CECAD: Research Area 1

Research Area 1

Molecular, cellular, and inter-tissue networks in organismal aging

Discern evolutionary conserved aging mechanisms in
cells, tissues and between organs

Research Area Focus

In RA-1, we combine efforts to define how the interplay between molecular, cellular, and inter-tissue networks leads to age-related changes and diseases. With age, cells undergo alterations in genome integrity, RNA fidelity, proteostasis, organelle homeostasis, and metabolism, collectively contributing to functional decline. Recent collaborative efforts of CECAD PIs have significantly increased our mechanistic understanding of these pathways and have not only underscored the importance of crosstalk, but also highlighted their interdependence.

Highlights

Genome and transcription fidelity
Collaborative work by the groups of Beyer, Partridge, Antebi, Müller, Benzing, and Hoeijmakers revealed that aging disrupts RNA polymerase II elongation, leading to lower transcript quality (Nature, 2023). This loss of fidelity contributes to splicing errors and proteostasis decline, while interventions such as dietary restriction or reduced insulin/IGF-1 signaling can restore accuracy. Antebi and Demetriades further linked splicing control to lifespan through mTOR signaling (Nature Aging, 2022).

Proteostasis and inter-tissue communication
Cabreiro discovered that a single amino acid substitution in ribosomal protein RPS23 increases translation accuracy and lifespan across species (Cell Metabolism, 2021). Hoppe and Vilchez showed that neuronal cues regulate proteostasis in distant tissues (Nature Aging, 2023; Nature Communications, 2022), while Brüning, Langer, and Wunderlich demonstrated that hypothalamic neurons influence liver proteostasis through non-cell-autonomous signaling (Science, 2024). Work from Vilchez and Trifunovic also revealed that non-neuronal tissues, like the germline, can influence organismal proteostasis and mitochondrial health (Science Advances, 2021).

Mitochondrial and organellar networks
Several CECAD groups, including Langer, Rugarli, Frezza, and Antebi, identified how mitochondria adapt to stress and communicate with other organelles to maintain cellular balance. Studies revealed that OXPHOS dysfunction alters lipid metabolism in the intestine (Nature, 2024) and that NFYB-1 coordinates lysosome-to-mitochondria signaling to enhance mitochondrial function (Nature Metabolism, 2020).

Metabolic and nutrient-sensing pathways
Beyer and Partridge demonstrated that lifespan-extending interventions have tissue-specific effects on proteostasis and mitochondrial function (Elife, 2021). Antebi and Partridge uncovered conserved metabolic signatures of longevity (Nature Communications, 2021). Deelen’s large-scale human genetic studies revealed shared longevity mechanisms across species (Nature Communications, 2020; 2019). Work by Fenselau and Brüning identified vagal sensory neurons as regulators of feeding and glucose metabolism (Cell Metabolism, 2021), while further studies linked hypothalamic neuron activity to liver autophagy and aging (Cell Metabolism, 2023).