Research on HPK-1 reveals novel mechanisms of promoting healthy aging

C. elegans, a tiny 1mm long soil worm continues to lead major findings in aging research since the discovery of long living insulin like signaling mutants more than two decades ago.

Recent study by Ritika Das and colleagues published in PLoS Genetics, identified precise mechanisms by which a protein kinase, a molecule that adds phosphate groups on other cellular molecules, named homeodomain protein kinase 1 (hpk-1) promotes longevity in the nematode by regulating two distinct processes.

First, it promotes ability of a transcription factor named Heat Shock Transcription Factor 1 (HSF-1) under heat stress to drive chaperone expression. Second, they found HPK-1 to be activating a self eating or autophagic pathway downstream of nutritional stress. Both of these cellular activities are known to get rid of misfolded damaging protein aggregates by either refolding them into proper functional state ( as by chaperones) or degrade them in acidic cellular compartments known as lysosomes (autophagy).

Further, Das et al. showed that increasing the levels of this kinase is sufficient in increasing longevity, promoting thermal stress tolerance and delaying accumulation of age associated protein aggregates.

The fact that all the above described genes/pathways are conserved in humans, this and similar basic research offers potential nodes of intervention points where targeting HPK-1 homologs in mammals or humans may delay or prevent the onset of neurodegenerative disorders such as Alzheimer’s and Parkinsosn’s disease.

Dysfunction of mammalian homolog of HPK-1, named, HIPK2 in mammals has been associated with Alzheimer’s in cell culture model showing the importance, convenience and rapidity of studying complex questions of aging in simpler model systems such as C. elegans.

The study was conducted by Ritika Das and colleagues from University of Rochester medical center (URMC). It was supervised and funded in Professor Samuelson’s lab at URMC in collaboration with Professor Pete Douglas from UT Southwestern and Professor Todd Lamitina from University of Pittsburgh.