Signaling mechanisms involved in lifespan regulation and the cellular response to genotoxic stress. (A) Signals promoting growth and survival (yellow portion of the cell). IGF-1 is secreted primarily by the liver in response to growth hormone and is the key mediator of its growth-promoting effects. IGF-1 binds its cell surface receptor IGF-1R, a tyrosine kinase that phosphorylates numerous substrates including SHC, which then recruits the adaptor protein GRB2 and activates the RAS-MAPK pathway, which stimulates cell proliferation and differentiation. A second key substrate is IRS-1, which leads to activation of the serine-threonine kinase AKT via PI3-kinase (PI3K). AKT promotes cell survival by directly phosphorylating and inhibiting pro-apoptotic factors including caspase-9, BAD and FOXO transcription factors. AKT also phosphorylates a subunit of IKK leading to activation of the transcription factor NF-κB, which drives expression of pro-survival genes. AKT inhibits p53-mediated apoptosis by phosphorylating and activating MDM2, an E3-ubiquitin ligase that polyubiquitinates p53, targeting it for proteosomal degradation. AKT also phosphorylates the TSC complex, allowing activation of mTOR. mTOR is a PI3K-like kinase that resides in multiprotein complexes. mTORC1 positively regulates growth by directly phosphorylating and inhibiting 4E-BP, causing it to release its binding partner eIF-4E, which then binds mRNA caps, the rate limiting step in protein translation. mTOR also negatively regulates autophagy and activates S6K, which promotes ribosomal maturation and growth. Decreased expression of the growth promoting factors IGF-1, IGF-1R, PI3K, AKT, TOR, e1F4E or S6K leads to lifespan extension in at least one model organism (yeast, worms, flies or mice).
(B) Pro-apoptotic signaling in response to genotoxic stress (blue portion of cell). DNA double strand breaks are sensed by the MRE11-RAD50-NBS1 (MRN) complex, which in turn activates the signal transducer ATM. ATM is a PI3K-like kinase with numerous protein targets. ATM phosphorylation of the transcription factor p53 leads to its stabilization and activation, promoting cell cycle arrest and apoptosis. ATM also phosphorylates IKKγ, the regulatory subunit of IKK, causing its translocation to the cytoplasm, activating IKK, which phosphorylates IκB. Phosphorylation of IκB leads to its polyubiquitination and proteosomal degradation, releasing NF-κB transcription factor, which moves to the nucleus and in response to genotoxic stress increases expression of pro-apoptotic genes. A third substrate of ATM is the transcription factor E2F1, which among other things induces expression of the histone deacetylase SIRT1. SIRT1 deacetylates numerous non-histone substrates including KU70 and FOXO transcription factors, leading to their activation and inhibition of apoptosis. SIRT1 also deacetylates p53 and NF-κB, causing their inactivation and dampening of pro-apoptotic signals. Hyperactivity of the pro-apoptotic factor p53 accelerates aging and NF-κB is associated with old age. Deletion of SIRT1 extends lifespan in metazoans and appears to delay aging in mammals, consistent with it being primarily growth promoting.