by Joan B. Mannick, Melody Morris, Hans-Ulrich P

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TORC1 inhibition enhances immune function and reduces infections in the elderly by Joan B. Mannick, Melody Morris, Hans-Ulrich P. Hockey, Guglielmo Roma, Martin Beibel, Kenneth Kulmatycki, Mollie Watkins, Tea Shavlakadze, Weihua Zhou, Dean Quinn, David J. Glass, and Lloyd B. Klickstein Sci Transl Med Volume 10(449):eaaq1564 July 11, 2018 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 1 Flow diagram showing participants and study design. Flow diagram showing participants and study design. The number of elderly subjects screened (assessed for eligibility), the number of subjects randomized to each treatment arm (allocation), and the number of subjects who discontinued study drug in each treatment arm. The term analyzed indicates the number of subjects in each cohort in the modified intention to treat population. Joan B. Mannick et al., Sci Transl Med 2018;10:eaaq1564 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 2 Increase in antibody titers to influenza virus vaccine strains in mTOR inhibitor treatment groups relative to the placebo group. Increase in antibody titers to influenza virus vaccine strains in mTOR inhibitor treatment groups relative to the placebo group. (A) Increase in the ratio (4 weeks after vaccination: baseline) in GMT for each of the three influenza virus vaccine strains in elderly subjects treated with RAD001, BEZ235, RAD001 + BEZ235, or placebo. The three influenza virus vaccine strains used were as follows: A/H1N1 (A/California/7/2009), A/H3N2 (A/Texas/50/2012), and B (B/Massachusetts/2/2012). The blue line indicates the 20% increase in GMT ratios relative to placebo that was required for two of the three influenza virus vaccine strains to meet the primary end point of the study. Asterisks indicate that the probability that the increase in GMT ratio relative to placebo exceeded 1.0 is 100%. (B) Forest plots of the data presented in (A) including 90% confidence intervals and probability that the GMT ratio compared to placebo is >1 or >1.2. Joan B. Mannick et al., Sci Transl Med 2018;10:eaaq1564 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 3 Low doses of RAD001 and BEZ235 inhibit TORC1. Low doses of RAD001 and BEZ235 inhibit TORC1. Western blots for phosphorylated (p) and total (t) protein amounts for S6K1, S6, and 4EBP1 in rat livers after 7 days of drug treatment. (A) Rats were treated daily for 7 days with RAD001 (RAD) at the dose equivalent of 0.1 mg (0.03 mg/kg) or 0.5 mg (0.15 mg/kg) in humans. (B) Rats were treated daily for 7 days with BEZ235 (BEZ) given at the dose equivalent of 10 mg (1.7 mg/kg) in humans alone or in combination with the dose equivalent of RAD001 0.1 mg (0.03 mg/kg). Tissues were collected 4 hours after the last drug dose. Left: Each lane in the immunoblots represents liver tissue from one rat. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is shown as a loading control. Right: The amounts of p-S6K1(T389) and p-S6(Ser240/244) on the immunoblots were quantified relative to their respective total protein amounts by densitometry. Amounts of p-4EBP1 (T37/46) were quantified relative to GAPDH. Y axes represent arbitrary units. For each group, n = 4 to 6 rats. Data are mean ± SD. Data were analyzed with a one-way analysis of variance (ANOVA) followed by Dunnett’s multiple comparison tests, where means from all groups were compared to the vehicle-treated group. In (A), *P = 0.048 and *P = 0.018 for p-S6K1 and p-S6, respectively. In (B), *P = 0.015 for p-S6K1, **P ≤ 0.005 for p-4EBP1, and ***P ≤ 0.001 for p-S6. Joan B. Mannick et al., Sci Transl Med 2018;10:eaaq1564 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works

Fig. 4 TORC1 inhibition decreases infection rates in the elderly. TORC1 inhibition decreases infection rates in the elderly. (A) Fitted annual rates of infections reported per person per year in the 0.1 mg of RAD001, 0.5 mg of RAD001, 10 mg of BEZ235, 0.1 mg of RAD001 + 10 mg of BEZ235, or placebo groups. *P = 0.008, **P = 0.001 versus placebo. (B) Fitted annual rates of respiratory tract infections (RTIs) reported per person per year in the placebo group and in the BEZ235 monotherapy and BEZ235 + RAD001 combination treatment groups. *P = 0.01, **P = 0.008 versus placebo. In both figures, error bars indicate 95% confidence intervals as determined by Poisson regression modeling. Joan B. Mannick et al., Sci Transl Med 2018;10:eaaq1564 Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works