title: Reducing signs of aging and increasing lifespan by drug synergy.
abstract: Disease incidence rises rapidly with age and increases both human suffering and economic hardship while shortening life. Advances in understanding the signaling pathways and cellular processes that influence aging support the possibility of reducing the incidence of age-related diseases and increasing lifespan by pharmacological intervention. Here, we demonstrate a novel pharmacological strategy that both reduces signs of aging in the budding yeast Saccharomyces cerevisiae and generates a synergistic increase in lifespan. By combining a low dose of rapamycin, to reduce activity of the target of rapamycin complex 1 (TORC1) protein kinase, and myriocin, to reduce sphingolipid synthesis, we show enhancement of autophagy, genomic stability, mitochondrial function, and AMP kinase pathway activity. These processes are controlled by evolutionarily conserved signal transduction pathways that are vital for maintaining a healthy state and promoting a long life. Thus, our data show that it ought to be possible to find pharmacological approaches to generate a synergistic reduction in the incidence of human age-related diseases to improve health quality in the elderly and enhance lifespan.
authors.affiliation: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, 741 S. Limestone, Lexington, KY 40536, USA.
authors.forename: Xinhe
authors.initials: X
authors.lastname: Huang
authors.forename: Jun
authors.initials: J
authors.lastname: Liu
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Withers
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Samide
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: Robert C
authors.initials: RC
authors.lastname: Dickson
mesh_terms: D001343:Autophagy; D004357:Drug Synergism; D004789:Enzyme Activation; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D042822:Genomic Instability; D050296:Microbial Viability / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000502:physiology*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D013312:Stress, Physiological; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D005229:Fatty Acids, Monounsaturated; D017382:Reactive Oxygen Species; D029701:Saccharomyces cerevisiae Proteins; C561842:TORC1 protein complex, S cerevisiae; D014157:Transcription Factors; C071570:SNF1-related protein kinases; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; C001996:thermozymocidin
keywords: S6 Kinase; TORC1; aging; autophagy; genomic stability; longevity