BBB Seminar: Riekelt Houtkooper
Metabolic drivers of human aging
Riekelt Houtkooper (external link), Amsterdam UMC, the Netherlands
Aging is accompanied by profound metabolic remodeling, yet the molecular mechanisms that distinguish healthy from unhealthy aging in humans remain incompletely understood. Increasing evidence suggests that metabolic pathways are not simply passive markers of aging but active determinants of tissue function, resilience, and disease susceptibility. Understanding these pathways offers new opportunities to identify biomarkers of biological aging and develop interventions that promote healthy aging.
Nicotinamide adenine dinucleotide (NAD⁺) has emerged as a central regulator of metabolism, integrating cellular energy production with stress responses, DNA repair, and mitochondrial function. Our recent studies in human cohorts demonstrate that NAD⁺ homeostasis is regulated in a highly tissue-specific manner: while circulating NAD⁺ levels remain remarkably stable across age, skeletal muscle NAD⁺ declines in association with reduced physical function and unhealthy aging. Molecular analyses of these tissues identified new pathways that contribute to tissue NAD⁺ homeostasis. These findings refine current views on NAD⁺ biology and have important implications for therapeutic strategies aimed at boosting NAD⁺ in humans.
In parallel, advances in lipidomics have uncovered complex membrane lipids as previously underappreciated regulators of aging. Our large-scale lipidomic analyses across tissues identified bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid, as one of the most conserved metabolic signatures of aging in mice and humans. The accumulation of BMP is associated with age-related functional decline, whereas exercise partially reverses these changes, suggesting an important role for lysosomal lipid homeostasis in healthy aging. Strikingly, we identified a new, unpublished, lipid profile that is associated with aging as well as age-related disease progression.
Together, these findings demonstrate how integrated omics approaches can reveal conserved metabolic mechanisms underlying human aging. Defining these metabolic drivers not only improves our understanding of the biology of aging but also provides a foundation for developing biomarkers and interventions that promote healthspan and reduce the burden of age-related disease.
Chairperson: Mathias Ziegler, Department of Biomedicine