Respiratory Control in Old Age

By 2030, ~70 million people in the USA will be >65 years old with ~10 million >85 years old. The studies proposed in this competitive renewal application are motivated by our previous finding that larger phrenic motor neurons (PhMNs) are selectively lost in old age and the work of others implicating mitochondrial disruption in motor neuron death. BDNF/TrkB signaling mediates CREB phosphorylation at serine 133 (pCREBs133), which promotes mitochondrial remodeling via gene targeting of PGC1a. Activity dependent pAMPK signaling also mediates pCREBs133 phosphorylation and PGC1a expression. It appears that BDNF/TrkB signaling in PhMNs is reduced in old age, but activity of smaller PhMNs persists to support breathing, which may underlie their sparing in old age. It is also well established that circulating TNFa is elevated with aging. In other cell types, we found that TNFa selectively activates the IRE1a/sXBP1 ER stress pathway, which induces mitochondrial fragmentation and mitophagy. Our experimental design involves a comprehensive array of novel techniques already established and validated in our lab. The results of the proposed studies will guide development of novel therapeutic approaches targeting BDNF/TrkB or pCREBs133 phosphorylation (e.g., quercetin) and/or TNFa induced IRE1a/sXBP1 ER stress (e.g., infliximab) to promote PhMN survival. Conceptual Framework: We hypothesize that mitochondrial volume density (MVD) and respiratory capacity (SDHmax) in PhMNs are affected by the balance between mitochondrial biogenesis and mitophagy. Mitochondrial biogenesis is regulated via pCREBs133 phosphorylation and PGC1a expression, which is triggered by both activity (via pAMPK – Aim 1) and BDNF/TrkB.FL signaling (Aim 2). In old age, the influence of BDNF/TrkB.FL signaling is diminished especially in larger PhMNs, while activity of smaller PhMNs persists. Furthermore, serum TNFa is elevated in old age, which induces pIRE1a/sXBP1 ER stress leading to mitophagy (Aim 3). Aim 1: Determine the role of pAMPK/pCREB/PGC1a signaling in maintaining mitochondrial volume density in smaller PhMNs.. Aim 2: Determine the impact of reduced BDNF/TrkB/pCREB signaling in age-related remodeling of mitochondria in PhMNs. Aim 3: Determine the impact of TNFa induced activation of the IRE1a/sXBP1 ER stress pathway in age-related remodeling of mitochondria in PhMNs.