Neuronal activation of Gαq EGL-30/GNAQ late in life rejuvenates cognition across species
Morgan E. Stevenson,
Gregor Bieri,
Rachel Kaletsky,
Jonathan St. Ange,
L. Remesal,
Karishma J.B. Pratt,
Shiyi Zhou,
Yifei Weng,
Coleen T. Murphy,
Saul A. Villeda
Affiliations
Morgan E. Stevenson
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Gregor Bieri
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA
Rachel Kaletsky
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Jonathan St. Ange
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
L. Remesal
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA
Karishma J.B. Pratt
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA
Shiyi Zhou
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Yifei Weng
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Coleen T. Murphy
Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Corresponding author
Saul A. Villeda
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, San Francisco, CA 94143, USA; Corresponding author
Summary: Loss of cognitive function with age is devastating. EGL-30/GNAQ and Gαq signaling pathways are highly conserved between C. elegans and mammals, and murine Gnaq is enriched in hippocampal neurons and declines with age. We found that activation of EGL-30 in aged worms triples memory span, and GNAQ gain of function significantly improved memory in aged mice: GNAQ(gf) in hippocampal neurons of 24-month-old mice (equivalent to 70- to 80-year-old humans) rescued age-related impairments in well-being and memory. Single-nucleus RNA sequencing revealed increased expression of genes regulating synaptic function, axon guidance, and memory in GNAQ-treated mice, and worm orthologs of these genes were required for long-term memory extension in worms. These experiments demonstrate that C. elegans is a powerful model to identify mammalian regulators of memory, leading to the identification of a pathway that improves memory in extremely old mice. To our knowledge, this is the oldest age at which an intervention has improved age-related cognitive decline.
