Gut health has become a major focus in the health and wellness world in recent years. It’s now widely accepted that the gut plays roles far beyond digestion, influencing mental health, immune function, and many other systems throughout the body. But the idea that gut health is tied to broader aspects of health is not new.
Over a century ago, zoologist Élie Metchnikoff proposed that breakdown of the intestinal barrier could drive systemic aging. The intestinal barrier forms a critical shield between the outside world, everything we eat, and the rest of the body. Compromised barrier function is a common feature of aging, linked to declining health and increased mortality in humans and many other organisms.
This aging effect reflects a deeper process that happens at the cellular level. Long before outward signs of aging like gray hair and wrinkles appear, cells gradually accumulate molecular defects and alterations that eventually affect how they function. One of these age-related cellular changes has to do with the way DNA is packaged and labeled.
Every single cell in the body contains the same DNA, encoding all the genes that any given cell could ever possibly use. Cells need to control gene expression, turning specific genes “on” or “off”, depending on their identity or in response to an external cue. Precise regulation of gene expression is essential for healthy cell function.
Gene expression is regulated in part by managing the way DNA is organized. DNA is wrapped around histone proteins to form chromatin, which gets labelled with chemical modifications that affect how tightly a stretch of DNA is packaged. The pattern of these modifications and the resulting alterations in chromatin structure determines which genes can be accessed and expressed. Aging is associated with widespread chromatin remodeling, causing certain genes to be inappropriately activated or silenced.
Given that chromatin remodeling and intestinal barrier decline are both hallmarks of aging, the Henikoff Lab in the Basic Sciences Division set out to investigate how age-related chromatin changes are linked to intestinal barrier breakdown. Dr. Steven Henikoff recently received the prestigious Lewis S. Rosenstiel Award for his “transformative research on genome organization and gene expression”. His lab has developed several powerful chromatin profiling techniques that precisely map chemical modifications and interactions between DNA and proteins, to study exactly how gene expression is affected in different biological contexts.
In a study recently published in Genome Research, postdoctoral researcher Dr. Sarah Leichter used one of these methods to examine chromatin modifications that silence gene expression in the intestines of aging fruit flies. The effect of aging on fruit fly intestines is strikingly demonstrated through a simple experiment, the Smurf assay, where flies are fed blue-dyed food. In young flies, the dye is neatly confined within the digestive tract while in older flies, the dye leaks throughout the body, clearly revealing a breakdown of the intestinal barrier.
What makes this observation especially intriguing is that even in older flies, the cells lining the intestine are remarkably young. The gut surface constantly renews itself, replacing old cells with new ones every 4-5 days. Despite this continuous regeneration, the intestinal barrier still weakens dramatically with age. As Dr. Henikoff noted, “How cells and tissues with high turnover accumulate aging-related changes is a big mystery”.
To explore this question the team used a chromatin profiling technique previously developed in the lab, single-cell combinatorial indexing CUT&Tag (sciCUT&Tag), to map a chromatin modification in thousands of individual intestinal cells from young, middle-aged, and old flies. The method involves attaching a molecular “barcode” to DNA fragments, allowing researchers to trace each piece back to the specific type of intestinal cell it came from.
The results revealed drastic age-associated changes in enterocytes, the cells responsible for secreting digestive enzymes and absorbing nutrients. In particular, genes involved with making chitin are inappropriately silenced in aged enterocytes. Chitin, a material composed of long carbohydrate chains, is typically associated with the hard outer shell of insects and crustaceans. However, it is also a key structural component in the protective layer that shields fruit fly intestines. As genes required to make chitin get repressed with age in enterocytes, the barrier becomes thinner and weaker, allowing substances in the gut to leak throughout the body, mirroring the blue flies from the Smurf assay.
A weakened intestinal barrier drives major shifts in the gut’s cellular composition during aging. Without this protective layer, enterocytes become damaged and decline in number. To compensate, intestinal stem cells ramp up proliferation, resulting in a higher proportion of undifferentiated progenitor cells. The team found that this expanding pool of progenitor cells activates a distinct set of genes strikingly similar to those seen in cancer, hinting at a shared mechanism between aging and cancer progression.
A deeper understanding of the causes and consequences of age-related changes in gene expression is crucial for understanding healthy aging. This work provides a key piece of that puzzle, showing that the story of an aging gut begins not at the surface, but deep within the very cells designed to protect it. These findings bring Metchnikoff’s century-old insight full circle by offering a modern, molecular explanation for his hypothesis.
The spotlighted research was funded by the NIH Ruth L. Kirschstein National Research Service Award and Howard Hughes Medical Institute.
Leichter SM, Ahmad K, & Henikoff S. 2025. Polycomb misregulation in enterocytes drives tissue decline in the aging Drosophila intestine. Genome Research. DOI: 10.1101/gr.281058.125
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.
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