# Aberrant enterocyte progenitor clustering as an early life biomarker of Drosophila aging

## TL;DR

This study identifies early-life signs of aging in fruit flies by finding clusters of abnormal gut cells that can be treated to improve health and lifespan.

## Contribution

The paper reveals that flawed Notch signaling in young Drosophila gut progenitors leads to early aging biomarkers.

## Key findings

- Young midguts have clusters of overproliferating mixed identity cells.
- Notch signaling flaws in progenitors contribute to aging and infection vulnerability.
- Reinforcing Notch signaling in enteroblasts extends survival and reduces dysplasia.

## Abstract

Stem cell accumulation and mutation-derived tumors are two hallmarks of Drosophila 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 Notch 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.

•Notch signaling between progenitors is already flawed in young adults•Young midguts contain aggregates of overproliferating mixed identity cells•ISC-like cell aggregates compromise resilience to infection and overall aging•ISC-like cell aggregates offer a treatable early life biomarker of old-age pathology

Notch signaling between progenitors is already flawed in young adults

Young midguts contain aggregates of overproliferating mixed identity cells

ISC-like cell aggregates compromise resilience to infection and overall aging

ISC-like cell aggregates offer a treatable early life biomarker of old-age pathology

Cell biology; Stem cells research