title: Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study.
abstract: Rapamycin, an mTOR inhibitor affects senescence through suppression of senescence-associated secretory phenotype (SASP). We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men. Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased. Adipose tissue expression of mRNAs (arbitrary units) for MCP-1 (3585 vs 2020, p=0.06), PPAR-γ (1257 vs 1166), PAI-1 (823 vs 338, p=0.08) increased, whereas interleukin-8 (163 vs 312), TNF-α (75 vs 94) and p16 (129 vs 169) decreased. Cellular senescence-associated beta galactosidase activity (2.2% vs 3.6%, p=0.18) tended to decrease. We observed some correlation between some senescence markers and physical performance but no improvement in frailty with rapamycin was noted. (NCT01649960).
authors.affiliation: Mandeep Singh, MD, MPH, 200 First street SW, Mayo Clinic, Rochester, MN 55905, Tel: 507-255-5891, Fax: 507-255-2550, Email: Singh.Mandeep@mayo.edu.
authors.forename: M
authors.initials: M
authors.lastname: Singh
authors.forename: M D
authors.initials: MD
authors.lastname: Jensen
authors.forename: A
authors.initials: A
authors.lastname: Lerman
authors.forename: S
authors.initials: S
authors.lastname: Kushwaha
authors.forename: C S
authors.initials: CS
authors.lastname: Rihal
authors.forename: B J
authors.initials: BJ
authors.lastname: Gersh
authors.forename: A
authors.initials: A
authors.lastname: Behfar
authors.forename: T
authors.initials: T
authors.lastname: Tchkonia
authors.forename: R J
authors.initials: RJ
authors.lastname: Thomas
authors.forename: R J
authors.initials: RJ
authors.lastname: Lennon
authors.forename: L R
authors.initials: LR
authors.lastname: Keenan
authors.forename: A G
authors.initials: AG
authors.lastname: Moore
authors.forename: J L
authors.initials: JL
authors.lastname: Kirkland
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism*; D016922:Cellular Senescence; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D003324:Coronary Artery Disease / Q000378:metabolism* / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005260:Female; D016330:Frail Elderly; D005684:Gait; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000235:genetics; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics; D062645:Percutaneous Coronary Intervention; D010641:Phenotype; D010865:Pilot Projects; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020123:Sirolimus / Q000008:administration & dosage*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000070857:Walk Test; D001616:beta-Galactosidase / Q000235:genetics
chemical_list: C111835:CCL2 protein, human; C493956:CDKN1A protein, human; C000614131:CDKN2A protein, human; C508606:CXCL8 protein, human; D018932:Chemokine CCL2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; C508600:IL6 protein, human; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D016209:Interleukin-8; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C051321:SERPINE1 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C061901:GLB1 protein, human; D001616:beta-Galactosidase; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; D020123:Sirolimus