Transcriptomic Effects of Healthspan-Promoting Dietary Interventions: Current Evidence and Future Directions

Abstract

Aging is the greatest risk factor most diseases, including cardiovascular disorders, cancers, diabetes, and neurodegeneration, but select nutritional interventions may profoundly reduce the risk for these conditions. These interventions include calorie restriction, intermittent fasting, protein restriction, and reducing intake of certain amino acids. Certain ad libitum diets, including the Mediterranean, Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability, and Okinawan diets also promote healthy aging. Evidence indicates that these dietary strategies influence aging and healthspan by acting on the biological “hallmarks of aging” and especially upstream nutrient sensing pathways. Recent advances in “omics” technologies, including RNA-sequencing (transcriptomics), have increased our understanding of how such nutritional interventions may influence gene expression related to these biological mediators of aging, primarily in pre-clinical studies. However, whether these effects are also reflected in the human transcriptome, which may provide insight on other downstream/related cellular processes with aging, is an emerging topic. Broadly, the investigation of how these nutritional interventions influence the transcriptome may provide novel insight into pathways associated with aging, and potential targets to treat age-associated disease and increase healthspan. Therefore, the purpose of this mini review is to summarize what is known about the transcriptomic effects of key dietary/nutritional interventions in both pre-clinical models and humans, address gaps in the literature, and provide insight into future research directions.

Gene expression changes in cerebellum induced by dietary restriction

“…Thus, a considerable proportion of down-regulated genes are involved in neuronal signaling, while many upregulated genes are linked to cytoprotective mechanisms, including DNA repair. Upregulation of cytoprotective and DNA repair pathways is consistent with data from other brain areas and tissues ( Xu et al, 2007 ; Swindell, 2009 ; Plank et al, 2012 ; Barger et al, 2017 ; Ma et al, 2020 ; Wahl and LaRocca, 2021 ), and can be mechanistically linked to the neuroprotective effect of DR in cerebellar neurodegeneration mouse models ( Cunha-Santos et al, 2016 ; Birkisdottir et al, 2021 ; Birkisdóttir et al, 2023 ). Upregulation of DNA repair pathways, for instance, may reduce the accumulation DNA damage in aging ( Heydari et al, 2007 ; Van Houten et al, 2018 ), and contribute to the strong beneficial effect of DR in DNA-repair-deficient accelerated aging mouse models ( Vermeij et al, 2016 ; Birkisdottir et al, 2021 ; Birkisdóttir et al, 2023 ).…”

A protein restricted diet induces a stable increased fat storage phenotype in flies

“…The increased catalase enzyme activity in PRD group could have been due to a lower ratio of TG/catalase activity when compared to HSD and HFD groups [36] . This may have caused a re-programming of multiple antioxidant/nutrient sensing pathways and metabolic processes which improved the health span and lifespan of the PRD group [99] , [115] , [116] . Furthermore, sugar diets at either low or high supplementation alter physiological function (reproduction) due to body size changes and organ size [117] .…”

Nutrition for precision health: The time is now

“…In addition, the transcriptome (the sum of the complete set of RNA transcripts produced by the genome) functions as the molecular linkages between genetic/epigenetic information and the proteome, leading to a comprehensive understanding of biological processes and diseases. However, human studies on the role of transcriptome in determining the individual variability of the responses to dietary factors are limited, mainly because of the challenges in assessing the tissue-specific transcriptomic profiles that are more relevant to various conditions affecting different metabolic organs or tissues (96). Various omics mechanisms may affect human health in a concerted manner.…”