging (p16^Ink4a ) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional β-cells for replacement therapies in diabetes.

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