Overfeeding in Infancy Programs the Gut to Speed Muscle Aging in Mice

What happens in the first days of life may echo decades later in the muscles of old age. A new mouse study published in Nature Communications reports that neonatal overfeeding acts as a developmental insult that accelerates age-related sarcopenia, the progressive loss of skeletal muscle mass and strength, in both males and females. The research, led by Yeyu Song, Jingyi Xu and Jingjie Zhao with senior authors Cen Xie, Jian-Gao Fan and Zhuo-Xian Meng, traces this long-range damage to an unexpected place: the mucus-producing cells of the gut lining and the microbial community they support.

Sarcopenia is one of the most consequential and least well understood consequences of aging. As muscle fibers shrink and mitochondria, the cell’s energy factories, falter, older adults lose the strength to climb stairs, carry groceries or recover from illness, and their risk of falls, frailty and metabolic disease climbs sharply. While adult lifestyle factors such as inactivity and poor diet are known contributors, the question of whether nutrition in the earliest window of life can set the trajectory of muscle aging has remained largely unexplored. The new findings suggest it can.

The team used mouse models in which pups were overfed during the neonatal period, a developmental stage in rodents that corresponds broadly to infancy in humans. Litter sizes were manipulated so that some pups received more milk than others during suckling, creating a controlled form of early overnutrition. The animals were then followed into old age. Compared with normally fed controls, the overfed mice had shorter lifespans, worse late-life muscle atrophy and clear metabolic dysfunction, including disturbances in glucose handling. Crucially, the effect appeared in both sexes, indicating that the developmental programming was not a sex-specific quirk.

The mechanistic heart of the study lies in the gut. Neonatal overfeeding, the researchers found, disrupts the development of goblet cells, the specialized epithelial cells that secrete the protective mucus layer lining the intestine. This layer is far more than passive lubrication. It forms a physical barrier that separates the dense microbial community of the gut from the underlying immune tissue, and its composition, particularly its supply of mucin glycans, determines which microbes can thrive there. When goblet cell development goes awry, the mucus barrier remains defective for life, and the consequences ripple outward across the lifespan.

One microbe proved especially sensitive to this altered environment: Akkermansia muciniphila, a well-known mucus-dwelling bacterium that has attracted intense interest for its associations with metabolic health. In the overfed mice, the persistent mucus barrier defects led to reduced colonization by A. muciniphila as the animals aged. The loss was not merely a correlate. When the researchers performed fecal microbiota transplantation, transferring gut microbes from overfed, sarcopenic mice into recipient animals, the sarcopenic phenotype came along with the microbes, directly implicating gut dysbiosis in the propagation of the muscle-wasting disease.

Why would the disappearance of a single gut bacterium weaken skeletal muscle? The answer appears to run through a short-chain fatty acid called acetate. A. muciniphila is a producer of acetate, a metabolite that circulates systemically and signals to host tissues through receptors including GPR43, also known as FFAR2, a G-protein-coupled receptor expressed in tissues including muscle and immune cells. In the mice lacking A. muciniphila, acetate production dropped, GPR43 signaling was suppressed, and muscle mitochondria suffered. Mitochondrial function in the aged muscle was impaired, meaning the fibers could not efficiently generate the energy required to maintain their mass and contractile performance. The result was aggravated sarcopenia.

The most striking part of the study is that the damage proved reversible, at least in aged mice. When the researchers reconstituted A. muciniphila, either by giving the bacterium directly or by supplementing acetate, mitochondrial homeostasis in the muscle was restored and physical performance improved. This rescue experiment closes the causal loop: it shows not only that the loss of the microbe accompanies muscle decline but that restoring the microbe or its key metabolite can meaningfully improve muscle function late in life. It also identifies acetate signaling through GPR43 as a concrete molecular target linking gut ecology to mitochondrial health in skeletal muscle.

The broader significance of the work is its reframing of sarcopenia as a disease with developmental origins. The concept of the developmental origins of health and disease holds that nutritional and environmental exposures during critical windows of early development can permanently shape physiology and disease risk decades later. Most research in this area has focused on cardiovascular and metabolic outcomes. This study extends the paradigm to the musculoskeletal system and supplies a mechanistic pathway: early overnutrition reprograms gut mucosal development, which reshapes the microbiota, which in turn alters metabolite availability and mitochondrial function in muscle across the lifespan. The gut-muscle axis, as the authors describe it, becomes a conduit through which an infantile dietary excess is converted into an aged, weakened body.

There are important caveats. The findings come from mice, and the neonatal overfeeding model, while well established, involves litter-size manipulation that does not map perfectly onto human infant feeding practices. Human infancy involves a different developmental timeline, different milk composition and a far more variable nutritional environment. Whether overfeeding during human infancy accelerates muscle aging through an analogous goblet cell and A. muciniphila pathway remains an open question that will require long-term human cohort studies. The authors themselves frame the work as revealing a developmental origin of age-related sarcopenia and defining a gut-muscle axis, rather than as a demonstration of a clinical intervention.

Even so, the preventive implications are considerable. If early-life overnutrition leaves a lifelong imprint on the gut barrier and microbiota, then optimizing infant nutrition could be a form of preventive medicine for healthy aging, protecting not only against childhood obesity and adult metabolic disease but against the frailty of old age. The rescue experiments point to a second, complementary possibility: that A. muciniphila or acetate-based interventions might one day help preserve muscle function in people already aging with an unfavorable microbial legacy. As populations worldwide grow older and sarcopenia imposes mounting costs on health systems, the idea that the seeds of late-life muscle decline are planted in the first weeks of life, and that they may be weeded out through the gut, is a finding likely to reshape how researchers think about aging, nutrition and the microbes that live along for the ride.

Subject of Research: How neonatal overfeeding programs lifelong gut mucosa and microbiota changes that accelerate age-related sarcopenia in mice

Article Title: Neonatal overfeeding accelerates age-related sarcopenia and metabolic disorders through lifelong gut mucosa and microbiota programming in mice

Article References: Song, Y., Xu, J., Zhao, J., Yang, R., Ma, Y., Hou, Y.-M., Cao, Y., Li, J., Yu, S., Liang, X., Zhang, Y., Wang, K., An, L., Liu, Y., Meng, Z.-X., Fan, J.-G., & Xie, C. (2026). Neonatal overfeeding accelerates age-related sarcopenia and metabolic disorders through lifelong gut mucosa and microbiota programming in mice. Nature Communications. https://doi.org/10.1038/s41467-026-78216-2

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78216-2

Keywords: sarcopenia, neonatal overfeeding, gut microbiota, Akkermansia muciniphila, goblet cells, mucus barrier, acetate, GPR43, mitochondria, muscle aging, developmental origins, metabolic disorders