Hijacking Cellular Stress Responses to Promote Lifespan

Abstract

Organisms are constantly exposed to stress both from the external environment and internally within the cell. To maintain cellular homeostasis under different environmental and physiological conditions, cell have adapted various stress response signaling pathways, such as the heat shock response (HSR), unfolded protein responses of the mitochondria (UPR^MT), and the unfolded protein response of the endoplasmic reticulum (UPR^ER). As cells grow older, all cellular stress responses have been shown to deteriorate, which is a major cause for the physiological consequences of aging and the development of numerous age-associated diseases. In contrast, elevated stress responses are often associated with lifespan extension and amelioration of degenerative diseases in different model organisms, including C. elegans. Activating cellular stress response pathways could be considered as an effective intervention to alleviate the burden of aging by restoring function of essential damage-clearing machinery, including the ubiquitin-proteosome system, chaperones, and autophagy. Here, we provide an overview of newly emerging concepts of these stress response pathways in healthy aging and longevity with a focus on the model organism, C. elegans.

Keywords: C. elegans; aging; endoplasmic reticulum; heat-shock; mitochondria; stress.

FIGURE 1

The cytosolic heat-shock response. (A) The heat-shock response (HSR) is regulated by the transcription factor, HSF-1, which contains four major structural domains: the DNA-binding domain (DBD), regulatory domain (RD), trans-activating domain (TAD), and the oligomerization domain divided into HR-A and HR-B. (B) Under basal conditions, HSF-1 is bound by regulatory proteins that prevent its activation. Upon stress, these proteins are released from HSF-1 as they are titrated away to serve as molecular chaperones to damaged proteins, allowing HSF-1 to trimerize and serve as a transcription factor to activate genes important to mitigate damage and increase survival. (C) The HSR can be communicated in a non-autonomous manner, whereby thermosensory and serotonergic neurons can communicate to peripheral tissue, including the intestine, to activate a systemic HSR and promote organismal health and lifespan.

FIGURE 2

The mitochondrial unfolded protein response. (A) ATFS-1 is a unique protein that can serve as a sensor for mitochondrial health and fitness. It contains both a nuclear localization signal (NLS) and a mitochondrial localization signal (MLS). Under basal, unstressed conditions, ATFS-1 is imported into the mitochondria where it is degraded by LON protease. Under conditions of mitochondrial stress or damage, mitochondrial import decreases, allowing ATFS-1 to instead accumulate in the mitochondria where it can activate UPR^MT with additional transcriptional regulators including DVE-1 and chromatin regulator JMJD-1.2. (B) Similar to the HSR, UPR^MT can also be communicated in a nonautonomous manner. Neurons that experience mitochondrial stress can signal to the peripheral tissue, including the intestine, through serotonin and WNT signaling to result in systemic activation of UPR^MT, increased stress resilience, and increased lifespan.

FIGURE 3

The endoplasmic reticulum unfolded protein response. (A) There are three branches of UPR^ER, each consisting of an ER transmembrane protein with different mechanisms of action. When IRE-1 senses misfolded proteins, it homodimerizes, autophosphorylates, and promotes splicing of xbp-1u to xbp-1s, which can then be translated into the transcription factor XBP-1s, which activates UPR^ER. Similar to IRE-1, PEK-1 undergoes oligomerization, which induces eIF2α phosphorylation and activation of ATF4 to inhibit global translation. ATF6 is activated by proteolytic cleavage under ER stress, which causes translocation to the Golgi for further processing, resulting in a transcriptionally active ATF6 that promotes UPR^ER. (B) The UPR^ER is communicated in a nonautonomous manner through multiple neuronal subtypes and through glial cells. Serotonergic, dopaminergic, and RIM/RIC neurons signal to peripheral cells using specific neurotransmitters, whereas glial cells communicate through neuropeptide signaling. While the exact identify of receptors involved have not yet been fully characterized, distal cells respond by promoting IRE-1-dependent splicing of xbp-1s to induce the UPR^ER.