1. Sato, E. et al. Larger dosage required for everolimus than sirolimus to maintain same blood concentration in two pancreatic islet transplant patients with tacrolimus. Drug Metab. Pharmacokinet. 24, 175–179 (2009).

2. Kaeberlein, M. Rapamycin and ageing: when, for how long, and how much? J. Genet. Genom. 41, 459–463 (2014).

3. Dodds, S. G. et al. Adaptations to chronic rapamycin in mice. Pathobiol. Aging Age Relat. Dis. 6, 31688 (2016).

4. Swindell, W. R. Rapamycin in mice. Aging 9, 1941–1942 (2017).

5. Blagosklonny, M. V. Disease or not, aging is easily treatable. Aging 10, 3067–3078 (2018).

6. Urfer, S. R. et al. A randomized controlled trial to establish effects of short-term rapamycin treatment in 24 middle-aged companion dogs. Geroscience 39, 117–127 (2017).

7. Ross, C. et al. Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus). Aging 7, 964–973 (2015).

8. Mannick, J. B. et al. mTOR inhibition improves immune function in the elderly. Sci. Transl. Med. 6, 268ra179 (2014).

9. Mannick, J. B. et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci. Transl. Med. 10, https://doi.org/10.1126/scitranslmed.aaq1564 (2018).

10. Avruch, J. et al. Insulin and amino-acid regulation of mTOR signaling and kinase activity through the Rheb GTPase. Oncogene 25, 6361–6372 (2006).

11. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell 124, 471–484 (2006).

12. Um, S. H., D’Alessio, D. & Thomas, G. Nutrient overload, insulin resistance, and ribosomal protein S6 kinase 1, S6K1. Cell Metab. 3, 393–402 (2006).

13. Menon, D. et al. Lipid sensing by mTOR complexes via de novo synthesis of phosphatidic acid. J. Biol. Chem. 292, 6303–6311 (2017).

14. Blagosklonny, M. V. & Hall, M. N. Growth and aging: a common molecular mechanism. Aging 1, 357–362 (2009).

15. Lamming, D. W. & Sabatini, D. M. A central role for mTOR in lipid homeostasis. Cell Metab. 18, 465–469 (2013).

16. Ricoult, S. J. & Manning, B. D. The multifaceted role of mTORC1 in the control of lipid metabolism. EMBO Rep. 14, 242–251 (2013).

17. Shimobayashi, M. & Hall, M. N. Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat. Rev. Mol. Cell Biol. 15, 155–162 (2014).

18. Caron, A., Richard, D. & Laplante, M. The roles of mTOR complexes in lipid metabolism. Annu. Rev. Nutr. 35, 321–348 (2015).

19. Ben-Sahra, I. & Manning, B. D. mTORC1 signaling and the metabolic control of cell growth. Curr. Opin. Cell Biol. 45, 72–82 (2017).

20. Tremblay, F. et al. Overactivation of S6 kinase 1 as a cause of human insulin resistance during increased amino acid availability. Diabetes 54, 2674–2684 (2005).

21. Krebs, M. et al. The mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man. Diabetes 56, 1600–1607 (2007).

22. Manning, B. D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. 167, 399–403 (2004).

23. Zoncu, R., Efeyan, A. & Sabatini, D. M. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12, 21–35 (2011).

24. Inoki, K. et al. mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J. Clin. Investig. 121, 2181–2196 (2011).

25. Cornu, M., Albert, V. & Hall, M. N. mTOR in aging, metabolism, and cancer. Curr. Opin. Genet. Dev. 23, 53–62 (2013).

26. Zhou, W. & Ye, S. Rapamycin improves insulin resistance and hepatic steatosis in type 2 diabetes rats through activation of autophagy. Cell Biol. Int. 42, 1282–1291 (2018).

27. Ueno, M. et al. Regulation of insulin signalling by hyperinsulinaemia: role of IRS-1/2 serine phosphorylation and the mTOR/p70 S6K pathway. Diabetologia 48, 506–518 (2005).

28. Reifsnyder, P. C., Flurkey, K., Te, A. & Harrison, D. E. Rapamycin treatment benefits glucose metabolism in mouse models of type 2 diabetes. Aging 8, 3120–3130 (2016).

29. He, S. et al. Rapamycin/GABA combination treatment ameliorates diabetes in NOD mice. Mol. Immunol. 73, 130–137 (2016).

30. Godel, M. et al. Role of mTOR in podocyte function and diabetic nephropathy in humans and mice. J. Clin. Investig. 121, 2197–2209 (2011).

31. Nagai, K. et al. Gas6 induces Akt/mTOR-mediated mesangial hypertrophy in diabetic nephropathy. Kidney Int. 68, 552–561 (2005).

32. Sataranatarajan, K. et al. Regulation of elongation phase of mRNA translation in diabetic nephropathy: amelioration by rapamycin. Am. J. Pathol. 171, 1733–1742 (2007).

33. Wittmann, S. et al. Long-term treatment of sirolimus but not cyclosporine ameliorates diabetic nephropathy in the rat. Transplantation 87, 1290–1299 (2009).

34. Lloberas, N. et al. Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats. J. Am. Soc. Nephrol. 17, 1395–1404 (2006).

35. Yang, Y. et al. Rapamycin prevents early steps of the development of diabetic nephropathy in rats. Am. J. Nephrol. 27, 495–502 (2007).

36. Sakaguchi, M. et al. Inhibition of mTOR signaling with rapamycin attenuates renal hypertrophy in the early diabetic mice. Biochem. Biophys. Res. Commun. 340, 296–301 (2006).

37. Mori, H. et al. The mTOR pathway is highly activated in diabetic nephropathy and rapamycin has a strong therapeutic potential. Biochem. Biophys. Res. Commun. 384, 471–475 (2009).

38. Flaquer, M. et al. The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats. Life Sci. 87, 147–153 (2010).

39. Reifsnyder, P. C., Doty, R. & Harrison, D. E. Rapamycin ameliorates nephropathy despite elevating hyperglycemia in a polygenic mouse model of type 2 diabetes, NONcNZO10/LtJ. PLoS ONE 9, e114324 (2014).

40. Lu, M. K., Gong, X. G. & Guan, K. L. mTOR in podocyte function: is rapamycin good for diabetic nephropathy? Cell Cycle 10, 3415–3416 (2011).

41. Wahl, P. R. et al. Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol. Dial. Transplant. 21, 598–604 (2006).

42. Roth, G. S. & Ingram, D. K. Manipulation of health span and function by dietary caloric restriction mimetics. Ann. N. Y Acad. Sci. 1363, 5–10 (2016).

43. Steven, S., Lim, E. L. & Taylor, R. Population response to information on reversibility of type 2 diabetes. Diabet. Med. 30, e135–e138 (2013).

44. Steven, S. & Taylor, R. Restoring normoglycaemia by use of a very low calorie diet in long- and short-duration type 2 diabetes. Diabet. Med. 32, 1149–1155 (2015).

45. Steven, S. et al. Very low-calorie diet and 6 months of weight stability in type 2 diabetes: pathophysiological changes in responders and nonresponders. Diabetes Care 39, 808–815 (2016).

46. Taylor, R. Calorie restriction for long-term remission of type 2 diabetes. Clin. Med. 19, 37–42 (2019).

47. Lean, M. E. et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet 391, 541–551 (2018).

48. Most, J., Tosti, V., Redman, L. M. & Fontana, L. Calorie restriction in humans: an update. Ageing Res. Rev. 39, 36–45 (2017).

49. Perry, R. J. et al. Mechanisms by which a very-low-calorie diet reverses hyperglycemia in a rat model of type 2 diabetes. Cell Metab. 27, 210–217 e213 (2018).

50. Lips, M. A. et al. Weight loss induced by very low calorie diet is associated with a more beneficial systemic inflammatory profile than by Roux-en-Y gastric bypass. Metabolism 65, 1614–1620 (2016).

51. Taylor, R. et al. Remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for beta cell recovery. Cell Metab. 28, 547–556 e543 (2018).

52. Sengupta, S., Peterson, T. R., Laplante, M., Oh, S. & Sabatini, D. M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 468, 1100–1104 (2010).

53. Leontieva, O. V., Paszkiewicz, G. M. & Blagosklonny, M. V. Fasting levels of hepatic p-S6 are increased in old mice. Cell Cycle 13, 2656–2659 (2014).

54. Carter, C. S. et al. Rapamycin versus intermittent feeding: dissociable effects on physiological and behavioral outcomes when initiated early and late in life. J. Gerontol. A Biol. Sci. Med. Sci. 71, 866–875 (2016).

55. Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012).

56. Yang, S. B. et al. Rapamycin induces glucose intolerance in mice by reducing islet mass, insulin content, and insulin sensitivity. J. Mol. Med. 90, 575-585 (2011).

57. Houde, V. P. et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue. Diabetes 59, 1338–1348 (2010).

58. Deblon, N. et al. Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br. J. Pharmacol. 165, 2325–2340 (2012).

59. Lundbaek, K. Metabolic abnormalities in starvation diabetes. Yale J. Biol. Med. 20, 533–544 (1948).

60. Peters, J. P. Starvation diabetes, the reason for the use of glucose in the treatment of diabetic acidosis. Yale J. Biol. Med. 17, 705–726 (1945).

61. Longo, V. D. & Fontana, L. Intermittent supplementation with rapamycin as a dietary restriction mimetic. Aging 3, 1039–1040 (2011).

62. Mercken, E. M., Carboneau, B. A., Krzysik-Walker, S. M. & de Cabo, R. Of mice and men: the benefits of caloric restriction, exercise, and mimetics. Ageing Res. Rev. 11, 390–398 (2012).

63. Blagosklonny, M. V. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discov. Today 12, 218–224 (2007).

64. Blagosklonny, M. V. Rapamycin-induced glucose intolerance: Hunger or starvation diabetes. Cell Cycle 10, 4217–4224 (2011).

65. Blagosklonny, M. V. Once again on rapamycin-induced insulin resistance and longevity: despite of or owing to. Aging 4, 350–358 (2012).

66. Blagosklonny, M. V. TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis. 4, e964 (2013).

67. Shivaswamy, V. et al. Hyperglycemia induced by tacrolimus and sirolimus is reversible in normal sprague-dawley rats. Endocrine 37, 489–496 (2010).

68. Liu, Y. et al. Rapamycin-induced metabolic defects are reversible in both lean and obese mice. Aging 6, 742–754 (2014).

69. Fang, Y. et al. Duration of rapamycin treatment has differential effects on metabolism in mice. Cell Metab. 17, 456–462 (2013).

70. Makki, K. et al. Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice. PLoS ONE 9, e92684 (2014).

71. Leontieva, O. V., Paszkiewicz, G., Demidenko, Z. N. & Blagosklonny, M. V. Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet. Cell Death Dis. 4, e472 (2013).

72. Crutchlow, M. F. & Bloom, R. D. Transplant-associated hyperglycemia: a new look at an old problem. Clin. J. Am. Soc. Nephrol. 2, 343–355 (2007).

73. Xu, K. Y., Shameem, R. & Wu, S. Risk of hyperglycemia attributable to everolimus in cancer patients: a meta-analysis. Acta Oncol. 55, 1196–1203 (2016).

74. Bono, P. et al. Outcomes in patients with metastatic renal cell carcinoma who develop everolimus-related hyperglycemia and hypercholesterolemia: combined subgroup analyses of the RECORD-1 and REACT trials. Clin. Genitourin. Cancer 14, 406–414 (2016).

75. Rachek, L. I. Free fatty acids and skeletal muscle insulin resistance. Prog. Mol. Biol. Transl. Sci. 121, 267–292 (2014).

76. Stannard, S. R. et al. Fasting for 72 h increases intramyocellular lipid content in nondiabetic, physically fit men. Am. J. Physiol. Endocrinol. Metab. 283, E1185–E1191 (2002).

77. Moller, L., Stodkilde-Jorgensen, H., Jensen, F. T. & Jorgensen, J. O. Fasting in healthy subjects is associated with intrahepatic accumulation of lipids as assessed by 1H-magnetic resonance spectroscopy. Clin. Sci. 114, 547–552 (2008).

78. Swaner, J. C. & Connor, W. E. Hypercholesterolemia of total starvation: its mechanism via tissue mobilization of cholesterol. Am. J. Physiol. 229, 365–369 (1975).

79. Savendahl, L. & Underwood, L. E. Fasting increases serum total cholesterol, LDL cholesterol and apolipoprotein B in healthy, nonobese humans. J. Nutr. 129, 2005–2008 (1999).

80. Samra, J. S., Clark, M. L., Humphreys, S. M., Macdonald, I. A. & Frayn, K. N. Regulation of lipid metabolism in adipose tissue during early starvation. Am. J. Physiol. 271, E541–E546 (1996).

81. Fainaru, M. & Schafer, Z. Effect of prolonged fasting on plasma lipids, lipoproteins and apolipoprotein B in 12 physicians participating in a hunger strike: an observational study. Isr. Med Assoc. J. 2, 215–219 (2000).

82. Johnston, O., Rose, C. L., Webster, A. C. & Gill, J. S. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J. Am. Soc. Nephrol. 19, 1411–1418 (2008).

83. Pavlakis, M. & Goldfarb-Rumyantzev, A. S. Diabetes after transplantation and sirolimus: what’s the connection? J. Am. Soc. Nephrol. 19, 1255–1256 (2008).

84. Kahan, B. D. Efficacy of sirolimus compared with azathioprine for reduction of acute renal allograft rejection: a randomised multicentre study. The Rapamune US Study Group. Lancet 356, 194–202 (2000).

85. Kasiske, B. L., Snyder, J. J., Gilbertson, D. & Matas, A. J. Diabetes mellitus after kidney transplantation in the United States. Am. J. Transpl. 3, 178–185 (2003).

86. Krentz, A. J. & Wheeler, D. C. New-onset diabetes after transplantation: a threat to graft and patient survival. Lancet 365, 640–642 (2005).

87. Kamar, N. et al. Diabetes mellitus after kidney transplantation: a French multicentre observational study. Nephrol. Dial. Transpl. 22, 1986–1993 (2007).

88. Cole, E. et al. A pilot study of steroid-free immunosuppression in the prevention of acute rejection in renal allograft recipients. Transplantation 72, 845–850 (2001).

89. Veroux, M. et al. New-onset diabetes mellitus after kidney transplantation: the role of immunosuppression. Transpl. Proc. 40, 1885–1887 (2008).

90. Veroux, M. et al. Sirolimus-based immunosuppression in kidney transplantation for type 2 diabetic nephropathy. Urol. Int. 84, 301–304 (2010).

91. Veroux, M. et al. Conversion to sirolimus therapy in kidney transplant recipients with new onset diabetes mellitus after transplantation. Clin. Dev. Immunol. 2013, 496974 (2013).

92. Rovira, J. et al. Effect of mTOR inhibitor on body weight: from an experimental rat model to human transplant patients. Transpl. Int. 21, 992–998 (2008).

93. Cohen, E. E. et al. Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients. Clin. Cancer Res. 18, 4785–4793 (2012).

94. Piccart, M. et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2dagger. Ann. Oncol. 25, 2357–2362 (2014).

95. Lai, Z. W. et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391, 1186–1196 (2018).

96. Kraig, E. et al. A randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: immunological, physical performance, and cognitive effects. Exp. Gerontol. 105, 53–69 (2018).

97. Brattstrom, C. et al. Pharmacokinetics and safety of single oral doses of sirolimus (rapamycin) in healthy male volunteers. Ther. Drug Monit. 22, 537–544 (2000).

98. Ceschi, A. et al. Acute sirolimus overdose: a multicenter case series. PLoS ONE 10, e0128033 (2015).

99. Fontana, L., Klein, S. & Holloszy, J. O. Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age 32, 97–108 (2010).

100. Duska, F., Andel, M., Kubena, A. & Macdonald, I. A. Effects of acute starvation on insulin resistance in obese patients with and without type 2 diabetes mellitus. Clin. Nutr. 24, 1056–1064 (2005).

101. Koffler, M. & Kisch, E. S. Starvation diet and very-low-calorie diets may induce insulin resistance and overt diabetes mellitus. J. Diabetes Complicat. 10, 109–112 (1996).

102. Kinzig, K. P., Honors, M. A. & Hargrave, S. L. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology 151, 3105–3114 (2010).

103. Schugar, R. C. & Crawford, P. A. Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease. Curr. Opin. Clin. Nutr. Metab. Care 15, 374–380 (2012).

104. Bielohuby, M. et al. Impaired glucose tolerance in rats fed low-carbohydrate, high-fat diets. Am. J. Physiol. Endocrinol. Metab. 305, E1059–E1070 (2013).

105. Ellenbroek, J. H. et al. Long-term ketogenic diet causes glucose intolerance and reduced beta- and alpha-cell mass but no weight loss in mice. Am. J. Physiol. Endocrinol. Metab. 306, E552–E558 (2014).

106. Grandl, G. et al. Short-term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high-fat diet. J. Physiol. 596, 4597–4609 (2018).

107. Kwiterovich, P. O. Jr., Vining, E. P., Pyzik, P., Skolasky, R. Jr. & Freeman, J. M. Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 290, 912–920 (2003).

108. Chung, H. Y. & Park, Y. K. Rationale, feasibility and acceptability of ketogenic diet for cancer treatment. J. Cancer Prev. 22, 127–134 (2017).

109. Branco, A. F. et al. Ketogenic diets: from cancer to mitochondrial diseases and beyond. Eur. J. Clin. Invest. 46, 285–298 (2016).

110. Gibas, M. K. & Gibas, K. J. Induced and controlled dietary ketosis as a regulator of obesity and metabolic syndrome pathologies. Diabetes Metab. Syndr. 11(Suppl 1), S385–S390 (2017).

111. Magnusdottir, O. K., Gunnarsdottir, I. & Birgisdottir, B. E. Dietary guidelines in type 2 diabetes: the Nordic diet or the ketogenic diet? Curr. Opin. Endocrinol. Diabetes Obes. 24, 315–319 (2017).

112. Hussain, T. A. et al. Effect of low-calorie versus low-carbohydrate ketogenic diet in type 2 diabetes. Nutrition 28, 1016–1021 (2012).

113. Mobbs, C. V., Mastaitis, J., Isoda, F. & Poplawski, M. Treatment of diabetes and diabetic complications with a ketogenic diet. J. Child Neurol. 28, 1009–1014 (2013).

114. Roberts, M. N. et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab. 26, 539–546 e535 (2017).

115. Deepa, S. S. et al. Rapamycin modulates markers of mitochondrial biogenesis and fatty acid oxidation in the adipose tissue of db/db mice. J. Biochem. Pharm. Res. 1, 114–123 (2013).

116. Das, A. et al. Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J. Biol. Chem. 289, 4145–4160 (2014).

117. Fraenkel, M. et al. mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57, 945–957 (2008).

118. Sataranatarajan, K. et al. Rapamycin Increases mortality in db/db Mice, a mouse model of type 2 diabetes. J. Gerontol. A Biol. Sci. Med Sci. 71, 850–857 (2016).

119. Fok, W. C. et al. Mice fed rapamycin have an increase in lifespan associated with major changes in the liver transcriptome. PLoS One 9, e83988 (2014).

120. Liao, C. Y., Rikke, B. A., Johnson, T. E., Diaz, V. & Nelson, J. F. Genetic variation in the murine lifespan response to dietary restriction: from life extension to life shortening. Aging Cell 9, 92–95 (2010).

121. Leibowitz, G., Cerasi, E. & Ketzinel-Gilad, M. The role of mTOR in the adaptation and failure of beta-cells in type 2 diabetes. Diabetes Obes. Metab. 10(Suppl 4), 157–169 (2008).

122. Ardestani, A., Lupse, B., Kido, Y., Leibowitz, G. & Maedler, K. mTORC1 Signaling: a double-edged sword in diabetic beta cells. Cell Metab. 27, 314–331 (2018).

123. Bachar, E. et al. Glucose amplifies fatty acid-induced endoplasmic reticulum stress in pancreatic beta-cells via activation of mTORC1. PLoS ONE 4, e4954 (2009).

124. Shigeyama, Y. et al. Biphasic response of pancreatic beta-cell mass to ablation of tuberous sclerosis complex 2 in mice. Mol. Cell Biol. 28, 2971–2979 (2008).

125. Blagosklonny, M. V. Aging and immortality: quasi-programmed senescence and its pharmacologic inhibition. Cell Cycle 5, 2087–2102 (2006).

126. Gems, D. & de la Guardia, Y. Alternative Perspectives on aging in caenorhabditis elegans: reactive oxygen species or hyperfunction? Antioxid. Redox Signal. 19, 321–329 (2013).

127. Leontieva, O. V., Demidenko, Z. N. & Blagosklonny, M. V. Rapamycin reverses insulin resistance (IR) in high-glucose medium without causing IR in normoglycemic medium. Cell Death Dis. 5, e1214 (2014).

128. Kleinert, M. et al. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo. Mol. Metab. 3, 630–641 (2014).

129. Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22, 159–168 (2006).

130. Tanimura, J. et al. The clinical course and potential underlying mechanisms of everolimus-induced hyperglycemia. Endocr. J. 66, 615–620 (2019).

131. Leontieva, O. V., Paszkiewicz, G. M. & Blagosklonny, M. V. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet. Aging Cell 13, 616–622 (2014).

132. Leontieva, O. V., Paszkiewicz, G. M. & Blagosklonny, M. V. Comparison of rapamycin schedules in mice on high-fat diet. Cell Cycle 13, 3350–3356 (2014).

133. Arriola Apelo, S. I., Pumper, C. P., Baar, E. L., Cummings, N. E. & Lamming, D. W. Intermittent administration of rapamycin extends the life span of female C57BL/6J mice. J. Gerontol. A Biol. Sci. Med Sci. 71, 876–881 (2016).

134. Lelegren, M., Liu, Y., Ross, C., Tardif, S. & Salmon, A. B. Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate. Pathobiol. Aging Age Relat. Dis. 6, 31793 (2016).

135. den Hartigh, L. J. et al. Chronic oral rapamycin decreases adiposity, hepatic triglycerides and insulin resistance in male mice fed a diet high in sucrose and saturated fat. Exp. Physiol. 103, 1469–1480 (2018).

136. Vodenik, B., Rovira, J. & Campistol, J. M. Mammalian target of rapamycin and diabetes: what does the current evidence tell us? Transpl. Proc. 41, S31–S38 (2009).

137. Leibowitz, G., Kaiser, N. & Cerasi, E. Balancing needs and means: the dilemma of the beta-cell in the modern world. Diabetes Obes. Metab. 11(Suppl 4), 1–9 (2009).

138. Blagosklonny, M. V. Aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells. Rejuvenation Res. 11, 801–808 (2008).

139. Yang, S. B. et al. Rapamycin ameliorates age-dependent obesity associated with increased mTOR signaling in hypothalamic POMC neurons. Neuron 75, 425–436 (2012).

140. Hebert, M. et al. Single rapamycin administration induces prolonged downward shift in defended body weight in rats. PLoS One 9, e93691 (2014).

141. Alamo, J. M. et al. Conversion from calcineurin inhibitors to mTOR inhibitors stabilizes diabetic and hypertensive nephropathy after liver transplant. World J. Transpl. 5, 19–25 (2015).

142. Weiss, R., Fernandez, E., Liu, Y., Strong, R. & Salmon, A. B. Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice. Aging. https://doi.org/10.18632/aging.101401 (2018).

143. Sehdev, A. et al. A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors. Cancer Chemother. Pharmacol. 82, 309–317 (2018).