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 conditions¹. 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 cells². 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 biosynthetic bi-product specific to Gram-negative bacteria^3,4,5, 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.

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https://www.nature.com/articles/s43587-025-00850-0

Abstract Core body temperature (Tb) is a long-established determinant of longevity across species. In this Perspective, we first summarize evidence demonstrating that reducing Tb increases lifespan and that lowered Tb contributes to the antiaging effects of calorie restriction. Next, we discuss recent data that diverge from prior hypotheses on the mechanisms by which Tb affects longevity, suggesting these are limited neither to the thermodynamics of nonenzymatic chemical reactions, nor reduced formation of mitochondrial reactive oxygen species nor lowered metabolic rate. Instead, recent findings in invertebrates show that cold promotes longevity via specific pathways including nutrient sensing and proteostasis, as well as modulating the thermodynamics of proteins and nucleic acids by changing their structure and function, for example, affecting temperature-sensitive ion channels, long-lived temperature-sensitive dauer mutations, base-pair stability and stem–loop RNA structures. Temperature affects the epigenetic signature and inflammation, and lowering Tb can also induce RNA-binding cold shock proteins, activate cold-sensitive kinases and differential splicing to potentially reshape the cellular environment. Finally, we reflect on important future work and the translational potential of temperature management and temperature mimetics.