A cytoprotective perspective on longevity regulation

Abstract

There are many mechanisms of lifespan extension, including the disruption of insulin/insulin-like growth factor 1 (IGF-1) signaling, metabolism, translation, and feeding. Despite the disparate functions of these pathways, inhibition of each induces responses that buffer stress and damage. Here, emphasizing data from genetic analyses in Caenorhabditis elegans, we explore the effectors and upstream regulatory components of numerous cytoprotective mechanisms activated as major elements of longevity programs, including detoxification, innate immunity, proteostasis, and oxidative stress response. We show that their induction underpins longevity extension across functionally diverse triggers and across species. Intertwined with the evolution of longevity, cytoprotective pathways are coupled to the surveillance of core cellular components, with important implications in normal and aberrant responses to drugs, chemicals, and pathogens.

Keywords: aging; cytoprotection; detoxification; hormesis; longevity; stress.

Figure 1. Cytoprotective Signaling Results in Lifespan Extension

Mutations and gene inactivations that extend lifespan may be classified into those that activate cytoprotective pathways through the disruption of essential cell functions, such as metabolism or translation, and those that do so through direct roles in stress signaling pathways. Cytoprotective pathways evolved to combat environmental stressors, such as pathogens and xenobiotics. Exposed tissues, such as the intestine, hypodermis, or some neurons, are the expected point of first contact with these threats. Non-autonomous signals, such as neuroendocrine signals, are predicted to orchestrate the systemic aspect of stress tolerance, inducing cytoprotective pathways that mitigate the accumulation of cellular damage and mediate lifespan extension.

Figure 2. Surveillance of Core Cellular Functions is a Distinct Mechanism of Xenobiotic and Pathogen Detection and Response

Prevalent models of pathogen and xenobiotic response require the detection of pathogen- or damage-associated ligands by cell surface receptors. Pathogen ligands are referred to as pathogen-associated molecular patterns (PAMPs) and include compounds such as lipid A on the outer membranes of Gram-negative bacteria or conserved proteins such as flagellins. Xenobiotics produced by pathogens may be detected as well. Damage-associated molecular patterns (DAMPs) are the secondary products of pathogen or xenobiotic damage, such as the detritus resulting from the breakdown of compromised cells, an example of which may be DNA released into the extracellular milieu by a pathogen-lysed cell. In each of these models, the receptor-mediated detection of the PAMP or DAMP initiates a signaling cascade that results in the induction of defense responses, such as innate immune gene induction. In contrast, cellular surveillance activated detoxification and defenses (cSADD) are initiated by decrements in the activity of core cellular functions, such as the mitochondria or ribosome, which are explicitly surveilled. Because many diverse pathogens and xenobiotics disrupt a small number of critical cell functions, monitoring core cellular processes provides an efficient mechanism of comprehensively detecting and responding to highly diverse stimuli, escaping the limitations of PAMP or DAMP ligand detection. These models are not mutually exclusive.