Mutational damage to nuclear DNA occurs constantly throughout life, and is suspected to contribute to degenerative aging in ways other than risk of cancer. But most mutational damage occurs in somatic cells with few replications left before the Hayflick limit, and in DNA sequences that are not used in that cell type. So how can this damage cause significant disruption of metabolism? One recent idea is that repeated activation of DNA repair processes can deplete factors necessary to maintain correct DNA structure and gene expression, producing detrimental epigenetic changes characteristic of aging. Separately, perhaps only some mutations are meaningfully harmful, those that occur in stem cells. A mutated stem cell will spread that mutation throughout a tissue as it creates a steady supply of mutated daughter somatic cells. Over time, tissues will develop a patchwork of different combinations of mutations that originally occurred in specific stem cells, creating what is known as somatic mosaicism.
Clonal hematopoiesis of indeterminate potential (CHIP) is one of the better researched manifestations of somatic mosaicism, occurring in the hematopoietic cell populations in bone marrow responsible for generating immune cells. It is known to be a risk factor for leukemia, and also correlates with other conditions, possibly because of an increased propensity for chronic inflammation on the part of the immune system as its somatic mosaicism grows. In today's open access paper, researchers report on a specific connection between the aging gut microbiome and CHIP, showing that one specific metabolite produced by microbial populations can promote the expansion of populations of potentially harmful mutated hematopoietic cells, raising the risk of a resulting leukemia.
Microbial metabolite drives ageing-related clonal haematopoiesis via ALPK1
Clonal haematopoiesis of indeterminate potential (CHIP) involves the gradual expansion of mutant pre-leukaemic haematopoietic cells, which increases with age and confers a risk for multiple diseases, including leukaemia and immune-related conditions. Although the absolute risk of leukaemic transformation in individuals with CHIP is very low, the strongest predictor of progression is the accumulation of mutant haematopoietic cells. Despite the known associations between CHIP and increased all-cause mortality, our understanding of environmental and regulatory factors that underlie this process during ageing remains rudimentary.
Here we show that intestinal alterations, which can occur with age, lead to systemic dissemination of a microbial metabolite that promotes pre-leukaemic cell expansion. Specifically, ADP-d-glycero-β-d-manno-heptose (ADP-heptose), a metabolic specific to Gram-negative bacteria, is uniquely found in the circulation of older individuals and favours the expansion of pre-leukaemic cells. ADP-heptose is also associated with increased inflammation and cardiovascular risk in CHIP. Mechanistically, ADP-heptose binds to its receptor, ALPK1, triggering transcriptional reprogramming and NF-κB activation that endows pre-leukaemic cells with a competitive advantage due to excessive clonal proliferation.
Collectively, we identify that the accumulation of ADP-heptose represents a direct link between ageing and expansion of rare pre-leukaemic cells, suggesting that the ADP-heptose-ALPK1 axis is a promising therapeutic target to prevent progression of CHIP to overt leukaemia and immune-related conditions.
View the full article at FightAging
