Advancements in the investigation of the mechanisms underlying cognitive aging

Abstract

Cognitive aging, a pivotal domain at the intersection of neuroscience and psychology, exhibits a strong association with neurodegenerative disorders; however, its comprehensive underlying mechanisms remain incompletely elucidated. This review aims to provide a thorough synthesis of recent advancements in the investigation of cognitive aging in the brain, highlighting multidimensional assessment techniques, neurobiological foundations, molecular regulatory pathways, systemic changes, environmental-gene interactions, and intervention strategies. Evidence suggests that cognitive aging is marked not only by widespread neuronal loss but also by subtle modifications within neural networks, protein homeostasis, mitochondrial functionality, and epigenetic regulation. The integration of various technological methodologies has shed light on the continuum that exists between cognitive aging and neurodegenerative disorders. Concurrently, multidimensional intervention strategies are being proposed; however, current research frameworks face challenges due to limitations in biomarker systems, indicating a need for a paradigm shift. Future investigations should leverage emerging technologies to develop more precise regulatory frameworks and personalized intervention strategies aimed at addressing the global challenges associated with aging, thereby enhancing the prevention and treatment of related pathologies.

Keywords: Brain cognitive aging; Environment-gene interaction; Intervention strategies; Molecular mechanisms; Neurobiology.

Fig. 1

Investigations using aging murine models have indicated a significant decrease in the levels of serine/arginine (SR) protein 11, also referred to as SR splicing factor 11 (SFRS11), within the PFC. SFRS11 is known to interact directly with the 3' untranslated region (UTR) of low-density lipoprotein receptor-related protein 8 mRNA (LRP8 mRNA) and the third exon of apolipoprotein E (apoE) mRNA, thereby stabilizing these mRNAs and inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. The age-related decline of SFRS11 in the PFC results in reduced levels of apoE and LRP8, which activates the JNK pathway and contributes to cognitive dysfunction

Fig. 2

Cyclin-dependent kinase-5 (Cdk5) substrates in brains with neurodegenerative diseases. In a neurodegenerative brain disease, there is Calpain cleavage in the N-terminal region of p35 to a more stable isoform p25, forming a CDK5/p25. This stable complex strongly phosphorylates neurofilaments, Tau, and another microtubule-associated protein, MAP1B compared with CDK5/p35 complex

Fig. 3

This study comprehensively investigates the mechanisms of cognitive aging, employing a multi-faceted approach. Cognitive aging is defined using established neuropsychological assessments, including MOCA, MMSE, and ADAS-Cog, and advanced multimodal techniques such as neuroimaging, molecular marker analysis, and digital phenotyping. Brain atrophy patterns are visualized to illustrate age-related structural changes. Molecular regulatory mechanisms, encompassing mitochondria, cytokines, and chromatin, are examined to elucidate dynamic molecular alterations. Systemic factors, including the gut microbiome, vascular system, and immune system, are analyzed for their adaptive and maladaptive roles in cognitive aging. Gene-environment interactions, specifically the influence of environmental factors like diabetes and obesity on genes such as APOE-ε4, are explored. Intervention strategies encompass pharmacological interventions, dietary modifications, cognitive training, and physical activity. The “Others” category encompasses additional relevant research areas and influencing factors