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1.5. Integrated Stress Responses (ISR): The linchpin of chronic and age-related illnesses

The integrated stress response (ISR) is a complex biological response to a wide range of environmental and physiological challenges. In the ISR, a variety of cellular pathways are activated to protect the cell from further damage and restore homeostasis. ISR involves the activation of several transcription factors, such as activating transcription factor 4 (ATF4), which induces the expression of a wide range of pro-survival genes, including those involved in autophagy, mitophagy, apoptosis, oxidative stress, and amino acid synthesis. ISR also initiates NLRP3 inflammasome assembly and activation, which modulates subsequent immune responses.

In addition to those inputs via pattern recognition receptors (PRRs), various cellular stress signals, either calcium disruption, oxidative stress, or misfolded proteins, also trigger unfold protein responses (UPR) in the endoplasmic reticulum (ER) and mitochondria. ER and mitochondrial stress orchestrates the machinery of proteostasis, energy production, and biomolecule acquisition. These metabolic responses modulate host tissue repair and control tissue damage while facilitating cellular waste removal.

However, upon the host’s tolerance failure, the overwhelming cellular wastes cause negative consequences. Disabled proteostasis and macroautophagy lead to dysfunctional organelles, cellular damage, and unrestrained inflammasome activation that are linked to chronic illnesses, such as metabolic disorders, neurodegenerative diseases, cancer, autoimmune disorders, and age-related conditions. Ultimately, regulated ISR is the linchpin that holds these pathophysiological processes that advance to common modern-day sickness.

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Andréasson C, Ott M, Büttner S. Mitochondria orchestrate proteostatic and metabolic stress responses. EMBO Rep. 2019 Oct 4;20(10):e47865. doi: 10.15252/embr.201947865. Epub 2019 Sep 18. PMID: 31531937; PMCID: PMC6776902.

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2022 Dec 26:S0092-8674(22)01377-0. doi: 10.1016/j.cell.2022.11.001. Epub ahead of print. PMID: 36599349.

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