Summary: The genes GRB10 and ABTB1 influence nutrient-sensing pathways and are linked to memory performance. Researchers propose these genes may be molecular connectors between diet, the aging of neural stem cells, and cognitive ability.
Source: King’s College London
Researchers combined laboratory experiments on human neural stem cells (NSCs) with epidemiological analysis of over 2,000 people to identify genes in nutrient-sensing pathways that relate to memory. The study highlights ABTB1 and GRB10 as genes that both function in nutrient sensing and show statistical associations with performance on standard memory tests. The analysis also revealed an interaction between exercise and variation in the SIRT1 gene that affected cognitive outcomes.
Over the last century medical advances have extended life expectancy, but aging remains accompanied by frailty and gradual cognitive decline. The degree of decline varies widely between individuals. Understanding the biological and lifestyle factors that influence cognitive aging could help extend the period of life spent free from disabling disease—often called “healthspan.”
Past research has pointed to the hippocampus and its population of neural stem cells as important contributors to age-related memory decline. NSCs are cells that can divide to produce more stem cells or differentiate into specialized brain cells, and maintaining a healthy NSC pool supports memory and learning. Environmental factors such as diet and exercise influence NSC maintenance, which may explain part of the variability in how aging affects cognition among different people.
While animal studies have explored how nutrient-sensing pathways regulate aging and stem cell maintenance, human data on these pathways and hippocampal NSCs has been limited. This study used a novel “back-translation” approach: laboratory findings from human NSCs were used to guide analysis of large human datasets, rather than relying on epidemiological associations alone to generate hypotheses.
In the laboratory, researchers exposed human NSCs to blood serum from young or older donors and to compounds that simulate aspects of cellular aging. They measured cellular and molecular readouts of NSC maintenance and identified nutrient-sensing genes whose expression changed with these aging-related manipulations. Those candidate genes were then tested in genetic and lifestyle data from the TwinsUK cohort, assessing memory performance on the Paired Associates Learning (PAL) task along with diet quality, calorie intake, and physical activity.
The combined cellular and population analyses revealed several key findings. Variations in ABTB1 were associated with PAL task performance. Genetic variation in GRB10 appeared to modify how adherence to a Mediterranean-style diet related to memory, suggesting that GRB10 may mediate diet’s effects on cognitive aging. Additionally, an interaction was observed between SIRT1 genotype and exercise level, where different SIRT1 variants corresponded to differential benefits from physical activity for memory performance.
Lead author Chiara de Lucia (Institute of Psychiatry, Psychology & Neuroscience, King’s College London) noted that these results indicate nutrient-sensing pathways are important to memory and that ABTB1 and GRB10 are plausible molecular links connecting diet, NSC aging, and cognition. She suggested that identifying such genes could guide targeted lifestyle recommendations and eventually inform drug development to preserve cognitive health during aging.
Senior author Sandrine Thuret (IoPPN) emphasized the value of the back-translation strategy. By using stem cell biology to refine hypotheses tested on large human datasets, the approach yields a targeted way to investigate how cellular mechanisms relate to real-world lifestyle and cognitive outcomes in people.
The investigators stress that lifestyle changes might delay cognitive decline, but the magnitude of benefit may depend on an individual’s genetic profile. For example, people with certain GRB10 variants might derive greater memory benefits from adherence to a Mediterranean-style diet, while those with specific SIRT1 variants could gain more from increased physical activity. The authors recommend replicating the findings in larger and diverse cohorts, which would permit testing three-way interactions among diet, exercise, and genetic variation to more fully map how these factors interrelate.
Funding for the study was provided by the Medical Research Council.
Source:
King’s College London
Media contacts:
Franca Davenport – King’s College London
Image source:
The image is in the public domain.
Original research: Open access
“Lifestyle mediates the role of nutrient-sensing pathways in cognitive aging: cellular and epidemiological evidence.” Chiara de Lucia, Tytus Murphy, Claire J. Steves, Richard J. B. Dobson, Petroula Proitsi & Sandrine Thuret. Communications Biology. DOI: 10.1038/s42003-020-0844-1.
Abstract (summary)
Aging triggers cellular and molecular shifts, including changes in stem cell pools. Alterations in neural stem cells are linked to age-related cognitive decline and can be modulated by lifestyle. Nutrient-sensing pathways offer a molecular framework connecting lifestyle and cognitive aging. Using a back-translation framework that applies stem cell biology to inform epidemiology, this study links cellular markers of NSC maintenance and expression of nutrient-sensing genes to aging-related serum exposure and repeated cell passaging. Epidemiological analyses of identified genes revealed associations between polymorphisms in SIRT1 and ABTB1 and cognitive performance, and interactions between SIRT1 genotype and physical activity as well as between GRB10 genotype and Mediterranean diet adherence. These results advance understanding of NSC-related mechanisms in human cognitive aging and point to lifestyle-modifiable factors.