Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.
Cellular allostatic load is linked to increased energy expenditure and accelerated biological aging.
复制标题
DOI：
10.1016/j.psyneuen.2023.106322
复制
发表时间：
2023-09
影响因子：
3.7
通讯作者：
Picard, Martin
中科院分区：
文献类型：
--
作者：
Bobba-Alves, Natalia;Sturm, Gabriel;Lin, Jue;Ware, Sarah A.;Karan, Kalpita R.;Monzel, Anna S.;Bris, Celine;Procaccio, Vincent;Lenaers, Guy;Higgins-Chen, Albert;Levine, Morgan;Horvath, Steve;Santhanam, Balaji S.;Kaufman, Brett A.;Hirano, Michio;Epel, Elissa;Picard, Martin
关键词：
应激触发促进生存的预期性生理反应，这种现象被称为稳态应变（allostasis）。然而，能量依赖型稳态应变反应的慢性激活会导致稳态应变负荷，这是一种失调状态，预示着功能衰退、加速衰老，并增加人类的死亡率。稳态应变负荷的能量消耗及其有害影响的细胞基础尚未明确。在此，通过对三种无亲缘关系的原代人成纤维细胞系在其整个生命周期中进行纵向分析，我们发现慢性糖皮质激素暴露使细胞能量消耗增加约60%，同时代谢从糖酵解转变为线粒体氧化磷酸化（OxPhos）。这种应激诱导的高代谢状态与线粒体DNA不稳定有关，非线性地影响与年龄相关的细胞因子分泌，并基于DNA甲基化时钟、端粒缩短速率和寿命缩短加速细胞衰老。在药理学上使氧化磷酸化活性正常化同时进一步增加能量消耗会加剧加速衰老的表型，这表明总能量消耗是衰老动态的一个潜在驱动因素。总之，我们的研究结果明确了应激适应的生物能量和多组学重新校准，强调能量消耗增加和细胞加速衰老作为细胞稳态应变负荷的相关特征。
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 ~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.
登录
查看更多内容
全基因组甲基化谱揭示了人类衰老速度的定量观点。
影响因子：
16
作者：
Hannum, Gregory;Guinney, Justin;Zhao, Ling;Zhang, Li;Hughes, Guy;Sadda, SriniVas;Klotzle, Brandy;Bibikova, Marina;Fan, Jian-Bing;Gao, Yuan;Deconde, Rob;Chen, Menzies;Rajapakse, Indika;Friend, Stephen;Ideker, Trey;Zhang, Kang
通讯作者：
Zhang, Kang
DOI：
10.15252/embj.201592862
发表时间：
2016-04-01
期刊：
The EMBO journal
影响因子：
--
作者：
Correia-Melo C;Marques FD;Anderson R;Hewitt G;Hewitt R;Cole J;Carroll BM;Miwa S;Birch J;Merz A;Rushton MD;Charles M;Jurk D;Tait SW;Czapiewski R;Greaves L;Nelson G;Bohlooly-Y M;Rodriguez-Cuenca S;Vidal-Puig A;Mann D;Saretzki G;Quarato G;Green DR;Adams PD;von Zglinicki T;Korolchuk VI;Passos JF
通讯作者：
Passos JF
影响因子：
3.7
作者：
Bobba-Alves, Natalia;Juster, Robert-Paul;Picard, Martin
通讯作者：
Picard, Martin
影响因子：
6.8
作者：
Harvanek ZM;Fogelman N;Xu K;Sinha R
通讯作者：
Sinha R
影响因子：
5.8
作者：
Boal, Rachel L.;Ng, Yi Shiau;McFarland, Robert
通讯作者：
McFarland, Robert