Ceccarelli Ceccarelli Daniela, Solerte Sebastiano Bruno
Geriatric Medicine Department, Morgagni-Pierantoni Hospital, Via Carlo Forlanini 34, 47121 Forlì, Italy.
Geriatric and Diabetology Unit, Department of Internal Medicine, University of Pavia, Corso Strada Nuova 63, 27100 Pavia, Italy.
Metabolites. 2025 Feb 27;15(3):159. doi: 10.3390/metabo15030159.
: Aging is characterized by shared cellular and molecular processes, and aging-related diseases might co-exist in a cluster of comorbidities, particularly in vulnerable individuals whose phenotype meets the criteria for frailty. Whilst the multidimensional definition of frailty is still controversial, there is an increasing understanding of the common pathways linking metabolic syndrome, cognitive decline, and sarcopenia, frequent conditions in frail elderly patients. : We performed a systematic search in the electronic databases Cochrane Library and PubMed and included preclinical studies, cohort and observational studies, and trials. : Metabolic syndrome markers, such as insulin resistance and the triglyceride/HDL C ratio, correlate with early cognitive impairment. Insulin resistance is a cause of synaptic dysfunction and neurodegeneration. Conversely, fasting and fasting-mimicking agents promote neuronal resilience by enhancing mitochondrial efficiency, autophagy, and neurogenesis. Proteins acting as cellular metabolic sensors, such as SIRT1, play a pivotal role in aging, neuroprotection, and metabolic health. In AD, β-amyloid accumulation and hyperphosphorylated tau in neurofibrillary tangles can cause metabolic reprogramming in brain cells, shifting from oxidative phosphorylation to aerobic glycolysis, similar to the Warburg effect in cancer. The interrelation of metabolic syndrome, sarcopenia, and cognitive decline suggests that targeting these shared metabolic pathways could mitigate all the conditions. Pharmacological interventions, including GLP-1 receptor agonists, metformin, and SIRT 1 inducers, demonstrated neuroprotective effects in animals and some preliminary clinical models. : These findings encourage further research on the prevention and treatment of neurodegenerative diseases as well as the drug-repurposing potential of molecules currently approved for diabetes, dyslipidemia, and metabolic syndrome.
衰老的特征是存在共同的细胞和分子过程，与衰老相关的疾病可能会在一系列共病中同时出现，尤其是在那些表型符合虚弱标准的脆弱个体中。虽然虚弱的多维定义仍存在争议，但人们对连接代谢综合征、认知衰退和肌肉减少症（虚弱老年患者常见病症）的共同途径的认识正在不断增加。
我们在电子数据库Cochrane图书馆和PubMed中进行了系统检索，纳入了临床前研究、队列研究、观察性研究和试验。
代谢综合征标志物，如胰岛素抵抗和甘油三酯/高密度脂蛋白胆固醇比值，与早期认知障碍相关。胰岛素抵抗是突触功能障碍和神经退行性变的一个原因。相反，禁食和禁食模拟剂通过提高线粒体效率、自噬和神经发生来促进神经元的恢复能力。作为细胞代谢传感器的蛋白质，如SIRT1，在衰老、神经保护和代谢健康中起关键作用。在阿尔茨海默病中，神经纤维缠结中的β-淀粉样蛋白积累和过度磷酸化的tau蛋白可导致脑细胞代谢重编程，从氧化磷酸化转变为有氧糖酵解，类似于癌症中的瓦伯格效应。代谢综合征、肌肉减少症和认知衰退之间的相互关系表明，针对这些共同的代谢途径可能会缓解所有这些病症。包括胰高血糖素样肽-1受体激动剂、二甲双胍和SIRT1诱导剂在内的药物干预在动物和一些初步临床模型中显示出神经保护作用。
这些发现鼓励进一步研究神经退行性疾病的预防和治疗，以及目前已获批用于治疗糖尿病、血脂异常和代谢综合征的分子的药物再利用潜力。
