To investigate the effect of normal aging process on the neuroenergetics in the human visual cortex under resting state, showing a significantly decline in the creatine kinase enzyme activity in the aging brains. To date, the resting-state functional MRI (rs-fMRI) studies have reported a strong correlation between normal aging and whole-brain functional connectivity change at the resting state, in particular, showing a strong and positive correlation in human visual network ^[1]. However, the aging effect on the underlying neuroenergetics in the resting-state human brain was not yet fully investigated. With advantages of the increased sensitivity and large chemical shift dispersion provided by ultrahigh field strength, in vivo ³¹P MRS incorporated with the magnetization transfer (³¹P-MT) method offers the ability to examine the key bioenergetic reactions catalyzed by the creatine kinase (CK) and ATPase enzymes in the brain ^[2-4]. Using the ³¹P-MT method, in this study, we investigated the aging effect on the CK activities in the human visual cortex at 7T. Ten young subjects (28.4±6.4 years old (mean±SD), 6 male/4 female) and 4 old subjects (58.5±6.8 years old, 3 female/1 male) participated in this study. All measurements were conducted at 7.0 Tesla/90 cm (Siemens) scanner. The RF probe consists of a butterfly-shape ¹H surface coil for anatomic imaging and B₀ shimming with FASTMAP ^[5], and a 5-cm-diameter single-loop ³¹P coil that is placed over the occipital lobe for collecting ³¹P-MT data from the human visual cortex (Fig. 1). To maintain the resting state, all subjects were asked to fix their eyes on a fixation point during the ³¹P-MT measurements. All ³¹P MR spectra were obtained using single-pulse-acquire sequence (150 FIDs averaging, 2s TR, 5kHz spectral bandwidth, 300 μs hard excitation pulse with an Ernst flip angle of 59°). The B₁ insensitive selective train to obliterate signal scheme ^[6] was applied to saturate the γ-ATP resonance for measuring the MT effects on the PCr resonance. The acquired ³¹P-MT data were analyzed with AMARES fitting algorithm ^[7]. After correcting for the T₁ saturation factor, absolute concentration of PCr was calibrated using a cerebral ATP concentration of 2.8 mM as an internal reference ^[8]. Subsequently, the forward reaction rate constant of CK, k_f,CK (PCr$$$\rightarrow$$$ATP), was calibrated according to: M_c/M_s ≈ 1 + k_f,CK · T₁^nom where M_c and M_s are control and γ-ATP saturated magnetization and T₁^nom is the nominal T₁ that was estimated in this study based on simulation (Fig. 2) ^[9]. The relationship between k_f,CK and subjects’ age was reported using a Pearson’s correlation coefficient. Finally, two-tailed t-test was used for statistical comparison of k_f,CK between young and old group, and a p value of < 0.05 was considered statistically significant. Figure 1 displays typical ³¹P-MT spectra of human visual cortex acquired with and without γ-ATP saturation, showing excellent spectral quality (with a linewidth of PCr < 10 Hz) and high detection sensitivity, which ensures reliable quantification of the brain intracellular PCr concentration and changes caused by the MT effect. Based on the simulated nominal T₁ value of PCr (3.18s), the measured forward rate constant of k_f,CK in young age group (0.32±0.02 s^-1 (mean±SD)) was in excellent agreement with the previously reported value ^[10]. Compared with young subjects, old subjects had a significantly lower k_f,CK (0.28±0.01 s^-1). The results showed a strong negative correlation between the k_f,CK and aging (r = -0.753, p < 0.001, Fig.3), leading to a significant group difference (12.7%, p = 0.002). The CK reaction and enzyme activity are tightly coupled with the ATP metabolism and neuroenergetics and play a critical role in transferring ATP energy between mitochondria and cytosol. Hence, the declined CK enzyme activities in the normal aging brains could suggest a decreased CK forward flux or ATP synthesis/utilization rate in the neuron. Since cerebral ATP concentration was assumed to be constant in our study, further investigation is necessary to explore the aging effects on ATP level changes, which will affect the measurement of PCr concentration as well as the CK reaction flux rate. Nevertheless, this uncertainty should not affect the k_f,CK measurement and outcomes as reported in this study. In this work, we are able to demonstrate a strong aging dependence of the CK enzyme activity in the normal human brain at the resting state. This finding provides valuable insights into the aging processing in the perspective of cellular energy metabolism. The decline of the CK enzyme activity, thus, neuroenergetics in aging population may partially explain the rs-fMRI finding of increased BOLD coherence in the visual network ^[1], suggesting the loss of resting-state connectivity specificity in aging people ^[11]. This study also demonstrates the utility of in vivo ³¹P-MT technique for clinical research aiming to investigate aging-related neurodegenerative diseases such as Alzheimer’s disease, as well as potential for other metabolic disorders/diseases.