Biology of Stress Responses in Aging

Abstract

On April 28^th, 2022, a group of scientific leaders gathered virtually to discuss molecular and cellular mechanisms of responses to stress. Conditions of acute, high-intensity stress are well documented to induce a series of adaptive responses that aim to promote survival until the stress has dissipated and then guide recovery. However, high-intensity or persistent stress that goes beyond the cell's compensatory capacity are countered with resilience strategies that are not completely understood. These adaptative strategies, which are an essential component of the study of aging biology, were the theme of the meeting. Specific topics discussed included mechanisms of proteostasis, such as the unfolded protein response (UPR) and the integrated stress response (ISR), as well as mitochondrial stress and lysosomal stress responses. Attention was also given to regulatory mechanisms and associated biological processes linked to age-related conditions, such as muscle loss and regeneration, cancer, senescence, sleep quality, and degenerative disease, with a general focus on the relevance of stress responses to frailty. We summarize the concepts and potential future directions that emerged from the discussion and highlight their relevance to the study of aging and age-related chronic diseases.

Figure 1.. Schematic of the unfolded protein response (UPR) and the integrated stress response (ISR).

Left, the accumulation of unfolded proteins in the endoplasmic reticulum (ER) can disrupt ER homeostasis and induces ER stress, with ensuing activation of the ‘unfolded protein response’ (UPR) to block the influx of more proteins until the balance is restored. The ER stress kinases are activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1) α, and protein kinase RNA (PKR)-like ER kinase (PERK). IRE1α precisely splices X-box-binding protein-1 (XBP1) mRNA, and the protein encoded by the cleaved mRNA is a transcription factor (XBP1s) that, together with ATF6, induces the transcription of UPR genes, including key chaperones. The PERK kinase phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α) to inhibit protein synthesis and prevent further flux of proteins through the ER. Right, eIF2α can also be phosphorylated by PKR in response to viral infection, GCN2 (general control nonderepressible 2) in response to amino acid starvation, and heme-regulated inhibitor (HRI) in response to heme deficiency. The general suppression of translation occurs concomitantly with the translation of select mRNAs, including that encoding the transcription factor ATF4. ATF4 in turn promotes the transcription of C/EBP homologous protein (CHOP), also a transcription factor, and both transcriptionally induce the production of growth arrest and DNA damage inducible 34 (GADD34), a protein that in complex with the PP1 phosphatase, dephosphorylates eIF2α, restoring translation. Bottom, together, the UPR and the ISR jointly control proteostasis during the stress response; they modulate protein translation, protein folding, particularly through the action of chaperones like HSP70 and HSP90, protein stability via ER-associated degradation (ERAD), and protein transport. The UPR and the ISR also control transcriptome dynamics through processes like the select transcription of mRNAs encoding stress response proteins and via unconventional processing events like specific cleavage of the XBP1 mRNA.

Figure 2.. Graphical abstracts of stress response pathways presented in the workshop.

a, b, c) Drs. Hatzoglou, Tifunovic and Booth presented work on stress adaptation cycles and the potential mechanisms for disease development. They also discussed chemical modulation of the ISR for potential therapies. d) Dr. Finkel presented pathways for lysosomal stress and repair that are independent from the classic ESCRT pathway. e) Dr. Longo discussed differential stress sensitization (DSS) as a mediator for cancer therapy. f) Dr. Kaushik presented selective autophagy in the context of the cellular and organismal response to stress and disease. g) Dr. Muñoz-Cánoves discussed cellular senescence and the role of senolytics in tissue repair and aging. h, i, j) Drs. Lithgow, Glick and Naidoo discussed ER stress and the role of the UPR in disease, neurodegeneration, and aging. They presented evidence for the chemical modulation of UPR as a potential avenue for disease intervention. See appropriate sections in text relevant to the different overview images for further information.

Figure 3.. Theoretical model of stress response efficiency.

Long duration and high intensity or frequency of stress can exhaust the finite capacity of cells, and correspondingly, the organism’s ability to respond and restore homeostasis. In old age, this ability can be further reduced, leading to an even lower efficiency of the stress response and eventual frailty, a state of biological vulnerability to even mild stressors and limited capacity for recovery.