St-Onge, M.-P. | bioRxiv Science

bioRxiv2024

Psychobiological regulation of plasma and saliva GDF15 dynamics in health and mitochondrial diseases

Growth Differentiation Factor 15 (GDF15) is a protein that reflects mitochondrial energetic stress and is linked to physical and mental health symptoms, aging, and mortality. Here, we tested the hypothesis that GDF15 is a stress-responsive biomarker through a series of observational and experimental studies. We report four main findings. First, in the UK Biobank (n=53,026) and Framingham Heart Study (FHS) Offspring (n=3,460) cohorts, plasma GDF15 levels were elevated in individuals with symptoms of depression and anxiety. In the FHS cohort, GDF15 was also higher in participants exposed to chronic psychosocial stressors, including lower educational attainment, lower family income, and higher job strain. Second, plasma GDF15 levels in the FHS cohort correlated positively with epigenetic clocks measuring biological aging and effect sizes of GDF15 associations with psychosocial stressors were comparable to those observed for the clocks. Third, in a two-participant intensive-sampling study (n=112 days), saliva GDF15 showed a robust awakening response similar to established stress-related hormones. However, it exhibited a distinct negative pattern, peaking at waking and declining by 42-92% within 30-45 minutes. Finally, in two laboratory experiments (n=148), acute social-evaluative stress significant increased GDF15 levels in plasma and saliva within minutes. Together, these findings suggest that psychosocial stress may contribute to mitochondrial energetic stress indexed by GDF15, with implications for aging and health. This work opens new avenues for using GDF15 as a non-invasive biomarker to study the biological embedding of stress and its impact on aging trajectories. Significance statementGrowth Differentiation Factor 15 (GDF15) is a circulating protein elevated with mitochondrial energetic stress, aging, and diseases. Our findings show that GDF15 is elevated with depressive and anxiety symptoms and in those exposed to chronic psychosocial stress. Elevated plasma GDF15 also correlates with accelerated biological aging, as measured by epigenetic clocks. The effect sizes linking GDF15 to psychosocial stressors were comparable to those observed for the epigenetic clocks. Saliva GDF15 shows a robust negative awakening response characterized by elevated levels at awakening before declining within 30-45 minutes. Acute social-evaluative stress induced increase in plasma and saliva GDF15. Together, these findings suggest GDF15 can be used to study the energetic mechanisms for the biological embedding of stress across the lifespan.

physiology↗

bioRxiv2023

Accelerated physiology and increased energy expenditure in animals and humans with mitochondrial defects: A meta-analysis

Mitochondria are key energy transforming organelles in mammalian cells. However, how defects in oxidative phosphorylation (OxPhos) and other mitochondrial functions influence whole-body energy expenditure (EE) has not been rigorously studied. Cellular and organismal responses to OxPhos defects likely involve a combination of functional downregulation to conserve energy and compensatory upregulation of stress responses. If the energy cost of compensatory responses exceeds the potential energy savings of functional downregulation, as recent work suggests, the result would be an increase in total EE. To address the hypothesis that OxPhos defects increase the energetic cost of living, we performed a meta-analysis of available studies reporting EE in animal models with mitochondrial gene defects. Of all reported experimental conditions (n = 91, from 29 studies), 51% reported a >10% elevation in EE relative to control animals, compared to 11% reporting <10% reduction in EE (p<0.0001, Chi-square). Of the experimental conditions where locomotor activity was also quantified, 39% showed that OxPhos-deficient animals had elevated EE despite reduced locomotor activity, which would be expected to decrease EE. To extend this finding in humans, we re-analyzed a high-quality clinical and multi-omics dataset (Sharma et al. 2021) of mitochondrial disease patients with the m.3243A>G mutation. This analysis similarly indicates an upregulation of energetically costly physiological, immune, and metabolic parameters in people with OxPhos deficiency. These results suggest that animals and humans with mitochondrial defects must expend more energy to sustain life, a state clinically called hypermetabolism. High-quality human energetics studies are needed to understand the magnitude, mechanisms, and modifiability of hypermetabolism in mitochondrial disorders.

cell biology↗