Growth hormone signaling is necessary for lifespan extension by dietary methionine

Brown‐Borg, Holly M.; Rakoczy, Sharlene; Wonderlich, Joseph; Rojanathammanee, Lalida; Kopchick, John J.; Armstrong, Vanessa; Raasakka, Debbie

doi:10.1111/acel.12269

Cited by 49 publications

(70 citation statements)

References 44 publications

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“…Also, methionine restriction increases the stress tolerance of human fibroblasts, reduces senescence and increases their doubling time [66, 67]. In mammals, the effect of MR appears to be growth hormone dependent [68]. …”

Section: Discussionmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human breast cancer cells in vivo, providing evidence for their potential clinical relevance. As such, increased mRNA translation could provide a novel mechanism for enhancing the proliferative clonal expansion of TICs. The proteomic findings were functionally validated using known inhibitors of protein synthesis, via three independent approaches. For example, puromycin (which mimics the structure of tRNAs and competitively inhibits protein synthesis) preferentially targeted CSCs in both mammospheres and monolayer cultures, and was ~10-fold more potent for eradicating TICs, than “bulk” cancer cells. In addition, rapamycin, which inhibits mTOR and hence protein synthesis, was very effective at reducing mammosphere formation, at nanomolar concentrations. Finally, mammosphere formation was also markedly inhibited by methionine restriction, which mimics the positive effects of caloric restriction in cultured cells. Remarkably, mammosphere formation was >18-fold more sensitive to methionine restriction and replacement, as directly compared to monolayer cell proliferation. Methionine is absolutely required for protein synthesis, since every protein sequence starts with a methionine residue. Thus, the proliferation and survival of CSCs is very sensitive to the inhibition of protein synthesis, using multiple independent approaches. Our findings have important clinical implications, since they may also explain the positive therapeutic effects of PI3-kinase inhibitors and AKT inhibitors, as they ultimately converge on mTOR signaling and would block protein synthesis. We conclude that inhibition of mRNA translation by pharmacological or protein/methionine restriction may be effective strategies for eliminating TICs. Our data also indicate a novel mechanism by which caloric/protein restriction may reduce tumor growth, by targeting protein synthesis in anabolic tumor-initiating cancer cells.

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Section: Discussionmentioning

confidence: 99%

Targeting tumor-initiating cells: Eliminating anabolic cancer stem cells with inhibitors of protein synthesis or by mimicking caloric restriction

Lamb¹,

Harrison

Smith

et al. 2015

Oncotarget

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“…It has been shown that GH signaling is necessary to discriminate levels of dietary methionine in mice (Brown-Borg et al . 2014). In rodents, protein/amino acid restriction also offers health benefits in models of acute stress and chronic disease.…”

Section: Dietary Interventions Mimicking Calorie Restrictionmentioning

confidence: 99%

Interventions to Slow Aging in Humans: Are We Ready?

et al. 2015

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The workshop entitled ‘Interventions to Slow Aging in Humans: Are We Ready?’ was held in Erice, Italy, on October 8–13, 2013, to bring together leading experts in the biology and genetics of aging and obtain a consensus related to the discovery and development of safe interventions to slow aging and increase healthy lifespan in humans. There was consensus that there is sufficient evidence that aging interventions will delay and prevent disease onset for many chronic conditions of adult and old age. Essential pathways have been identified, and behavioral, dietary, and pharmacologic approaches have emerged. Although many gene targets and drugs were discussed and there was not complete consensus about all interventions, the participants selected a subset of the most promising strategies that could be tested in humans for their effects on healthspan. These were: (i) dietary interventions mimicking chronic dietary restriction (periodic fasting mimicking diets, protein restriction, etc.); (ii) drugs that inhibit the growth hormone/IGF-I axis; (iii) drugs that inhibit the mTOR–S6K pathway; or (iv) drugs that activate AMPK or specific sirtuins. These choices were based in part on consistent evidence for the pro-longevity effects and ability of these interventions to prevent or delay multiple age-related diseases and improve healthspan in simple model organisms and rodents and their potential to be safe and effective in extending human healthspan. The authors of this manuscript were speakers and discussants invited to the workshop. The following summary highlights the major points addressed and the conclusions of the meeting.

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“…Restricting a single amino acid such as methionine also increases longevity in normal rats and mice (74,83,119) yet does not impact lifespan in GH signaling mutants (Ames dwarf, GHRKO) (20). Thus intact signaling of the somatotropic pathway appears to be necessary for amino acid sensing in terms of metabolism and lifespan regulation (19).…”

Section: Interventions That Alter Gh or Igf-imentioning

confidence: 99%