Aberrant enterocyte progenitor clustering as an early life biomarker of aging.

Stem cell accumulation and mutation-derived tumors are two hallmarks of midgut aging. They imply a decline in stem cell signaling homeostasis late in life and a robust homeostasis in young adults. Contrary to this, we find spontaneously developing stem-like cells that vary in size and ploidy, have a stem-enteroblast mixed identity, achieve higher mitotic rate per cell, exhibit DNA replication stress, and are inherently prone to clustering. Reduction of mitosis or DNA replication stress lessens the production of these cells but does not explain the loss of their proper differentiation. However, young enterocyte progenitors also display epigenetic plasticity in Notch signaling network genes and locus instability. Strikingly, reinforcing Notch signaling in enteroblasts, alleviates dysplasia and extends overall survival and survival to infection. Thus, Notch signaling between prospective stem cells and enteroblasts is never sufficiently on, producing stem-enteroblast mixed identity cells that cluster and compromise homeostasis and overall aging.