As the population ages, problems pertaining to health and life expectancy due to the aging heart have become increasingly prominent. The gut microbiota has become a potential therapeutic target in several diseases, including cardiovascular diseases. Current studies on the roles of the gut microbiota in the cardiovascular system have focused mainly on cardiovascular diseases; therefore, the effects of the gut microbiota on the natural aging of myocardial tissue remain unclear. The present study aimed to explore the roles and mechanisms of the gut microbiota and related metabolites in the natural aging of the heart. Animal models of fecal microbiota transplantation (FMT) were established in elderly and young rats. 16S rRNA sequencing revealed that the gut microbiota of the recipients shifted toward the profile of the donors, with concomitant cardiac structure and diastolic function changes detected via ultrasound and positron emission tomography-computed tomography (PET-CT). A group of significantly enriched myocardial metabolites detected by LC/MS were involved in the fatty acid β-oxidation process. Together with altered glucose uptake, as revealed by PET-CT, changes in ATP content and mitochondrial structure further verified a metabolic difference related to energy among rats transplanted with the gut microbiota from donors of different ages. This study demonstrated that gut microbes may participate in the physiological aging process of the rat heart by regulating oxidative stress and autophagy. The gut microbiota has been shown to be involved in the natural aging of the heart at multiple levels, from the organ level to the metabolically plastic myocardiocytes and associated molecules.

The cognitive decline associated with ageing is the most critical health issue affecting elderly individuals, and there is still a lack of effective interventions available. This study was designed to identify a drug capable of ameliorating age-related cognitive decline and the underlying mechanisms. Utilizing data mining of multisource databases and drug repositioning approaches based on transcriptome similarity, the cardiovascular drug ranolazine (Ran), was identified as a potential candidate with similar effects to those of resveratrol (RSV). Network pharmacology analysis predicted that Ran's effects on cognitive decline through the PI3K/AKT/mTOR signalling pathway. These predictions were subsequently verified using a combination of molecular, cellular, and tissue experiments, animal models of ageing induced by D-galactose, and omics studies. The results revealed that Ran extended the lifespan of Caenorhabditis elegans (C. elegans), improved the head swinging ability of ageing C. elegans, and alleviated mitochondrial membrane potential (MMP) damage in ageing hippocampal neuronal cells (HT22). In ageing rats, Ran not only enhanced spatial memory, exploratory behaviors and motor ability, but also alleviated mitochondrial structural damage in hippocampus and medial prefrontal cortex (mPFC). Notably, Ran alleviated age-related cognitive decline by regulating mitochondrial autophagy in hippocampus and mPFC through the PI3K/AKT/mTOR signalling pathway, rather than through its conventional mechanism of regulating fatty acid metabolism. In summary, this study reveals Ran's previously unrecognized role in alleviating age-related cognitive decline for the first time. These findings provide new options for the treatment of age-related cognitive decline and broaden the potential clinical applications of Ran.

Brain aging primarily manifests as cognitive decline. Spermidine (SPD) is known to ameliorate age-related cognitive decline, and the gut microbiota is an important source of SPD. Clostridium butyricum (C. butyricum), a probiotic, can alleviate cognitive decline in individuals with various neurodegenerative diseases, and C. butyricum might generate SPD. However, the role of C. butyricum in natural brain aging and the efficacy of C. butyricum and the metabolite SPD in ameliorating age-related cognitive decline remain unclear. Here, we investigated the effects of C. butyricum and its metabolite SPD on cognitive decline during natural brain aging and the mechanisms underlying these effects. Aged rats (aged 17 months, n = 12 per group) were randomly divided into normal saline (NS), C. butyricum (1 ×10⁸∼10⁹ CFU/ml, by gavage for two months) and SPD (6.5 mg/kg/d, by gavage for one month) groups. Compared with the NS group, the C. butyricum and SPD groups presented improved spatial reference and recognition memory, reduced aging marker levels by immunohistochemical staining, improved synaptic plasticity-related tissue structure by transmission electron microscopy and Golgi staining, and increased level of synaptophysin and BDNF by immunofluorescence staining and western blotting in the brain. Furthermore, treatment with C. butyricum and SPD enhanced intestinal barrier function and decreased serum proinflammatory factor levels and brain tissue damage due to oxidative stress. There were no significant differences in relevant indicators between the C. butyricum and SPD groups. In conclusion, C. butyricum and its metabolite SPD may delay the cognitive decline caused by normal brain aging by reducing oxidative stress and inflammation.

While transplanting the fecal microbiota from young to aged rodents has been extensively studied (that is, young FMT [yFMT]), its mechanism of alleviating working memory decline has not been fully elucidated. In this report, we aimed to investigate the effect of yFMT on the working memory of aged recipient rats performing delayed match-to-position (DMTP) tasks and the associated cellular and molecular mechanisms. The results revealed that yFMT mitigated the decline in DMTP task performance of aged recipients. This improvement was associated with a reshaped gut microbiota and increased levels of brain-derived neurotrophic factor, N-methyl-D-aspartate receptor subunit 1, and synaptophysin, enhancing synaptic formation and transmission. The remodeling of the gut microbiome influenced peripheral circulation and the hippocampus and medial prefrontal cortex by regulating the Th17/Treg ratio and microglial polarization. Ultimately, interleukin-4 and interleukin-17 emerged as potential key molecules driving the beneficial effects of FMT. These observations provide new insights into the gutbrain axis, emphasizing the connection between the gut and brain through the circulation system, and suggest an immunological mechanism that may help reverse age-related declines in the gut microbiota.