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.
Institute of Healthy Ageing, Centre for Diabetes and Endocrinology, Department of Medicine, University College London, London WC1E 6JJ, UK.
Colin
C
Selman
Jennifer M A
JM
Tullet
Daniela
D
Wieser
Elaine
E
Irvine
Steven J
SJ
Lingard
Agharul I
AI
Choudhury
Marc
M
Claret
Hind
H
Al-Qassab
Danielle
D
Carmignac
Faruk
F
Ramadani
Angela
A
Woods
Iain C A
IC
Robinson
Eugene
E
Schuster
Rachel L
RL
Batterham
Sara C
SC
Kozma
George
G
Thomas
David
D
Carling
Klaus
K
Okkenhaug
Janet M
JM
Thornton
Linda
L
Partridge
David
D
Gems
Dominic J
DJ
Withers
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