Grant Brewing – Eyleen O’Rourke, PhD

Uncovering metabolic drivers of aging and geroprotection

Metabolic dysregulation is a defining characteristic of aging. Nevertheless, transcriptomics atlases of aging tissues such as the Tabula Muris Senis and the C. elegans Aging Atlas, and histochemical and biochemical studies have shown that the nature and extent of the metabolic changes differ among and within cell types depending on a cell’s location. Despite this large body of correlative evidence, whether local metabolic dysregulation is a defining feature of aging remains to be established. Furthermore, even though the most robust geroprotective interventions are metabolic (e.g. calorie restriction), whether and how they impede or delay the spatially heterogeneous changes in metabolism that would drive aging remains to be defined. The O’Rourke lab recently reported the overexpression of Alcohol DeHydrogenase 1 (ADH-1^OE) as a robust and conserved geroprotective metabolic intervention (Current Biology, 2023). To gain knowledge of the spatial changes in metabolic activity that promote aging in C. elegans and geroprotection in the ADH-1^OE longevity model, we will: (1A) Deploy our spatial transcriptomics and world-leading capabilities in spatial metabolomics augmented with in vivo isotope-tracing of key nutrients developed by our collaborators to obtain spatially-resolved gene expression and metabolic data of aged wild-type and ADH-1^OE C. elegans; (1B) Integrate the resulting whole-body spatial metabolomics and transcriptomics data through in silico modeling to predict metabolites and metabolic pathways that are robustly altered in aging C. elegans and also modified/reversed by overexpression of ADH-1; and (1C) Test in vivo the “pro-aging” or geroprotective capacity of the identified metabolic changes through tissue-level resolution genetic, dietary, and/or chemical manipulations coupled to healthspan and lifespan assessments. Finally, to test ADH-1’s conservation, we will (2) conditionally activate in primary human fibroblasts the adh-1 human homologues ADH1 and ADH4, and longitudinally assess cellular markers of aging.

The impact of the proposed studies includes: (i) A C. elegans metabolic atlas of aging, (ii) Systems and local level mechanistic understanding of a geroprotective metabolic intervention, (iii) The testing of the conservation in a human model of a geroprotective enzymatic activity that is necessary and sufficient for healthy aging and longevity in yeast and C. elegans, and (iv) The promise of spatial metabolic intervention becoming a new strategy to promote healthy aging.

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