Ding Sarah, Banerjee Anisha, Burke Sara N, Hernandez Abbi R
Division of Gerontology, Geriatrics and Palliative Care, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Department of Neuroscience, University of Florida, Gainesville, FL, USA.
Geroscience. 2025 Mar 28. doi: 10.1007/s11357-025-01632-7.
Many of the "hallmarks of aging" involve alterations in cellular and organismal metabolism. One pathway with the potential to impact several traditional markers of impaired function with aging is the PI3K/AKT metabolic pathway. Regulation of this pathway includes many aspects of cellular function, including protein synthesis, proliferation, and survival, as well as many downstream targets, including mTOR and FOXOs. Importantly, this pathway is pivotal to the function of every organ system in the human body. Thus, we investigated the expression of several genes along this pathway in multiple organs, including the brain, liver, and skeletal muscle, in aged subjects that had been on different experimental diets to regulate metabolic function since mid-life. Specifically, rats were fed a control ad lib diet (AL), a time restricted feeding diet (cTRF), or a time restricted feeding diet with ketogenic macronutrients (kTRF) for the majority of their adult lives (from 8 to 25 months). We previously reported that regardless of macronutrient ratio, TRF-fed rats in both macronutrient groups required significantly less training to acquire a biconditional association task than their ad lib fed counterparts. The current experiments expand on this work by quantifying metabolism-related gene expression across tissues and interrogating for potential relationships with cognitive performance. Within the brain, SIRT1 and MAPK8 were reduced in CA3 of kTRF-fed rats. Additionally, IGF1 expression was significantly upregulated in the CA1 of cTRF-fed rats, but this effect was ameliorated in the kTRF fed group. AKT and FOXO1 expression were significantly reduced in kTRF-fed rats within liver. Interestingly, AKT expression within the perirhinal cortex (PER) was higher in kTRF rats with the best cognitive performance, and FOXO1 expression was higher in the CA3 of AL-fed rats correlated with the poorest cognitive performance. Together, these data demonstrate diet- and tissue-specific alterations in metabolism-related gene expression and their correlation with cognitive status.
许多“衰老的标志”都涉及细胞和机体新陈代谢的改变。PI3K/AKT代谢途径是一条有可能影响多个与衰老相关的传统功能受损标志物的途径。该途径的调节包括细胞功能的许多方面，如蛋白质合成、增殖和存活，以及许多下游靶点，如mTOR和FOXO。重要的是，这条途径对人体每个器官系统的功能都至关重要。因此，我们研究了中年以来接受不同实验饮食以调节代谢功能的老年受试者多个器官（包括大脑、肝脏和骨骼肌）中这条途径上几个基因的表达。具体而言，大鼠在成年期的大部分时间（从8个月到25个月）被喂食对照随意饮食（AL）、限时饮食（cTRF）或含有生酮常量营养素的限时饮食（kTRF）。我们之前报道过，无论常量营养素比例如何，两个常量营养素组中接受限时饮食喂养的大鼠在获得双条件联想任务时所需的训练都比随意饮食喂养的大鼠显著减少。当前的实验通过量化各组织中与代谢相关的基因表达并探究其与认知表现的潜在关系，对这项工作进行了拓展。在大脑中，kTRF喂养的大鼠CA3区的SIRT1和MAPK8减少。此外，cTRF喂养的大鼠CA1区的IGF1表达显著上调，但在kTRF喂养组中这种作用有所改善。kTRF喂养的大鼠肝脏中的AKT和FOXO1表达显著降低。有趣的是，认知表现最佳的kTRF大鼠的鼻周皮质（PER）中的AKT表达较高，而认知表现最差的AL喂养大鼠的CA3区中的FOXO1表达较高。总之，这些数据表明了与代谢相关的基因表达存在饮食和组织特异性改变及其与认知状态的相关性。
