The paper here is an example of the point that there are many ways to influence any given longevity-related mechanism. The vast majority of the diverse approaches shown to slow aging in short-lived laboratory species, such as nematode worms, in fact act through a small number of core mechanisms. These are related to cellular stress responses, such as an increased operation of maintenance processes that include, prominently, autophagy. Unfortunately they also have diminishing returns as species life span increases: it is possible to produce large gains in short-lived species via manipulation of these mechanisms, but not in humans. Other approaches are needed if the goal is rejuvenation of the old.
Physiological aging is a complex process, influenced by a plethora of genetic and environmental factors. While being far from fully understood, a number of common aging hallmarks have been elucidated in recent years. Among these, transcriptomic alterations are hypothesized to represent a crucial early manifestation of aging. Accordingly, several transcription factors (TFs) have previously been identified as important modulators of lifespan in evolutionarily distant model organisms.
Based on a set of TFs conserved between nematodes, zebrafish, mice, and humans, we here perform a RNA interference screen in C. elegans to discover evolutionarily conserved TFs impacting aging. We identify a basic helix-loop-helix TF, named HLH-2 in nematodes (Tcf3/E2A in mammals), to exert a pronounced lifespan-extending effect in C. elegans upon impairment. We further show that its impairment impacts cellular energy metabolism, increases parameters of healthy aging, and extends nematode lifespan in a reactive oxygen species dependent manner.
We then identify arginine kinases, orthologues of mammalian creatine kinases, as a target of HLH-2 transcriptional regulation, serving to mediate the healthspan-promoting effects observed upon impairment of hlh-2 expression. Consistently, HLH-2 is shown to epistatically interact with core components of known lifespan-regulating pathways, i.e. AAK-2/AMPK and LET-363/mTOR, as well as the aging-related TFs SKN-1/Nrf2 and HSF-1. Lastly, single-nucelotide polymorphisms (SNPs) in Tcf3/E2A are associated with exceptional longevity in humans. Together, these findings demonstrate that HLH-2 regulates energy metabolism via arginine kinases and thereby affects the aging phenotype dependent on ROS-signaling and established canonical effectors.