mTOR inhibition improves immune function in the elderly

被引：544

作者：

Mannick, Joan B. ^{[1
]}

Del Giudice, Giuseppe ^{[2
]}

Lattanzi, Maria ^{[2
]}

Valiante, Nicholas M. ^{[3
]}

Praestgaard, Jens ^{[4
]}

Huang, Baisong ^{[1
]}

Lonetto, Michael A. ^{[1
]}

Maecker, Holden T. ^{[5
]}

Kovarik, John ^{[6
]}

Carson, Simon ^{[7
]}

Glass, David J. ^{[1
]}

Klickstein, Lloyd B. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, Cambridge, MA 02139 USA

[2] Novartis Vaccines & Diagnost, I-53100 Siena, Italy

[3] Novartis Vaccines & Diagnost, Cambridge, MA 02139 USA

[4] Novartis Pharmaceut, E Hanover, NJ 07936 USA

[5] Stanford Univ, Sch Med, Stanford, CA 94305 USA

[6] Novartis Pharmaceut, CH-4002 Basel, Switzerland

[7] Southern Clin Trials, Christchurch 8024, New Zealand

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 268期

关键词：

T-CELLS; ANTIBODY-RESPONSE; INFLUENZA; MICE; VACCINATION; VIRUS; PD-1;

D O I：

10.1126/scitranslmed.3009892

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.

引用

收藏

页数：7

相关论文

共 24 条

[1] mTOR regulates memory CD8 T-cell differentiation [J].

Araki, Koichi ;

Turner, Alexandra P. ;

Shaffer, Virginia Oliva ;

Gangappa, Shivaprakash ;

Keller, Susanne A. ;

Bachmann, Martin F. ;

Larsen, Christian P. ;

Ahmed, Rafi .

NATURE, 2009, 460 (7251) :108-U124

[2] Molecular analyses provide insight into mechanisms underlying sarcopenia and myofibre denervation in old skeletal muscles of mice [J].

Barns, Mitchell ;

Gondro, Cedric ;

Tellam, Ross L. ;

Radley-Crabb, Hannah G. ;

Grounds, Miranda D. ;

Shavlakadze, Tea .

INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2014, 53 :174-185

[3] CONTROLLING THE FALSE DISCOVERY RATE - A PRACTICAL AND POWERFUL APPROACH TO MULTIPLE TESTING [J].

BENJAMINI, Y ;

HOCHBERG, Y .

JOURNAL OF THE ROYAL STATISTICAL SOCIETY SERIES B-STATISTICAL METHODOLOGY, 1995, 57 (01) :289-300

[4] The Gracefully Aging Immune System [J].

Boraschi, Diana ;

Aguado, M. Teresa ;

Dutel, Catherine ;

Goronzy, Joerg ;

Louis, Jacques ;

Grubeck-Loebenstein, Beatrix ;

Rappuoli, Rino ;

Del Giudice, Giuseppe .

SCIENCE TRANSLATIONAL MEDICINE, 2013, 5 (185)

[5] mTOR Regulation and Therapeutic Rejuvenation of Aging Hematopoietic Stem Cells [J].

Chen, Chong ;

Liu, Yu ;

Liu, Yang ;

Zheng, Pan .

SCIENCE SIGNALING, 2009, 2 (98) :ra75

[6] Viral acute lower respiratory infections impair CD8+ T cells through PD-1 [J].

Erickson, John J. ;

Gilchuk, Pavlo ;

Hastings, Andrew K. ;

Tollefson, Sharon J. ;

Johnson, Monika ;

Downing, Melissa B. ;

Boyd, Kelli L. ;

Johnson, Joyce E. ;

Kim, Annette S. ;

Joyce, Sebastian ;

Williams, John V. .

JOURNAL OF CLINICAL INVESTIGATION, 2012, 122 (08) :2967-2982

[7] Cutting Edge: Rapamycin Augments Pathogen-Specific but Not Graft-Reactive CD8+ T Cell Responses [J].

Ferrer, Ivana R. ;

Wagener, Maylene E. ;

Robertson, Jennifer M. ;

Turner, Alexa P. ;

Araki, Koichi ;

Ahmed, Rafi ;

Kirk, Allan D. ;

Larsen, Christian P. ;

Ford, Mandy L. .

JOURNAL OF IMMUNOLOGY, 2010, 185 (04) :2004-2008

[8] Late-life rapamycin treatment reverses age-related heart dysfunction [J].

Flynn, James M. ;

O'Leary, Monique N. ;

Zambataro, Christopher A. ;

Academia, Emmeline C. ;

Presley, Michael P. ;

Garrett, Brittany J. ;

Zykovich, Artem ;

Mooney, Sean D. ;

Strong, Randy ;

Rosen, Clifford J. ;

Kapahi, Pankaj ;

Nelson, Michael D. ;

Kennedy, Brian K. ;

Melov, Simon .

AGING CELL, 2013, 12 (05) :851-862

[9] Antibody response to influenza vaccination in the elderly: A quantitative review [J].

Goodwin, K ;

Viboud, C ;

Simonsen, L .

VACCINE, 2006, 24 (08) :1159-1169

[10] Rapamycin fed late in life extends lifespan in genetically heterogeneous mice [J].

Harrison, David E. ;

Strong, Randy ;

Sharp, Zelton Dave ;

Nelson, James F. ;

Astle, Clinton M. ;

Flurkey, Kevin ;

Nadon, Nancy L. ;

Wilkinson, J. Erby ;

Frenkel, Krystyna ;

Carter, Christy S. ;

Pahor, Marco ;

Javors, Martin A. ;

Fernandez, Elizabeth ;

Miller, Richard A. .

NATURE, 2009, 460 (7253) :392-U108