As women experience menopause, hormonal transition predisposes the likelihood of developing metabolic syndrome(MetS), cardiovascular disease, and type 2 diabetes 1–3. It is estimated that one in three postmenopausal women is affected by MetS, experiencing a heightened risk 4,5. MetS is characterized by factors such as abdominal obesity, insulin resistance, dyslipidemia, and hypertension in post-menopausal women, mostly related to the decline in estrogen but elevation in androgen levels 6–8. These hormonal shifts lead to alterations in body fat distribution and the onset of abdominal obesity9.
The liver is among the primary organs affected by MetS10, and it plays a crucial role in various metabolic functions, such as detoxification of harmful substances, producing proteins, generating bile, and maintaining energy balance. As the liver ages, it undergoes a range of morphological and physiological changes 11. For example, accumulation of fat due to aging and dyslipidemia can impair the liver's normal functioning and result in the development of fatty liver disease along with associated histopathological damage 12. While the exact reasons behind liver aging are not fully understood, numerous studies have suggested that some genes might be essential in controlling lifespan and upholding cell balance. 13
One of the genes that have recently been reported to act as an anti-aging agent is Cisd2, a CDGSH iron-sulfur domain-containing protein family member 14. This gene is primarily situated within the endoplasmic reticulum (ER), the outer membrane of mitochondria, and the mitochondria-associated ER membrane (MAM). It plays a key role in preserving calcium (Ca2+) balance, regulating mitochondrial performance, and managing oxidative stress, leading to various forms of cellular protection by controlling both ER and mitochondrial functions 15,16. Furthermore, Cisd2 appears to inhibit the age-related disruption of several transcription regulators, including interleukin-6 (IL-6) and nuclear factor erythroid 2-related factor 2 (NRF2). As a result, it protects the transcriptional network, leading to liver rejuvenation. 17
On the other hand, HNF4α plays a pivotal role as a primary controller of liver metabolism and the balance of lipids by interacting with various signaling pathways to effectively manage nutrient metabolism 18. The expression of hepatic HNF4α is significantly reduced in conditions like diabetes and non-alcoholic fatty liver disease (NAFLD) 19–21. Hence, increasing Hnf4a expression in insulin-resistant situations might help restore the normal function of the liver, suggesting that activating Hnf4a may be the key to achieving the benefits of Cisd2TG.22,23
Acknowledging prevention's superiority over treatment in medicine, the spotlight has increasingly turned to non-pharmacological methods, such as exercise and diet, over recent years. Research shows that physical exercise, including both aerobic and resistance training, reduces liver fat by improving insulin sensitivity and fat metabolism and reducing inflammation. These findings strongly support the idea that regular exercise, with specific intensity, frequency, and duration, benefits NAFLD management and, consequently, MetS 24–26.
The European Association for the Study of Obesity has verified the ample evidence endorsing the effectiveness of aerobic, resistance, and high-intensity interval training (HIIT)27.HIIT has demonstrated its effectiveness in addressing cardiometabolic risk factors, especially among individuals who are overweight or obese28. Prior studies have shown that HIIT can be more effective than moderate-intensity exercise for managing fatty liver. It can improve aerobic capacity and lipid profiles, reduce insulin resistance, and lower liver enzyme levels while recovering liver stiffness and function. 29
On the other hand, the gut-liver axis has gotten attention in the last few years due to the important influence of microbiota and its metabolic byproducts on liver health 30. In this context, probiotics, which are beneficial living microorganisms, play an essential role in activating the immune system, modulating gastrointestinal function, and contributing to overall well-being. On the contrary, alterations in the gut microbiota have been linked to various disturbances, including the aging process 31,32, metabolic disorders, neurodegenerative, immune system dysregulation, and gastrointestinal disorders. Moreover, gut microbial imbalance, or dysbiosis, is believed to occur as part of the natural aging process, and its prevention has been associated with an increased potential for longevity33.
Considering the lack of an appropriate solution for MetS and liver dysfunction, finding a new strategy to prevent the progression of MetS toward diabetes is of great importance. Therefore, this study aimed to investigate the effect of probiotic supplementation and HIIT on liver health in ovariectomized rats, pointing to revitalization genes. To achieve these goals, we employed ovariectomized rats as a model for both menopause and metabolic syndrome.