Mahajan, A. A. | bioRxiv Science

bioRxiv2026

Developmental regulation of progenitor aging shapes long-term intestinal homeostasis in Drosophila

Aging causes a progressive loss of tissue homeostasis, with stem cell exhaustion as a major hallmark. Age-associated decline in organ function is widely perceived as emanating from progressive accumulation of cellular damage in adult tissues. However, whether aging trajectories are established early on during development remains an open question. Here, we demonstrate that genetic modulation of cellular aging pathways in larval adult midgut progenitors (AMPs), which serve as the precursors of adult intestinal stem cells and differentiated epithelial cells, dictates the long-term trajectory of intestinal aging in Drosophila. Accelerated cellular aging by genetic perturbation employing Toll or Imd pathway overactivation or elevation of reactive oxygen species (ROS) using ND42 (mitochondrial complex I) knockdown in the AMPs results in aberrant progenitor proliferation, skewed lineage allocation, epithelial barrier dysfunction, and genomic instability. These alterations are accompanied by marked destabilization of AMP islet architecture and widespread changes in age-related molecular signatures, as revealed by bulk transcriptomic analysis. In contrast, decelerated cellular aging mediated by Foxo or Atg8a overexpression results in a decrease in enteroendocrine population and the intestinal barrier remained unaffected. Intriguingly, early-life activation of immune and oxidative stress signaling manifested later in the adult gut as elevated enteroendocrine differentiation, highlighting lasting effects on intestinal regenerative capacity and lineage balance. Together, our findings demonstrate that cellular aging is tightly regulated early on in development and its perturbation can cause developmental disruption hampering adult gut homeostasis, establishing AMPs as key developmental determinants that regulate the trajectory of intestinal aging in Drosophila.

developmental biology↗

bioRxiv2022

Optimization of information transmission through a noisy biochemical pathway explains the choice of reaction rates

Living organisms are required to sense the environment accurately in order to ensure appropriate responses. The cells utilize specific signaling pathways to estimate the signal. The accuracy of estimating the input signal is severely limited by noise stemming from inherent stochasticity of the chemical reactions involved in signaling pathways. Cells employ multiple strategies to improve the accuracy by tuning the reaction rates, for instance amplifying the response, reducing the noise etc.. However, the pathway also consumes energy through incorporating ATP in phosphorylating key signaling proteins involved in the reaction pathways. In many instances, improvements in accuracy elicit extra energetic cost. For example, higher deactivation rate suppresses the basal pathway activity effectively amplifying the dynamic range of the response which leads to improvement in accuracy. However, higher deactivation rate also enhances the energy dissipation rate. Here, we employed a theoretical approach based on non-equilibrium thermodynamics of information to explore the role of accuracy and energetic cost in the performance of a MAPK signaling system. Our study shows that the accuracy-energy trade-off can explain the optimality of the reaction rates of the reaction pathways rather than accuracy alone. Our analysis elucidates the important role of the interplay between accuracy and related energetic cost in evolutionary shaping of the parameter space of signaling pathways.

systems biology↗