Ageing is a complex process characterised by the gradual deterioration of physiological functions and increased susceptibility to various age-related diseases. Mitochondrial dysfunction is an important factor contributing to ageing. Sirtuin 3 (Sirt3), a mitochondrial protein essential for energy homeostasis, plays a critical role in maintaining mitochondrial function, as loss of Sirt3 reduces energy and impairs cellular repair, which accelerates ageing. The aim of this study was to investigate the role of Sirt3 in male and female mouse embryonic fibroblasts (MEF) exposed to etoposide-induced DNA damage. We employed state-of-the-art genetic, molecular, and imaging technologies as well as metabolomic analyses to provide insights into the molecular mechanisms underlying these responses. We found that the loss of Sirt3 affected metabolic responses differently depending on sex: while male MEF showed minimal damage, possibly due to earlier stress adaptation, female MEF lacking Sirt3 were more vulnerable, suggesting that Sirt3 plays a critical role in enhancing their ability to withstand such challenges. By focusing on Sirt3 and sex-specific signalling pathways it modulates, this study has a potential for developing new strategies to combat diseases associated with DNA damage — a cornerstone of the ageing process.

Variations in body size and shape might be linked to different biological processes that affect breast cancer risk. Еpidemiological studies have confirmed that obesity, which is characterized by increased overall adiposity and assessed using body mass index (BMI), has direct relationship with the risk of breast cancer among postmenopausal women, and opposite relationship with the risk among premenopausal women (“obesity paradox”). In addition to BMI, anthropometric descriptors of body shape, like waist and hip circumference and waist-to-hip ratio are directly associated with both pre- and postmenopausal breast cancer risk. Excess adipose tissue, adipose tissue dysfunction, and adipose tissue-to-breast cancer crosstalk have important role in the initiation and progression of breast cancer due to the altered production of proinflammatory and proangiogenic mediators, growth factors, adipokines, and sex hormones, dysregulated insulin signaling pathway, as well as mitochondrial dysfunction and oxidative stress. Fat distribution pattern exerts an effect beyond the effect of overall obesity in relation to breast cancer development because of more adverse systemic metabolic effects related to visceral adiposity. Body height and its components have direct association with postmenopausal breast cancer risk. Increased risk of breast cancer in taller persons is probably due to increased levels of insulin-like growth factor (IGF-1), which is one of the major determinants of height, plays an important role in regulating breast stem cell number, and can affect cancer growth. Adult-attained height also reflects different aspects of maturation, including genetic, nutritional, and environmental factors. Assessment of changes in body height, mass, and distribution of adipose tissue throughout life is another important aspect of understanding the complex processes of metabolic reprogramming of energy pathways in breast cancer pathophysiology. Use of anthropometric descriptors of body size and shape can provide insight into underlying biological mechanisms, which is essential for developing targeted prevention and treatment strategies.

This research was supported by the Science Fund of the Republic of Serbia, #7750238, Exploring new avenues in breast cancer research: Redox and metabolic reprogramming of cancer and associated adipose tissue - REFRAME.