Caroline Haikal ^1* Robert Weissert ^2*

• ¹ Neurological Surgery, Weill Cornell Medicine, Cornell University, New York, New York, United States
• ² Department of Neurology, University of Regensburg, Regensburg, Germany

A recent study examined the directional relationships in which the biological age of one organ selectively a ects the biological age of other organ systems and found that the advanced age of several body systems explained advanced brain age 3 . In the review by Kong et al. (fnagi-16-1389454), the authors explore how oxidative stress links brain and lung health. Oxidative stress has damaging e ects on lipids, proteins and DNA all of which are a ected in pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and fibrosis as well as brain diseases such as stroke, traumatic brain injury (TBI), and neurodegenerative diseases. They also examine the role of reactive oxygen species (ROS) in brain-lung crosstalk, identifying amongst other things, iron homeostasis disruption, breakdown of the blood brain barrier, and activation of the immune system. In their bibliometric analysis, Liu et al. (fnagi-16-1417989) map the research landscape of ferroptosis, an iron-dependent form of cell death, within neurodegenerative diseases. The study shows that ferroptosis research, particularly related to AD and PD, has grown significantly. This cell death pathway is associated with oxidative stress and lipid peroxidation, suggesting it may be a target for therapeutic intervention across neurodegenerative diseases. The role of iron dysregulation in neuroinflammation is further examined by Ashraf et al. (fnagi-16-1393351). In this study, the authors examined the e ects of lipopolysaccharide (LPS)-induced inflammation on cognitive performance and regional brain metabolism following mild iron priming. They reported that iron priming had di erent metabolic e ects on the hippocampus and cortex but induced hyperramification of microglia in both regions following LPS administration. The nuanced, region-specific brain responses to iron priming -both alone and when combined with LPS-induced inflammation underscore the need for comprehensive analyses in such studies, and reinforce a link between iron dysregulation, inflammation, and neurodegenerative disease. Perturbation of iron (and copper) homeostasis is also discussed in Wimalasena et al.'s article (fnagi-16-1339295). Here, the authors propose a new hypothesis to account for the selective vulnerability of neuromelanin-containing dopaminergic neurons in the substantia nigra pars compacta and noradrenergic neurons in the locus coeruleus. They argue that these neurons' high energy demands and complex metabolic roles render them more susceptible to oxidative stress and metal dysregulation (particularly iron and copper), which, in turn, promotes alpha-synuclein aggregation. This aggregation is a critical factor in Parkinson's disease pathology, providing a comprehensive framework for understanding selective neurodegeneration. Aging is linked to altered microbiome composition, though its role in inflammation remains uncertain 4 . Importantly, chronic inflammation and dysbiosis are both key features of neurodegenerative diseases and IBD. Several studies have examined the link between inflammatory bowel disease (IBD)-Crohn's disease, ulcerative colitis-and PD, yet controversy exists whether the correlation is real. Adding to this field, Wang et al. (fnagi-15-1294879) performed a large-scale cohort study and found no significant link between risk of IBD and risk of PD in general; however, specific subgroups, such as females with ulcerative colitis, did show a slight increased risk of PD. This finding provides evidence for a potential, but not universal, relationship between IBD and PD. Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease in which neuropsychiatric, particularly cognitive dysfunction, can be prevalent. Histological examination has highlighted neuronal loss resulting in loss of volume of both white and gray matter areas and elevated levels of neurofilament light protein and glial fibrillary acidic protein (GFAP) in the CSF indicating the neurodegenerative nature of these changes. Kuchcinski et al., (fnagi-15-1274061) utilized a deep learning method called BrainAGE that estimates the age gap, i.e the di erence in chronological age vs biological age of the brain, using magnetic resonance images of patients with SLE and age matched controls. They found a higher brain age gap in SLE patients, particularly those with higher disease activity, linking SLE's inflammatory e ects with accelerated brain aging and cognitive decline. There is an epidemiological association between frailty-an increased state of vulnerability-and insomnia, both of which increase