Investigating an enzyme that stops cells from dividing could be a fruitful avenue for research into how to slow aging and treat aging-related diseases.
This was the conclusion that researchers at Kobe University in Japan came to after studying the enzyme D-amino acid oxidase (DAO) and its role in cells.
DAO metabolizes D-amino acids, which, unlike their mirror-image cousins the L-amino acids, only have a small presence in mammal biology.
For this reason, until the recent study, scientists knew little about the impact of DAO in the body.
The new finding reveals that, in the process of metabolizing D-amino acids, DAO produces reactive oxygen species (ROS), which are a group of unstable molecules that cause cell stress.
Stressors such as DNA damage and ROS prompt cells into senescence, an irreversible state in which they can no longer replicate.
The finding uncovers a molecular mechanism that has been missing in previous studies that have linked ROS to cell senescence and aging.
ROS are important players in the biology of aging and many diseases that tend to increase with advancing age, such as Parkinson’s, Alzheimer’s, diabetes, and many cancers.
The recent study adds to a growing understanding of the role of senescent cells in this relationship.
Entering an irreversible state in which it can no longer divide and proliferate does not necessarily diminish a cell’s capacity for change and influence.
Early research suggested that the main impact of cell senescence on human biology involved protecting against cancer. Confined to a senescent state, cells with damaged DNA cannot multiply and give rise to tumors.
Since then, however, studies have revealed that senescent cells are active in tissue repair, wound healing, embryonic development, and aging.
A major focus of continuing research is on the various stressors that can trigger cells to enter the irreversible state.
In addition, there is a growing body of knowledge about how aging-related biological changes and diseases involve ROS and senescence.
In previous work, the Kobe University researchers had discovered that senescence triggers the tumor suppressor molecule p53 and that this activates the gene for DAO.
However, that “study did not fully explore the direct relationship between DAO and senescence,” they note.
In their more recent investigation, the researchers coaxed cancer cells into senescence by exposing them to low levels of “an anticancer drug that induces DNA double-strand breaks.”
They found, however, that reducing DAO activity, either with drugs or by silencing its gene, reduced senescence and ROS production.
In another experiment, they used a mutant of DAO that stopped it behaving like an enzyme. This version of DAO, however, neither produced ROS nor promoted senescence.
The team suggests that this proves that it is DAO’s ability as an enzyme to make ROS that allows it to promote senescence in cells.
In further experiments, the scientists discovered other pathways that help DAO to promote senescence triggered by DNA damage.
A key factor is the transporter gene SLC52A1, which helps increase levels of the coenzyme flavin adenine dinucleotide (FAD).
DAO needs a supply of FAD, and SLC52A1 ensures this supply by increasing the availability of vitamin B-2, an ingredient of FAD.
The researchers are cautious about the implications of their findings. ROS are not always the bad guys: They can also benefit health. For example, low levels of ROS can lengthen the lifespan, and the immune system needs them to fight infection.
Perhaps it is the overproduction of ROS that causes problems and tips the balance toward cell stress, disease, and aging. In this respect, the study identifies a previously unknown role for DAO.
The researchers conclude:
“Our results clearly show a novel function of DAO as a promoter of DNA damage-induced senescence, which may provide new insights into the roles of [D]-amino acids in various physiological and pathological processes including senescence, cancer, and aging.”