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The molecular genetics of sirtuins: association with human longevity and age-related diseases.

ABSTRACT: The sirtuins are a family of proteins remarkably conserved from yeast to humans. In organisms such as yeast, worms and flies it is quite well established that the activity of sirtuins prolongs lifespan. As a result of promising findings in simple organisms, sirtuins are now investigated in higher organisms in relation to the ageing process. In mammals there are seven different sirtuin proteins each encoded by individual genes (SIRT1-7). Although sirtuins share a highly conserved catalytic domain, they differ in their biological function. Some mammalian sirtuins have been implicated in different ageing pathways and their modulation has been deemed to be beneficial in different models of age-associated diseases. Overall, sirtuins could contribute to mechanisms of human longevity and avoid or delay the onset of age-associated disorders. Here we review and discuss the potential impact of genetic variation in the sirtuin genes in relation to human longevity and age-related diseases.

SUBMITTER: Polito L

PROVIDER: S-EPMC3076766 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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The molecular genetics of sirtuins: association with human longevity and age-related diseases.

Polito Letizia L Kehoe Patrick G PG Forloni Gianluigi G Albani Diego D

International journal of molecular epidemiology and genetics 20100620 3

The sirtuins are a family of proteins remarkably conserved from yeast to humans. In organisms such as yeast, worms and flies it is quite well established that the activity of sirtuins prolongs lifespan. As a result of promising findings in simple organisms, sirtuins are now investigated in higher organisms in relation to the ageing process. In mammals there are seven different sirtuin proteins each encoded by individual genes (SIRT1-7). Although sirtuins share a highly conserved catalytic domain ...[more]

PMID: 21537393

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Project description:Canonical WNT signaling through Frizzled and LRP5/6 receptors is transduced to the WNT/β-catenin and WNT/stabilization of proteins (STOP) signaling cascades to regulate cell fate and proliferation, whereas non-canonical WNT signaling through Frizzled or ROR receptors is transduced to the WNT/planar cell polarity (PCP), WNT/G protein-coupled receptor (GPCR) and WNT/receptor tyrosine kinase (RTK) signaling cascades to regulate cytoskeletal dynamics and directional cell movement. WNT/β-catenin signaling cascade crosstalks with RTK/SRK and GPCR-cAMP-PKA signaling cascades to regulate β-catenin phosphorylation and β-catenin-dependent transcription. Germline mutations in WNT signaling molecules cause hereditary colorectal cancer, bone diseases, exudative vitreoretinopathy, intellectual disability syndrome and PCP-related diseases. APC or CTNNB1 mutations in colorectal, endometrial and prostate cancers activate the WNT/β-catenin signaling cascade. RNF43, ZNRF3, RSPO2 or RSPO3 alterations in breast, colorectal, gastric, pancreatic and other cancers activate the WNT/β-catenin, WNT/STOP and other WNT signaling cascades. ROR1 upregulation in B-cell leukemia and solid tumors and ROR2 upregulation in melanoma induce invasion, metastasis and therapeutic resistance through Rho-ROCK, Rac-JNK, PI3K-AKT and YAP signaling activation. WNT signaling in cancer, stromal and immune cells dynamically orchestrate immune evasion and antitumor immunity in a cell context-dependent manner. Porcupine (PORCN), RSPO3, WNT2B, FZD5, FZD10, ROR1, tankyrase and β-catenin are targets of anti-WNT signaling therapy, and ETC-159, LGK974, OMP-18R5 (vantictumab), OMP-54F28 (ipafricept), OMP-131R10 (rosmantuzumab), PRI-724 and UC-961 (cirmtuzumab) are in clinical trials for cancer patients. Different classes of anti-WNT signaling therapeutics are necessary for the treatment of APC/CTNNB1-, RNF43/ZNRF3/RSPO2/RSPO3- and ROR1-types of human cancers. By contrast, Dickkopf-related protein 1 (DKK1), SOST and glycogen synthase kinase 3β (GSK3β) are targets of pro-WNT signaling therapy, and anti-DKK1 (BHQ880 and DKN-01) and anti-SOST (blosozumab, BPS804 and romosozumab) monoclonal antibodies are being tested in clinical trials for cancer patients and osteoporotic post-menopausal women. WNT-targeting therapeutics have also been applied as reagents for in vitro stem-cell processing in the field of regenerative medicine.

Dataset Information

The molecular genetics of sirtuins: association with human longevity and age-related diseases.

Publications

The molecular genetics of sirtuins: association with human longevity and age-related diseases.

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