CREB-regulated transcription coactivator 1 (Mucoepidermoid carcinoma translocated protein 1) (Transducer of regulated cAMP response element-binding protein 1) (TORC-1) (Transducer of CREB protein 1) [KIAA0616] [MECT1] [TORC1] [WAMTP1]
развернуть
TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling.
The sensation of pain is associated with increased mortality, but it is unknown whether pain perception can directly affect aging. We find that mice lacking TRPV1 pain receptors are long-lived, displaying a youthful metabolic profile at old age. Loss of TRPV1 inactivates a calcium-signaling cascade that ends in the nuclear exclusion of the CREB-regulated transcriptional coactivator CRTC1 within pain sensory neurons originating from the spinal cord. In long-lived TRPV1 knockout mice, CRTC1 nuclear exclusion decreases production of the neuropeptide CGRP from sensory endings innervating the pancreatic islets, subsequently promoting insulin secretion and metabolic health. In contrast, CGRP homeostasis is disrupted with age in wild-type mice, resulting in metabolic decline. We show that pharmacologic inactivation of CGRP receptors in old wild-type animals can restore metabolic health. These data suggest that ablation of select pain sensory receptors or the inhibition of CGRP are associated with increased metabolic health and control longevity.
MeSH Terms
- Animals
- CREB-Binding Protein
- Caenorhabditis elegans
- Cells, Cultured
- Diet
- Female
- Insulin
- Longevity
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mutation
- Neurons
- Nociceptors
- Signal Transduction
- TRPV Cation Channels
- Transcription Factors
развернуть
Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies.
To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10⁻⁶⁰) and 9q31.2 (P = 2.2 × 10⁻³³), we identified 30 new menarche loci (all P < 5 × 10⁻⁸) and found suggestive evidence for a further 10 loci (P < 1.9 × 10⁻⁶). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.
MeSH Terms
- Adolescent
- Aging
- Body Height
- Body Size
- Child
- DNA Copy Number Variations
- Female
- Genetic Loci
- Genetic Predisposition to Disease
- Genome-Wide Association Study
- Humans
- Inheritance Patterns
- Menarche
- Obesity
- Polymorphism, Single Nucleotide
- Quantitative Trait Loci
- Reproducibility of Results
- Time Factors