Introduction Research in older adults has generally found greater emotional well-being despite physical and cognitive decline. A literature review indicates that although older adults have structural and functional degradation in the dorsolateral and ventrolateral prefrontal cortices (dlPFC, vlPFC, key brain regions related to emotion regulation in younger adults), they may adaptively and automatically use strategies that involve alternative or additional brain regions to regulate emotion as a compensatory mechanism (for example, ventromedial prefrontal cortex, vmPFC). However, few studies have confirmed this hypothesis. More importantly, it is imperative to examine emotion regulation patterns in older adults with major depression (also known as late-life depression, LLD) to clarify the neural mechanisms of emotion regulation deficits in LLD. We hypothesize that LLD may have weakened connectivity between vmPFC and dlPFC in regulating activity of brain regions related to emotional processing (such as the amygdala). Methods We have analyzed the 7-min resting-state fMRI and T1-weighted brain imaging data which was acquired from NBOLD project conducted at University of Connecticut Health Center (UCHC). The data was from 37 healthy older subjects (9 males, age(mean±SD)= 75.5±7.5 yrs) and 102 LLD patients (32 males, age(mean±SD)=71.5 ±7.4 yrs). We first examined whether in healthy subjects, smaller dlPFC volume is associated with greater vmPFC activity measured by amplitude of low-frequency fluctuation (ALFF) using DPABI program. The dlPFC volume was measured using FreeSurfer software on T1-weighted images. We then examined whether vmPFC exert greater control on amygdala activity than dlPFC using spectral dynamic causal modelling (spDCM) program of SPM12. Finally we compared differences between healthy and LLD subjects in information flow among dlPFC, vlPFC, vmPFC and amygdala using spDCM. Results As we predicted, there was significant correlation between lower left dlPFC volume and greater ALFF in the vmPFC (r=-0.42, p Conclusions Negative correlation between the vmPFC resting activity and dlPFC volume in the healthy older adults suggest a possible compensatory activity of vmPFC. The spDCM analysis confirmed our hypothesis that vmPFC may exert a key role in regulating emotion to compensate the dlPFC volume reduction in healthy older adults, whereas the compensatory effect is weaker in the LLD group compared with healthy subjects, which could explain poor emotion regulation in LLD. Future studies using emotion regulation tasks directly are warranted to confirm the compensatory role of the vmPFC in emotion regulation in older adults and its the weakened role of emotion regulation in LLD. This research was funded by: The study was supported by NIMH grant R01 MH108578 (PI, David C. Steffens).