miR-71 mediates age-dependent opposing contributions of the stress-activated kinase KGB-1 in Caenorhabditis elegans.

Studying the evolutionary processes that shaped aging offers a path for understanding the causes of aging. The antagonistic pleiotropy theory for the evolution of aging proposes that the inverse correlation between age and natural selection strength allows positive selection of gene variants with early-life beneficial contributions to fitness despite detrimental late-life consequences. However, mechanistic understanding of how this principle manifests in aging is still lacking. We previously identified antagonistic pleiotropy in the function of the Caenorhabditis elegans JNK homolog KGB-1, which provided stress protection in developing larvae, but sensitized adults to stress and shortened their lifespan. To a large extent, KGB-1's contributions depended on age-dependent and opposing regulation of the stress-protective transcription factor DAF-16, but the underlying mechanisms remained unknown. Here, we describe a role for the microRNA miR-71 in mediating effects of KGB-1 on DAF-16 and downstream phenotypes. Fluorescent imaging along with genetic and survival analyses revealed age-dependent regulation of mir-71 expression by KGB-1-upregulation in larvae, but downregulation in adults-and showed that mir-71 was required both for late-life effects of KGB-1 (infection sensitivity and shortened lifespan), as well as for early life resistance to cadmium. While mir-71 disruption did not compromise development under protein-folding stress (known to depend on KGB-1), disruption of the argonaute gene alg-1, a central component of the microRNA machinery, did. These results suggest that microRNAs play a role in mediating age-dependent antagonistic contributions of KGB-1 to survival, with mir-71 playing a central role and additional microRNAs potentially contributing redundantly.

Integration of Stress Signaling in Caenorhabditis elegans Through Cell-Nonautonomous Contributions of the JNK Homolog KGB-1.

Dealing with physiological stress is a necessity for all organisms, and the pathways charged with this task are highly conserved in Metazoa . Accumulating evidence highlights cell-nonautonomous activation as an important mode of integrating stress responses at the organism level. Work in Caenorhabditis elegans highlighted the importance of such regulation for the unfolded protein response (UPR) and for gene expression downstream of the longevity-associated transcription factor DAF-16 Here we describe a role for the JNK homolog KGB-1 in cell-nonautonomous regulation of these two response modules. KGB-1 protects developing larvae from heavy metals and from protein folding stress (which we found to be independent of canonical UPR pathways), but sensitizes adults to the same stress, further shortening life span under normal conditions. This switch is associated with age-dependent antagonistic regulation of DAF-16 Using transgenic tissue-specific KGB-1 expression or tissue-specific KGB-1 activation we examined the contributions of KGB-1 to gene regulation, stress resistance, and life span. While cell-autonomous contributions were observed, particularly in the epidermis, cell-nonautonomous contributions of neuronal KGB-1 (and also in muscle) were effective in driving intestinal gene induction, age-dependent regulation of intestinal DAF-16, and stress resistance, and did not require KGB-1 expression in the target tissue. Additional genetic analyses revealed requirement for UNC-13 in mediating neuronal contributions, indicating involvement of neurotransmission. Our results expand the role of KGB-1 in stress responses from providing local cellular protection to integrating stress responses at the level of the whole organism.