CECAD: Research Area 2

Research Area 2

Beneficial and maladaptive stress signaling in aging and aging-associated diseases

Influence of timing, dosage, duration and type of stress
and stress responses in different organs on healthy aging

Research Area Focus

In its life time, an organism is exposed to a range and combination of intrinsic and extrinsic stresses that can cause DNA, RNA, and protein damage. Cells thus constantly need to sense and respond to stress to repair while also activating downstream adaptive pathways to maintain tissue and organismal integrity. Persistence of damage can lead to cell death and induce chronic stress responses including sustained inflammation – a hallmark of aging. While adaptive stress responses to low doses of stressors render cells and organisms more robust and support longevity, maladaptive responses promote damage and tissue degeneration leading to aging-associated diseases. Research in RA-2 examines how the nature, duration, dosage, and timing, of stress response pathways determine whether the outcome is beneficial or detrimental.

Highlights

Collage of the posterior midgut of a Drosophila adult intestine. Immunostaining was used to visualize the different cell types comprising the gut, including the stem cells and the differentiated absorptive enterocytes and hormone-producing enteroendocrine cells.

Genome integrity and stress adaptation
Schumacher and colleagues revealed that dietary formaldehyde impairs detoxification, causing oxidative DNA damage that requires multiple repair mechanisms (Nucleic Acids Research, 2024; Nature Communications, 2022). Hoeijmakers demonstrated that DNA damage responses vary across tissues: apoptosis dominates in the rapidly dividing intestine, whereas the liver favors repair (Aging Cell, 2022). These findings help explain organ-specific vulnerabilities in aging.

The integrated stress response (ISR) and mitochondrial signaling
CECAD researchers uncovered how mitochondrial dysfunction activates ISR to reprogram metabolism. Frezza identified that defects in Krebs cycle enzymes trigger ATF4-dependent ISR and metabolic rewiring (Elife, 2021). Langer showed that the mitochondrial peptidase OMA1 orchestrates mitoISR to protect against ferroptotic cell death in a mouse model of cardiomyopathy (Cell Metabolism, 2022). Eming, Trifunovic, Langer, and Brüning revealed that moderate mitoISR activation in hypothalamic neurons or macrophages can promote systemic metabolic health and tissue repair (Cell Metabolism, 2020; Cell Metabolism, 2021). However, chronic or excessive ISR becomes detrimental, leading to stress-induced pathology, as demonstrated by Brachvogel’s work on skeletal growth retardation and matrix defects (J Biol Chem, 2021).

Complex outcomes of mitochondrial stress
Rugarli, Langer, and Trifunovic showed that the NAD-consuming enzyme SARM1 exerts distinct effects on different neuronal populations: loss of SARM1 protects the cerebellum from inflammation but worsens spinal cord degeneration (Brain, 2023). Bergami and Motori discovered that mitochondrial remodeling in astrocytes after injury supports vascular repair and regeneration (Cell Metabolism, 2020). Together, these studies define mitoISR as a double-edged process that can maintain or disrupt tissue integrity depending on context.

Mechanical stress and tissue architecture
Niessen and Wickström revealed that chromatin architecture acts as a mechano-responsive element preventing DNA damage during acute stress, while persistent strain triggers supracellular alignment of the tissue to dissipate stress(Cell, 2020). Aging-related changes in the extracellular matrix alter these mechanical cues, impairing stem-cell renewal and differentiation (Nature Cell Biology, 2021).

Inflammation, innate immunity, and brain aging
Chronic inflammation (inflammaging) emerged as a central theme. Frezza demonstrated that fumarate hydratase accumulation triggers an inflammatory response due, in part, to leakage of mitochondrial DNA into the cytosol (Nature, 2023). Langer’s group identified nucleotide imbalances as another source of mtDNA leakage-driven inflammation (Nature Metabolism, 2021). Pasparakis provided key insights into RNA and DNA-sensing pathways, including ADAR1-ZBP1 regulation of Z-RNA structures that control inflammatory responses (Nature, 2022). Schäfer and Ising uncovered how microglial stress responses link neuronal hyperactivity, inflammasome activation, and Tau pathology (Nature, 2019; J Neurochem, 2023), while Ramirez and Jessen identified new genetic loci for Alzheimer’s disease connecting microglial signaling to neurodegeneration (Nature Genetics, 2022).

Dietary restriction and stress resilience
Dietary restriction (DR) remains the most effective non-genetic intervention to promote healthspan. Müller and Benzing showed that DR protects against stress-induced kidney injury (J Am Soc Nephrol, 2020). Collaborative work with Beyer, Krüger, Schermer, and Trifunovic identified kynureninase (KYNU) as a key DR target linking NAD⁺ biosynthesis to metabolic resilience (J Am Soc Nephrol, 2023). Partridge and Beyer demonstrated that DR maintains immune competence by preserving B-cell diversity (Cell Reports, 2023).