Protein synthesis and the antagonistic pleiotropy hypothesis of aging.
Growth and somatic maintenance are thought to be antagonistic piciotropic traits, but the molecular basis for this tradeoff is poorly understood. Here it is proposed that changes in protein synthesis mediate the tradeoffs that take place upon genetic and environmental manipulation in various model systems including yeast, worms, flies and mice. This hypothesis is supported by evidence that inhibition of the TOR (target of rapamycin) pathway and various translation factors that inhibit protein synthesis lead to slowing of growth and development but extend lifespan. Furthermore, dietary restriction (DR) that leads to antagonistic changes in growth and lifespan, also mediates this change by inhibiting protein synthesis. Direct screens to identify genes that extend lifespan from a subset of genes that are essential for growth and development have also uncovered a number of genes involved in protein synthesis. Given the conserved mechanisms of protein synthesis across species, I discuss potential mechanisms that mediate the lifespan extension by inhibition of protein synthesis that are likely to be important for aging and age-related disorders in humans.
Kapahi
Pankaj
P
Buck Institute for Age Research, 8001 Redwood Blvd., Novato, California 94945, USA. pkapahi@buckinstitute.org
D000375:Aging / Q000502:physiology*; D000818:Animals; D031204:Caloric Restriction; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases
D047908:Intracellular Signaling Peptides and Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases