Blazing a trail for the clinical use of rapamycin as a geroprotecTOR.
Aging
Everolimus
Metabolism
Muscle
Sirolimus
mTOR
Journal
GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
received:
23
06
2023
accepted:
04
09
2023
medline:
15
11
2023
pubmed:
6
10
2023
entrez:
6
10
2023
Statut:
ppublish
Résumé
Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
Identifiants
pubmed: 37801202
doi: 10.1007/s11357-023-00935-x
pii: 10.1007/s11357-023-00935-x
pmc: PMC10643772
doi:
Substances chimiques
Sirolimus
W36ZG6FT64
Senotherapeutics
0
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
MTOR Inhibitors
0
Mechanistic Target of Rapamycin Complex 2
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2769-2783Subventions
Organisme : NIA NIH HHS
ID : U01-AG081482
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG067464
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK133479
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062328
Pays : United States
Organisme : NIA NIH HHS
ID : AG056771
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG056771
Pays : United States
Organisme : NIA NIH HHS
ID : U01-AG076941
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG076941
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG083782
Pays : United States
Organisme : NIA NIH HHS
ID : R21 AG061635
Pays : United States
Organisme : NIA NIH HHS
ID : AG061635
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK125859
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002373
Pays : United States
Organisme : NIA NIH HHS
ID : AG062328
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG081482
Pays : United States
Investigateurs
Brittany A Grasso
(BA)
Rebecca C Marrah
(RC)
Sara Decker
(S)
Neetika Garg
(N)
Yeonhee Park
(Y)
Sin Yin Lim
(SY)
Judith A Simcox
(JA)
Cara L Green
(CL)
Isaac Grunow
(I)
Amanjot K Yadev
(AK)
Rebecca C Marrah
(RC)
Brittany A Grasso
(BA)
Sara Decker
(S)
Samantha Pabich
(S)
Didier Mandelbrot
(D)
Thomas R Wallhaus
(TR)
Oliver Wieben
(O)
Fay Osman
(F)
Richard J Chappell
(RJ)
Irene M Ong
(IM)
Reid S Alisch
(RS)
Judith A Simcox
(JA)
Christian J Elliehausen
(CJ)
Dennis M Minton
(DM)
Michaela E Trautman
(ME)
Alma Spahic
(A)
Barbara B Bendlin
(BB)
Sanjay Asthana
(S)
Alexey Terskikh
(A)
Informations de copyright
© 2023. The Author(s), under exclusive licence to American Aging Association.
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