Overexpression of VRK-1 Extends Life Span in Nematode Worms
A great many approaches exist to slow aging in short-lived laboratory species such as nematodes, flies, and mice. The example here is an illustrative example, similar to dozens of other discoveries regarding life span and upregulation or downregulation of the expression of specific proteins. Since cellular biochemistry is a connected web of interactions, most such methods involve adjusting different parts of the same underlying system of regulation. An increased operation of cellular stress responses is the most common such regulator of the pace of aging. Unfortunately this type of intervention has much larger effects on life span in short-lived species than it does in long-lived species. This has led to much of the field of aging research focusing on projects that appear interesting in mice, but cannot possibly produce large gains in human life span.
Mitochondria are essential subcellular organelles for cellular energy production. Mitochondria also play important functions in a wide array of other cellular processes, ranging from cellular signaling to apoptosis. In addition, mitochondria play crucial roles in organismal aging, and functional declines in mitochondria are associated with age-related diseases. However, mild inhibition of mitochondrial respiration has been shown to promote longevity in multiple species. In Caenorhabditis elegans, the genetic inhibition of mitochondrial respiration genes prolongs life span. Inhibition of mitochondrial respiration also increases life span in Drosophila and mammals.
Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK), a critical cellular energy sensor that increases life span in multiple species, is one of the factors required for the enhanced longevity caused by inhibition of mitochondrial respiration in C. elegans. The vaccinia virus-related kinase (VRK) family consists of three serine-threonine protein kinases (VRK1 to VRK3) in mammals, which are related to casein kinases. Among these three, the best characterized is VRK1, a cell cycle regulator that is abundant in proliferative tissues. Unlike mammals, C. elegans has a single VRK ortholog, VRK-1, whose function in cell proliferation is relatively well established. However, it remains unknown whether VRK-1 acts in postmitotic cells or has a role in adult life span.
In this study, we sought to elucidate the role of VRK-1 in regulation of adult life span in C. elegans. We found that overexpression of VRK-1::GFP (green fluorescent protein), which was detected in the nuclei of cells in multiple somatic tissues, including the intestine, increased life span. Conversely, genetic inhibition of vrk-1 decreased life span. We further showed that vrk-1 was essential for the increased life span of mitochondrial respiratory mutants. We demonstrated that VRK-1 was responsible for increasing the level of active and phosphorylated form of AMPK, thus promoting longevity.