PMID- 37423094 OWN - NLM STAT- MEDLINE DCOM- 20230807 LR - 20240404 IS - 1873-3360 (Electronic) IS - 0306-4530 (Print) IS - 0306-4530 (Linking) VI - 155 DP - 2023 Sep TI - Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging. PG - 106322 LID - S0306-4530(23)00300-1 [pii] LID - 10.1016/j.psyneuen.2023.106322 [doi] AB - Stress triggers anticipatory physiological responses that promote survival, a phenomenon termed allostasis. However, the chronic activation of energy-dependent allostatic responses results in allostatic load, a dysregulated state that predicts functional decline, accelerates aging, and increases mortality in humans. The energetic cost and cellular basis for the damaging effects of allostatic load have not been defined. Here, by longitudinally profiling three unrelated primary human fibroblast lines across their lifespan, we find that chronic glucocorticoid exposure increases cellular energy expenditure by approximately 60%, along with a metabolic shift from glycolysis to mitochondrial oxidative phosphorylation (OxPhos). This state of stress-induced hypermetabolism is linked to mtDNA instability, non-linearly affects age-related cytokines secretion, and accelerates cellular aging based on DNA methylation clocks, telomere shortening rate, and reduced lifespan. Pharmacologically normalizing OxPhos activity while further increasing energy expenditure exacerbates the accelerated aging phenotype, pointing to total energy expenditure as a potential driver of aging dynamics. Together, our findings define bioenergetic and multi-omic recalibrations of stress adaptation, underscoring increased energy expenditure and accelerated cellular aging as interrelated features of cellular allostatic load. CI - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved. FAU - Bobba-Alves, Natalia AU - Bobba-Alves N AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States. FAU - Sturm, Gabriel AU - Sturm G AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States; Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, United States. FAU - Lin, Jue AU - Lin J AD - Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, United States. FAU - Ware, Sarah A AU - Ware SA AD - Department of Medicine, Vascular Medicine Institute and Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, United States. FAU - Karan, Kalpita R AU - Karan KR AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States. FAU - Monzel, Anna S AU - Monzel AS AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States. FAU - Bris, Celine AU - Bris C AD - Department of Genetics, Angers Hospital, Angers, France; MitoLab, UMR CNRS 6015, INSERM U1083, Institut MitoVasc, Universite d'Angers, Angers, France. FAU - Procaccio, Vincent AU - Procaccio V AD - MitoLab, UMR CNRS 6015, INSERM U1083, Institut MitoVasc, Universite d'Angers, Angers, France. FAU - Lenaers, Guy AU - Lenaers G AD - Department of Genetics, Angers Hospital, Angers, France; MitoLab, UMR CNRS 6015, INSERM U1083, Institut MitoVasc, Universite d'Angers, Angers, France; Department of Neurology, Angers Hospital, Angers, France. FAU - Higgins-Chen, Albert AU - Higgins-Chen A AD - Department of Psychiatry, Yale University School of Medicine, New Haven CT, United States. FAU - Levine, Morgan AU - Levine M AD - Altos Labs, San Diego Institute of Science, San Diego, CA United States. FAU - Horvath, Steve AU - Horvath S AD - Altos Labs, San Diego Institute of Science, San Diego, CA United States. FAU - Santhanam, Balaji S AU - Santhanam BS AD - Departments of Biological Sciences, Systems Biology, and Biochemistry and Molecular Biophysics, Institute for Cancer Dynamics, Columbia University, New York, NY, United States. FAU - Kaufman, Brett A AU - Kaufman BA AD - Department of Medicine, Vascular Medicine Institute and Center for Metabolic and Mitochondrial Medicine, University of Pittsburgh, Pittsburgh, PA, United States. FAU - Hirano, Michio AU - Hirano M AD - Department of Neurology, Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, United States. FAU - Epel, Elissa AU - Epel E AD - Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, United States. FAU - Picard, Martin AU - Picard M AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, United States; Department of Neurology, Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, United States; New York State Psychiatric Institute, New York, NY, United States. Electronic address: martin.picard@columbia.edu. LA - eng GR - R01 AG066828/AG/NIA NIH HHS/United States GR - R01 AG065403/AG/NIA NIH HHS/United States GR - R21 MH123927/MH/NIMH NIH HHS/United States GR - R35 GM119793/GM/NIGMS NIH HHS/United States GR - R01 MH122706/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20230614 PL - England TA - Psychoneuroendocrinology JT - Psychoneuroendocrinology JID - 7612148 SB - IM MH - Humans MH - *Allostasis/physiology MH - Aging/physiology MH - Adaptation, Physiological/physiology MH - Cellular Senescence MH - Energy Metabolism PMC - PMC10528419 MID - NIHMS1912434 OTO - NOTNLM OT - Aging OT - Allostatic load OT - Chronic stress OT - Epigenetic aging OT - Glucocorticoid OT - Hypermetabolism OT - Mitochondria OT - Telomere COIS- Declaration of Competing Interest The authors have no conflict of interest to declare. EDAT- 2023/07/10 00:41 MHDA- 2023/08/07 06:42 PMCR- 2023/09/27 CRDT- 2023/07/09 18:07 PHST- 2023/01/13 00:00 [received] PHST- 2023/05/08 00:00 [revised] PHST- 2023/06/10 00:00 [accepted] PHST- 2023/08/07 06:42 [medline] PHST- 2023/07/10 00:41 [pubmed] PHST- 2023/07/09 18:07 [entrez] PHST- 2023/09/27 00:00 [pmc-release] AID - S0306-4530(23)00300-1 [pii] AID - 10.1016/j.psyneuen.2023.106322 [doi] PST - ppublish SO - Psychoneuroendocrinology. 2023 Sep;155:106322. doi: 10.1016/j.psyneuen.2023.106322. Epub 2023 Jun 14.