Investigating inter- and transgenerational metabolic priming of neuro-cardio interfaces and their interdependence in health and aging

• Applicants: Professor Miguel Angel Alejandre Alcázar, Ph.D.; Dr. Julian Wagner
• Subject Area: Cardiology, Angiology ; Biogerontology and Geriatric Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 570861213

Cardiovascular diseases (CVD) are among the top causes of death. The increase in prevalence of CVD at older ages suggests an age-associated loss of cardiac regenerative mechanisms. The aging population emphasizes the urgent need to decipher the cellular and molecular mechanisms that determine susceptibility to CVD. We recently demonstrated the neuro-heart-axis to be central in the aging heart and cardiac functional decline. In aging, a decline of the sympathetic and sensory nerve densities was associated with reduced heart rate variability, susceptibility for arrhythmias, and lower heart function. Besides aging, lifestyle factors, such as higher BMI and obesity are major risk factors for CVD. An adverse metabolic environment, especially early in life, can disrupt the balance of ageing and anti-ageing mechanisms. Obese condition is characterized by a chronic subacute inflammation (inflamm-aging) and is thus closely related to the hallmarks of aging (e.g., genomic instability and senescence) and the pathogenesis of CVD. In an inter-generational mouse model, we showed that maternal and perinatal obesity cause pulmonary vascular remodeling with muscularization and ultimately pulmonary hypertension through an adipocytokine-mediated proliferation of vascular smooth muscle cells. Based on our previous findings, we now aim to test the hypothesis that inter- and transgenerational obesity impairs maturation of the neuro-cardiac interplay and accelerates cardiac aging, remodeling and functional decline. To address this research question we will pursue three specific aims: (i) First, we will perform a spatio-temporal characterization of heart and neuronal network across ages and generations using an intergenerational model of obesity. (ii) Second, we aim to decipher the inter- and transgenerational epigenetic imprinting of the neuro-heart axis after maternal obesity with a focus on the cardiac and neuronal site. (iii) Finally, we will employ an interventional approach by which we aim to prevent or de-accelerate cardiac and neuronal aging by targeting metabolic origins using novel pharmacological treatment with GLP1-analoga. This project proposal is a collaborative approach between metabolic and cardiac aging research. Our project will thus provide new global mechanistic insights into the impact of inter- and transgenerational metabolic priming of neuro-cardiac interplay and identify potential molecular targets for therapeutic approaches.

• DFG Programme: Research Grants