Editorial: Similarities and differences between cellular and molecular mechanisms of normal brain aging and neurodegeneration

First, in their original research, Cao et al show that chronic exposure to hypoxia leads to changes in protein expression with increased expression of caspase-3 mRNA and protein levels (caspase-3 being a key regulator of neuronal apoptosis) and of a series of genes leading to accelerated cellular senescence(definition), such as p16, p21, and p53. These changes occurred mainly in the prefrontal cortex and hippocampus of studied mice, and were associated with a decrease in the gray matter volume of the left piriform cortex, caudate nucleus and left visceral area, as well as with an altered functional connectivity between the basal ganglia, hippocampus and anterior limbic cortex despite a compensatory increase in the diameter of both common carotid arteries and left internal carotid artery.The importance of a proper brain oxygenation is emphasized also by Jiao in his mini-review which explains how hypoxic pockets -transient cortical areas of oxygen depletion where oxygen supply no longer matches metabolic demands for milliseconds to seconds -are due to disruptions in capillary perfusion or increased local metabolic demands during intense neural activity. Although these sporadically occurring hypoxic pockets activate angiogenesis and neurovascular remodeling, their effects tend to cumulate and can progressively impair neural function, mainly in the prefrontal cortex and hippocampus, igniting neurodegeneration.In their submitted perspective, Jia and Shen draw attention of the contribution of chronic inflammation to neurodegeneration, an area of active research (Jurcau et al, 2024). The term "inflammaging(definition)" refers to a persistent low-grade inflammation characteristically found in aging organisms and linked to damaged or malfunctioning cells as well as to aberrant immune responses (Soraci et al, 2024). Mitigating inflammation has been shown to successfully delay aging. One such strategy is the use of platelet factor 4 (or platelet-derived exerkine CXCL4), which increases in the plasma following exercise or under the influence of the longevity factor klotho (Park et al, 2023) and reduces inflammation by activating the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway (Buka et al, 2024).In their review, Komleva et al outline the challenges that need to be overcome when developing "aging clocks" able to show significant deviations from the normal aging trajectory and to identify individuals with accelerated brain aging at risk for cognitive impairment. They emphasize the non-linear changes in gene expression in middle life, which makes the study of methylation of CpG subgroups in DNA as well as of the expression of genes which increase the susceptibility to impaired brain bioenergetics especially important in establishing the biological age of an individual, but a number of other factors, such as inflammatory biomarkers, or altered metabolic signaling should be integrated in these predictive tools. As such, assessing the brain aging gap becomes increasingly more complex, having to integrate cognitive tests, neuroimaging techniques, serological biomarkers, and genetic tests, a task in which artificial intelligence, or the digital twin technology may help in a more personalized approach (Lehman et al, 2024).Nonetheless, because rejuvenating therapeutic approaches are still in their infancy (Nunkoo et al, 2024) and have serious side-effects, all manuscripts submitted to this special issue emphasize that to date the only proven methods to date that can help in achieving healthy brain aging are a healthy diet, even with periods of caloric restriction(definition), physical exercise, and memory training, which act in synergy to delay brain aging, improve neurovascular coupling and increase synaptic plasticity (Bennett et al, 2024).