How metabolic flexibility can help slow ageing
One of the first studies to show that ageing is a malleable process, in 1993, looked at the insulin receptor gene involved in metabolic processes. Altering this gene extended lifespan in lab worms. Since then, mounting evidence suggests that metabolism changes with age and can be targeted for health interventions. Metabolic flexibility refers to the way that human cells use nutrients based on their functional requirements. With age, metabolic flexibility declines and cells no longer use nutrients as efficiently. This can contribute to the development of metabolic diseases such as type 2 diabetes or heart disease. The EU-funded MetaFlex project identified several genes and interventions that can prolong healthy lifespan in worms. The team found that the amino acid glycine significantly extended lifespan. They also found biomarkers of ageing which could help measurements of biological age in worms, with results on mice soon to be published. “This shows promise to help track ageing and the effect of treatments, but needs to be further validated, especially in humans,” says principle investigator Riekelt Houtkooper from the Genetic Metabolic Diseases laboratory of Amsterdam, UMC, the project’s host.
Metabolic flexibility
Explaining the inspiration for MetaFlex, Houtkooper recalls: “We had looked at whether healthy diets were universally healthy and unhealthy diets universally unhealthy. In other words, do individuals respond the same to these diets? Based on the limited data then available, I was convinced this would be individualised not universal.” The team developed a fat diet that shortened the lives of lab worms, then searched for genes that could protect against this. They found a gene that when deleted did indeed protect worms against the diet’s harmful effects. MetaFlex set out to unravel how the processes involved worked. The experiments were chiefly performed in 1 mm long worms treated with different drugs or diets, or had genes deactivated. The impact the interventions had on the lifespan and later health of the worms was then tested. To uncover the processes underlying the beneficial effects of the treatments, large-scale exploratory techniques such as transcriptomics and metabolomics were used to identify precisely the gene expression and metabolism changes. Metabolomics was also the prime technique used to find biomarkers of ageing, detecting small amounts of molecules in biological material. Optimising this technology allowed the team to identify glycine as a potential marker of ageing and target for intervention. “While we worked with worms, not all results are worm-specific. After finding that glycine treatment extended lifespan in worms, researchers published that it extends lifespan in mice too, with a link also found between glycine quantity in human blood and health,” explains Houtkooper.
Human implications
While broad applications from the research are still a way off, a number of areas for further investigation are already clear. Glycine could be tested in humans and, if successful, added to dietary advice. If the biomarkers for aged individuals are validated in humans, they could help track biological ageing through simple blood samples. Additionally, the metabolic mechanisms uncovered could help develop new drugs to slow aspects of ageing. More immediately, there are several research loose ends to tie up, for instance with further examination of genes of interest. “One gene involved in metabolism of a particular fat looks especially promising. Blocking the synthesis of this lipid extends lifespan in worms,” says Houtkooper. The team will soon publish further details of their findings.
Keywords
MetaFlex, metabolism, diet, amino acid, glycine, ageing, lifespan, biomarkers, gene, nutrient, worms
