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Neuronal TORC1 modulates longevity via AMPK and cell nonautonomous regulation of mitochondrial dynamics in C. elegans

Yue Zhang1, Anne Lanjuin1, Suvagata Roy Chowdhury1

  • 1Department of Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, United States.

Elife
|August 15, 2019
PubMed

Insights

Neuronal AMP-activated protein kinase (AMPK) is crucial for extending lifespan by inhibiting the Target of Rapamycin Complex 1 (TORC1). TORC1 suppression promotes longevity through distinct, non-autonomous mechanisms, suggesting CNS TORC1 as a target for healthy aging.

Area of Science:

  • Cellular metabolism and aging research
  • Neuroscience and longevity studies
  • Molecular mechanisms of aging

Background:

  • Target of Rapamycin Complex 1 (TORC1) and AMP-activated Protein Kinase (AMPK) are key regulators of cellular metabolism and aging.
  • The precise coordination between TORC1 and AMPK in determining lifespan and their distinct functional mechanisms remain incompletely understood.

Purpose of the Study:

  • To elucidate the role of neuronal AMPK in TORC1-mediated lifespan extension.
  • To investigate whether TORC1 suppression extends lifespan through mechanisms separable from global AMPK activation.
  • To identify the specific cellular pathways and factors involved in TORC1's non-autonomous regulation of longevity.

Main Methods:

  • Utilized genetic models in *C. elegans* with null mutations in *raga-1* (RagA) and *rsks-1* (S6K) to study TORC1 function.
  • Employed neuronal-specific rescue experiments to assess the requirement of neuronal AMPK.
  • Investigated the role of mitochondrial dynamics (fusion and fission) and specific genes like UNC-64/syntaxin and DRP-1 in TORC1-mediated longevity.
  • Analyzed lifespan extension and its suppression by genetic manipulations.

Main Results:

  • Neuronal AMPK activity is essential for lifespan extension induced by TORC1 inhibition.
  • TORC1 suppression extends lifespan via cell non-autonomous mechanisms distinct from global AMPK activation.
  • Loss of RAGA-1 (a TORC1 component) extends lifespan by maintaining mitochondrial fusion.
  • Neuronal RAGA-1 abrogation of longevity requires UNC-64/syntaxin and promotes mitochondrial fission non-autonomously.
  • Deletion of the mitochondrial fission factor DRP-1 abrogates the pro-aging effects of neuronal RAGA-1.

Conclusions:

  • Neuronal TORC1 plays a significant role in the cell non-autonomous regulation of longevity.
  • TORC1 acts through distinct mechanisms, including modulation of mitochondrial dynamics, to influence lifespan.
  • Targeting TORC1 within the central nervous system presents a potential therapeutic strategy for promoting healthy aging.
Keywords:
AMPKC. elegansTORC1aginggeneticsgenomicsmitochondria

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