Vaccinia virus-related kinase (VRK) is an evolutionarily conserved serine-threonine protein kinase. In Caenorhabditis elegans, the sole VRK family member VRK-1 functions in cell cycle regulation, cell division and germline proliferation. However, the post-mitotic role of VRK-1 remains unknown. Here we show that somatic VRK-1 promotes longevity through activating AMP-activated protein kinase (AMPK). VRK-1 was expressed in the somatic tissues including intestine, hypodermis and neurons where VRK-1 was localized to nucleus. We found that overexpressing
vrk-1 in somatic cells but not in germ cells extended lifespan and that conversely RNAi-mediated
vrk-1 knockdown decreased lifespan. Furthermore, we demonstrated that
vrk-1 was specifically required for the longevity of
isp-1(
qm150) and
clk-1(
qm30) mitochondrial respiration mutants. In contrast, longevity in
daf-2(
e1370)/Insulin/IGF-1 receptor mutants,
eat-2(
ad111) dietary restriction-mimetic mutants,
vhl-1(
ok161) HIF-1-hyperactive mutants and
osm-5(
p813) sensory mutants was indiscriminately decreased by
vrk-1 RNAi. Through RNA-seq. analysis, we found that knockdown of
vrk-1 suppressed the induction of many putative targets of AAK-2/AMPK in
isp-1(-) mutants. In contrast,
vrk-1 RNAi did not influence the expression of targets of other factors that mediate the longevity of
isp-1 mutants, including HIF-1, ATFS-1, CEH-23, CEP-1 and SKN-1. We showed that
aak-2(
ok524) mutations completely suppressed the life-extending effect of
vrk-1 overexpression. In addition,
vrk-1 RNAi and
aak-2(
ok524) mutations did not display additive life-shortening effects on the longevity of
isp-1(
qm150) mutants. These data suggest that VRK-1 acts together with AMPK to extend lifespan. We then showed that the active phospho-AMPK level in C. elegans was increased by
vrk-1 overexpression, while being decreased by
vrk-1 RNAi knockdown. Furthermore, we showed that mammalian VRK1 phosphorylated AMPK by using cultured human cells and in vitro kinase assays. Thus, the role of VRK-1 as an upstream activating kinase of AMPK appears to be evolutionarily conserved. Together, our data suggest that VRK-1 promotes organismal longevity by acting in post-mitotic cells via increasing the activity of AMPK.