Abstract
Neurons have a lifespan that parallels that of the organism and are largely irreplaceable. Their unusually long lifespan predisposes neurons to neurodegenerative disease. We sought to identify physiological mechanisms that delay neuron aging in Caenorhabditis elegans by asking how neuron morphological aging is arrested in the long-lived, alternate organismal state, the dauer diapause. We find that a hormone signaling pathway, the abnormal DAuer Formation (DAF) 12 nuclear hormone receptor (NHR) pathway, functions cell-intrinsically in the dauer diapause to arrest neuron morphological aging, and that same pathway can be cell-autonomously manipulated during normal organismal aging to delay neuron morphological aging. This delayed aging is mediated by suppressing constitutive endocytosis, which alters the subcellular localization of the actin regulator T cell lymphoma Invasion And Metastasis 1 (TIAM-1), thereby decreasing age-dependent neurite growth. Intriguingly, we show that suppressed endocytosis appears to be a general feature of cells in diapause, suggestive that this may be a mechanism to halt the growth and other age-related programs supported by most endosome recycling.
Highlights
Neurons are largely irreplaceable and must survive and function for the lifespan of the organism
Neuron morphological aging can be cell-autonomously stalled by the dauer- and aging-related DAuer Formation (DAF)-12 nuclear hormone receptor (NHR)
We reasoned that specific signaling components involved in the organismal dauer state decision may dictate whether the PVD dendrite grows to the reproductive development (RD)-like versus dauerlike morphology
Summary
Neurons are largely irreplaceable and must survive and function for the lifespan of the organism. Diverse neuron pathologies are thought to underlie various neurodegenerative diseases, increased age is a common risk factor [2]. Whether this is due to age of the organism, the neurons, or both is not clear; still, the idea that delaying aging could postpone the onset of these diseases, as well as age-associated cognitive decline, is a major motivation for aging research. The endosomal pathways of this system promote constant sampling of the environment—evocatively, mouse embryonic fibroblasts recycle their entire cell surface in under 15 minutes [3]. Endosomal pathways modulate activity of plasma membrane
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