Gene-activity clock shows that mouse intestinal epithelium is temporarily younger than undamaged tissue at the peak of healing, that old mice reach their minimum age later, and that the liver of old mice is younger after partial removal than before surgery: a preprint from the Gladyshev group
Gene-activity clock shows that mouse intestinal epithelium is temporarily younger than undamaged tissue at the peak of healing, that old mice reach their minimum age later, and that the liver of old mice is younger after partial removal than before surgery: a preprint from the Gladyshev group
On October 13, Sharif Iqbal and Vadim Gladyshev of Harvard Medical School posted a preprint on bioRxiv. The authors tracked how the age of the epithelium, the inner lining of the mouse intestine, changes after injury. They measured it with an “aging clock”, a model that estimates the age of a tissue from the activity of its genes.
In 2023 the Gladyshev group showed that stress raises biological age and that recovery brings it back down. The authors now ask whether healing itself lowers age. After injury, epithelial cells partly switch on programs of the embryonic intestine, and age might fall along with them.
After injury, the proportions of immune cells and connective tissue cells in a tissue change, and this shift alone changes the estimated age of the tissue as a whole. The authors therefore trained the clock on epithelium only, using data from 14 studies, and tested it on studies that were not used in training. They ran two further checks of the clock. It scored embryonic epithelium as younger than adult epithelium. It also scored the epithelium of newborn mice with an intestinal disease in which the epithelium recovers poorly as older than healthy epithelium.
In every healing model tested (colitis, irradiation, cultures of intestinal cells), the epithelium at its point of minimum age was younger than the control, and in seven comparisons the difference was significant. After irradiation (one mouse per day), epithelial age rose on day 1, fell below baseline on day 3, at the peak of recovery, and by days 7 and 14 had risen above baseline.
In the states that the clock reads as “young”, the epithelium is in repair mode. Genes that depend on the protein YAP (which starts the healing program in cells) are switched on, and so are genes of rare stem cells that replenish the stem cell pool after injury. Genes of the mature cells that absorb nutrients are turned down.
Earlier work by Iqbal showed that in old mice the protein asporin prolongs the regenerative state of the epithelium. To test whether the timing of the response depends on age, the authors gave mice aged 4 and 21 months 5-fluorouracil, which kills dividing cells, and measured epithelial gene activity over six days (two mice per age and day). In young mice, epithelial age reached its minimum on day 4 and by day 6 was slightly above baseline. In old mice the decline began on day 4, the minimum came later than in young mice, and on day 6 age rose further above baseline than in young mice. The authors write:
“The ability to exit the regenerative state may be as important as the ability to enter it.”
For the liver, where cells normally do not divide, the authors used published data from 2023, in which removal of two thirds of the organ reversed age-related changes in how DNA is packaged. They applied 24 existing clocks from a 2026 Nature paper. A significant decrease in the old liver came mostly from multi-species clocks, which are built to work across several species. The most robust of these placed age below the pre-surgery level at every time point from 48 hours to day 10, whereas in the intestine age returned to baseline. The decrease amounted to about half of the clock-measured difference between old and young liver.
The epithelial clock also scores tumor foci in the mouse colon as “younger”, while whole-tissue clocks score them as “older”. The authors explain that the first reflects the regenerative state of the epithelium and the second reflects inflammation and remodeling of connective tissue. They conclude: “A prediction of younger age needs to be read together with what the cells are doing.”