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Target of rapamycin complex 1 (TORC1) and AMP-activated protein kinase (AMPK) antagonistically modulate metabolism and aging. However, how they coordinate to determine longevity and if they act via separable mechanisms is unclear. Here, we show that neuronal AMPK is essential for lifespan extension from TORC1 inhibition, and that TORC1 suppression increases lifespan cell non autonomously via distinct mechanisms from global AMPK activation. Lifespan extension by null mutations in genes encoding (RagA) or (S6K) is fully suppressed by neuronal-specific rescues. Loss of RAGA-1 increases lifespan via maintaining mitochondrial fusion. Neuronal RAGA-1 abrogation of mutant longevity requires UNC-64/syntaxin, and promotes mitochondrial fission cell nonautonomously. Finally, deleting the mitochondrial fission factor DRP-1 renders the animal refractory to the pro-aging effects of neuronal RAGA-1. Our results highlight a new role for neuronal TORC1 in cell nonautonomous regulation of longevity, and suggest TORC1 in the central nervous system might be targeted to promote healthy aging.
This article was published in the following journal.
Reduced mRNA translation delays aging, but the underlying mechanisms remain underexplored. Mutations in both DAF-2 (IGF-1 receptor) and RSKS-1 (ribosomal S6 kinase/S6K) cause synergistic lifespan exte...
Eisosomes are furrows in the yeast plasma membrane that form a membrane domain with distinct lipid and protein composition. Recent studies highlighted the importance of this domain for the regulation ...
Nutrient starvation induces the degradation of specific plasma membrane proteins through the multivesicular body (MVB) sorting pathway and of vacuolar membrane proteins through microautophagy. Both of...
As a master regulator for metabolic and energy homeostasis, AMPK controls the activity of metabolic enzymes and transcription factors in response to cellular ATP status. AMPK has been thus recognized ...
Autophagy plays a broad role in health and disease. Here, we show that inositol polyphosphate multikinase (IPMK) is a prominent physiological determinant of autophagy and is critical for liver inflamm...
This phase II trial studies how well mTOR complex 1 and 2 (TORC1/2) Inhibitor INK128 works in treating patients with acute lymphoblastic leukemia that has returned after a period of improv...
This phase I trial studies the side effects and best dose of transducer of regulated CREB activity 1/2 (TORC1/2) inhibitor INK128 when given together with epidermal growth factor receptor ...
Advanced renal cell carcinoma is invariably fatal, with a life expectancy of 2-3 years since diagnosis. Sunitinib is the standard first-line treatment for this condition, but it is associa...
The objective of this study was to establish a formulation, containing both Hibiscus sabdariffa L. (HS) and Lippia citriodora L. (LC) extracts (Metabolaid®) that had significant capacity ...
Palomid 529 is a dual TORC1/2 inhibitor of the PI3K/Akt/mTOR pathway having broad activity in angiogenesis and cellular proliferation. Palomid 529 will be examined to determine if the saf...
Clusters of neuronal cell bodies in invertebrates. Invertebrate ganglia may also contain neuronal processes and non-neuronal supporting cells. Many invertebrate ganglia are favorable subjects for research because they have small numbers of functional neuronal types which can be identified from one animal to another.
A member of the immunoglobulin superfamily of neuronal cell adhesion molecules that is required for proper nervous system development. Neural cell adhesion molecule L1 consists of six Ig domains, five fibronectin domains, a transmembrane region and an intracellular domain. Two splicing variants are known: a neuronal form that contains a four-amino acid RSLE sequence in the cytoplasmic domain, and a non-neuronal form that lacks the RSLE sequence. Mutations in the L1 gene result in L1 disease. Neural cell adhesion molecule L1 is predominantly expressed during development in neurons and Schwann cells; involved in cell adhesion, neuronal migration, axonal growth and pathfinding, and myelination.
An E3 ubiquitin ligase primarily involved in regulation of the metaphase-to-anaphase transition during MITOSIS through ubiquitination of specific CELL CYCLE PROTEINS. Enzyme activity is tightly regulated through subunits and cofactors, which modulate activation, inhibition, and substrate specificity. The anaphase-promoting complex, or APC-C, is also involved in tissue differentiation in the PLACENTA, CRYSTALLINE LENS, and SKELETAL MUSCLE, and in regulation of postmitotic NEURONAL PLASTICITY and excitability.
Formation of neuronal processes (AXONS; NEURITES) toward a target cell.
A hyalectin family member that is expressed in neuronal tissue and plays a role in neuronal CELL ADHESION.