1. Cycle p19 ARF expression in pancreatic compartment (old mice) Islets Exocrine Krishnamurthy et al., Supp. Figure 1 a Cycle ∆ Reaction Age-induced increase in p16 INK4a expression in purified islets Old Young bc Old Islet (64-80 weeks) Young Islet (12-14 weeks) = p15 INK4b p18 INK4c p19 INK4d p21 CIP p27 KIP 0.06 0.13 0.25 0.5 1 2 4 8 16 Relative Expression p16 INK4a Arf Pdx1 ExocrineIsletExocrineIslet 12-14 weeks64-80 weeksAge: 0.06 0.13 0.25 0.5 1 2 4 8 16 Relative Expression pdx expression in pancreatic compartment (old mice) Cycle Islets Exocrine

2. Krishnamurthy et al., Supp. Figure 2 Tg Line Hi Tg Line Lo 129SvEv C57/bl6 129SvEv 7.2 kb 8.5 kb PI = Intron encoded nuclease PI-SceI RI = Eco RI IIII = Variable microsatellite region  = PCR screening primers R1 11 23 11 Ink4a/Arf locus Linearised BAC PI probe R1 11 23  9.8 kb  54 kb PI   Relative Expression (transgenic/wild-type) a bc 0.5 1 2 4 8 16 32 p16 INK4a Arf << << < < < Adrenal Heart Intestine Kidney Liver Lung Pancreas Skin Spleen Geometric Mean < = undetectable in wild-type

3. Krishnamurthy et al., Supp. Figure 3 spleenuteruspancreasInk4a -/- cerebellum spleenuteruspancreas cerebellum lung p16 INK4a +/+p16 INK4a TG p16 INK4a IP: p16

4. 40-52 week old mice (all) 40-52 week old mice (excluding tumor-bearing outliers) 17-20 week old mice p16 INK4a +/+ (N=13) 100 200 300 400 500 020406080100 p16 INK4a -/- (N=13) Serum glucose (mg/dl) 100 200 300 400 500 020406080100 p16 INK4a +/+ (N=10) p16 INK4a -/- (N=8) Minutes post-IP glucose 100 200 300 400 500 020406080100 p16 INK4a +/+ (N=10) p16 INK4a -/- (N=6) Krishnamurthy et al., Supp. Figure 4 17-20 Week40-52 WeekAge: Weight (grams) 10 20 30 40 p16 INK4a +/+ p16 INK4a -/- a b

5. Untreated 3 days post-STZ 0 2. 5 5. 0 7. 5 10.0 0% 2% 4% 6% 8% 10% 12% 04812162024 28 ki67 positive Islet area (arbitrary units) Days post-STZ treatment # * * * * Islet Size %Ki67+ islet cells Krishnamurthy et al., Supp. Figure 5 b a

6. tonsilappendix Krishnamurthy et al., Supp. Figure 6 Ki67 = brown stain