Fig. 5. FOXO4-DRI decreases senescence and counters features of frailty in fast aging Xpd^TTD/TTD mice.

A) Representative mice and quantification of p16^ink4a-driven RLUC Radiance in 26wk young wildtype and Xpd^TTD/TTD mice crossed into p16∷3MR. B) Left: Timeline for visualization of effects of FOXO4-DRI or PBS on p16-driven senescence by bioluminescence in Xpd^TTD/TTD. Middle: Representative visualization of p16^ink4a-driven senescence in the same Xpd^TTD/TTD-p16∷3MR mouse before and after FOXO4-DRI. Right: Quantification of the effects of FOXO4-DRI or PBS on senescence in a larger cohort of Xpd^TTD/TTD-p16∷3MR mice. C) Timeline for measuring the effects of FOXO4-DRI or PBS on hair density, behavior and running wheel activity in D–I. D) FOXO4-DRI improves fur appearance of Xpd^TTD/TTD mice. Left panels: Representative images of the same Xpd^TTD/TTD animal before and after treatment with FOXO4-DRI. Right panel: quantification of the average change in fur score (See also Fig. S5A). E) Quantification of abdominal temperature measured by infrared thermometer as measure for fur density of wt vs. Xpd^TTD/TTD mice (left) and the effects of FOXO4-DRI and PBS in the mice from D and Fig. S5A (right). F) Quantification of the response of the Xpd^TTD/TTD mice from D to gentle physical stimuli before and after treatment with FOXO4-DRI or PBS. Note that Xpd^TTD/TTD mice are generally relatively non-responsive. See also Fig. S5B. G) Quantification of the average distance run per day of wt. vs Xpd^TTD/TTD. H) Example of changes in running wheel behavior of a wt vs. Xpd^TTD/TTD mouse treated with FOXO4-DRI. Data normalized to 100% for respective running wheel activity at baseline. On day 10 a blood sample was taken, resulting in a transient decrease in activity. I) Quantification of the average change in running wheel activity in wildtype and Xpd^TTD/TTD mice after PBS or FOXO4-RI treatment.