Ribosomal protein S6 kinase 1 signaling regulates mammalian life span.
Caloric restriction (CR) protects against aging and disease, but the mechanisms by which this affects mammalian life span are unclear. We show in mice that deletion of ribosomal S6 protein kinase 1 (S6K1), a component of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway, led to increased life span and resistance to age-related pathologies, such as bone, immune, and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian life-span and suggest that therapeutic manipulation of S6K1 and AMPK might mimic CR and could provide broad protection against diseases of aging.
Selman
Colin
C
Institute of Healthy Ageing, Centre for Diabetes and Endocrinology, Department of Medicine, University College London, London WC1E 6JJ, UK.
Tullet
Jennifer M A
JM
Wieser
Daniela
D
Irvine
Elaine
E
Lingard
Steven J
SJ
Choudhury
Agharul I
AI
Claret
Marc
M
Al-Qassab
Hind
H
Carmignac
Danielle
D
Ramadani
Faruk
F
Woods
Angela
A
Robinson
Iain C A
IC
Schuster
Eugene
E
Batterham
Rachel L
RL
Kozma
Sara C
SC
Thomas
George
G
Carling
David
D
Okkenhaug
Klaus
K
Thornton
Janet M
JM
Partridge
Linda
L
Gems
David
D
Withers
Dominic J
DJ
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D000818:Animals; D015519:Bone Density; D031204:Caloric Restriction; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D018482:Muscle, Skeletal / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D058570:TOR Serine-Threonine Kinases; D014158:Transcription, Genetic
D007328:Insulin; D011494:Protein Kinases; C546843:mTOR protein, mouse; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512964:Rps6ka1 protein, mouse; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases