Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging

Abstract

There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in longchain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

Neuron-type specific aging-rate reveals age decelerating interventions preventing neurodegeneration

“…We computed age-correlations of z-score normalized gene counts for all human brain regions in the GTEx dataset 33 , the Tabula Muris Senis (TMS) dataset 5 , and an additional mouse Hypothalamus aging cohort (GSE157025). Similarly, we calculated the enriched pathways for several "anti-aging" treatments like young serum injections 34 , the platelet factor PF4 35 , sport in humans 36 , and krilloil in C. elegans 37 . An unbiased clustering analysis revealed that the aging-trajectories of C. elegans, mouse, and humans cluster together.…”

Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing

“…Neurodegeneration, protein aggregation, mitochondrial dysfunction, and reactive oxygen species formation are endpoints well explored in both PD and AD C. elegans models (Naranjo-Galindo et al 2022 ; SenGupta et al 2021 ). Worth mentioning, that steadily piling omics approaches in C. elegans AD and PD model allow for investigation of the molecular mechanism underlying DNT and ANT (SenGupta et al 2022 ; Sánchez-Martínez et al 2023 ).…”