Advancing age is associated with gene expression changes resembling mTOR inhibition: evidence from two human populations.
Interventions which inhibit TOR activity (including rapamycin and caloric restriction) lead to downstream gene expression changes and increased lifespan in laboratory models. However, the role of mTOR signaling in human aging is unclear. We tested the expression of mTOR-related transcripts in two independent study cohorts; the InCHIANTI population study of aging and the San Antonio Family Heart Study (SAFHS). Expression of 27/56 (InCHIANTI) and 19/44 (SAFHS) genes were associated with age after correction for multiple testing. 8 genes were robustly associated with age in both cohorts. Genes involved in insulin signaling (PTEN, PI3K, PDK1), ribosomal biogenesis (S6K), lipid metabolism (SREBF1), cellular apoptosis (SGK1), angiogenesis (VEGFB), insulin production and sensitivity (FOXO), cellular stress response (HIF1A) and cytoskeletal remodeling (PKC) were inversely correlated with age, whereas genes relating to inhibition of ribosomal components (4EBP1) and inflammatory mediators (STAT3) were positively associated with age in one or both datasets. We conclude that the expression of mTOR-related transcripts is associated with advancing age in humans. Changes seen are broadly similar to mTOR inhibition interventions associated with increased lifespan in animals. Work is needed to establish whether these changes are predictive of human longevity and whether further mTOR inhibition would be beneficial in older people.
Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter EX2 5DW, UK.
Lorna W
LW
Harries
Alexander D
AD
Fellows
Luke C
LC
Pilling
Dena
D
Hernandez
Andrew
A
Singleton
Stefania
S
Bandinelli
Jack
J
Guralnik
Jonathan
J
Powell
Luigi
L
Ferrucci
David
D
Melzer
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007558:Italy; D050356:Lipid Metabolism / Q000502:physiology*; D008136:Longevity / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011446:Prospective Studies; D015398:Signal Transduction / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D059467:Transcriptome
C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases