title: mTOR inhibition improves immune function in the elderly.
abstract: 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.
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA. joan.mannick@novartis.com.
authors.forename: Joan B
authors.initials: JB
authors.lastname: Mannick
authors.affiliation: Novartis Vaccines and Diagnostics, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Del Giudice
authors.affiliation: Novartis Vaccines and Diagnostics, 53100 Siena, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Lattanzi
authors.affiliation: Novartis Vaccines and Diagnostics, Cambridge, MA 02139, USA.
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Valiante
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Praestgaard
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Baisong
authors.initials: B
authors.lastname: Huang
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lonetto
authors.affiliation: Novartis Pharmaceuticals Corporation, CH-4002 Basel, Switzerland.
authors.forename: Holden T
authors.initials: HT
authors.lastname: Maecker
authors.affiliation: Stanford University School of Medicine, Stanford, CA 94305-5124, USA.
authors.forename: John
authors.initials: J
authors.lastname: Kovarik
authors.affiliation: Southern Clinical Trials, Christchurch 8024, New Zealand.
authors.forename: Simon
authors.initials: S
authors.lastname: Carson
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Glass
authors.affiliation: Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
authors.forename: Lloyd B
authors.initials: LB
authors.lastname: Klickstein
mesh_terms: D000368:Aged; D000914:Antibodies, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D015331:Cohort Studies; D000068338:Everolimus; D006801:Humans; D007109:Immunity / Q000187:drug effects*; D007252:Influenza Vaccines / Q000276:immunology; D010919:Placebos; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012621:Seasons; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014611:Vaccination
chemical_list: D000914:Antibodies, Viral; D007252:Influenza Vaccines; C105992:PDCD1 protein, human; D010919:Placebos; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus