Table 2.

Summary of the effects of rapamycin and rapalogs on aging-related pathways.

	Protein Homeostasis/Autophagy	Hormesis/Stress Priming	Protein Translation	Cell Proliferation	Inflammation	Apoptosis	Anti-Cancer	Neuroprotective	Other
Rapamycin
Mouse Oocyte (100 nm, 2 h) [181]			↓
Juvenile Human Fibroblasts (2DD; 500 nm, 120 h) [220]	↑		↓	↓					Up-regulation of Cytokine-cytokine receptor signalling, regulated by STAT5A/B TF
Maternally Inherited Leigh Syndrome Human iPS (20 nm, 6 h) [192]	↑		↓	↓					Alleviates mitochondrial defects
Amyotrophic Lateral Sclerosis Mice Spinal Cord (2.33 mg/kg/day, 60 days) [193]	↑		↓	↓					Suppressed immune response/increased mouse survival
Human Prostate Cancer Cell Lines (LNCaP, 22RV1, PC3, DU145; 20 nm, 72 h) [185]				↓	↓	↑			Correlation between Cyclin D1 and rapamycin sensitivity of prostate cancer cells
C57BL/6 mice (endotoxin-uveitis and retinitis induced: retinal inflammation model; 6.0 mg/kg/day) [187]					↓			↑	Decreased NF-kB activity, neuroprotection (decreased rhodopsin)
Wistar Rats (Heart Failure (HF) Model; 1.4 mg/kg/day, from 8 weeks old) [187]	↑		↓			↓
Sprague-Dawley Rats (Cerebral Ischemia (CI); Kidney and Blood Tissues, Males; 1 mg/kg, 0.5 h prior to CI) [183]	↑				↓	↓			↑ autophagy (↑ BCL-2, ATG13; ↓ULK1); ↓ inflammation (↓TNF-a, IL-1b)
7PA2 cells (APP familial mutation; 0.5 mg/mL, 24 h) [197]	↑		↓					↑	Clearance of ND-linked protein aggregates
3xTg-AD mice (AD model; 2.24 mg/kg, 10 weeks) [197]	↑		↓					↑	Clearance of ND-linked protein aggregates, ↑ autophagy (↑ATG5, ATG7, ATG12)
ND-model (20 nm, 6 h) [192]	↑		↓						Promote energy balance
SAMP8 mice neurons (ND model; 0.5 μM, 72 h) [194]	↑		↓			↓		↑	Clearance of ND-linked protein aggregates,
Humans (0.001% topically. 4 months) [210]									↓ cellular senescence (↓ p16, p21, p53); Decrease in fine wrinkling (↑ collagen VII)
Lmna-/- BAT, WAT (8 mg/kg, every other day) [204]									↓ lipolysis, energy expenditure, fatty acid oxidation; ↑ thermogenesis
Everolimus
Human T1D (1 month before islet transplant; 0.1 mg/kgbw/day) [206]					↓				↓ inflammation (CCL2, CCL3)
Human melanoma cells: Lu1205, WM793 (5 nm, 24 h) [221]				↓
3xTg-AD mice (AD model) (One dose of 0.167 μg/μL in a volume of 6 μL) [222]								↓
Elderly Humans (0.5–20 mg/week, 6 weeks) [223]			↓						Enhanced immune response
RT112 and T24 cells (bladder cancer cell models; 0.5–500 nM, 1 h) [224]			↓						↑ AKT phosphorylation (feedback signalling; ↑ GSK3-β phosphorylation)
Post-menopausal women with early breast cancer (5 mg/day, 14 days) [225]				↓			↓		↓ Ki67, S6K1, AKT phosphorylation
HEK293 cells (liver cancer cell model) (1–20 nm, 24 h) [226]			↓						↓ c-Myc
HGPS Fibroblasts (0.1 μM, 2 weeks) [227]	↑								Reversed some cellular aging phenotypes

STAT5A/B: signal transducer and activator of transcription 5; BCL-2: B-cell lymphoma 2; ATG: autophagy-related genes; CCL: C-C motif chemokine ligand; S6K1: ribosomal protein S6 kinase β -1; BAT: brown adipose tissue.