The research team drew on the UK Biobank Pharma Proteomics Project, which measured 2,916 plasma proteins in more than 44,000 participants using the Olink Explore 3072 platform. From these protein profiles, the scientists built organ-specific aging clocks using elastic net regression, training models to predict chronological age from protein abundance within each organ domain. The difference between predicted biological age and actual chronological age—known as the age gap—served as the key outcome. A positive residual signals accelerated aging in that organ; a negative residual indicates the tissue is biologically younger than expected. In total, 18 organ-specific indices plus one composite index were generated, covering systems from the brain and heart to the thyroid, adrenal glands, and salivary glands.

After linking these aging indices to self-reported birth weight and breastfeeding status, the researchers analyzed fully adjusted models accounting for age, sex, ethnicity, childhood body size, adult body mass index, socioeconomic deprivation, education, smoking, alcohol use, physical activity, and major cardiometabolic diseases. The final analytic samples comprised 21,446 participants for the birth weight analysis and 29,713 for the breastfeeding analysis. The results were striking in their breadth: higher birth weight was associated with slower biological aging across 11 of the organ systems examined, pointing to a systemic rather than organ-isolated effect of fetal growth conditions.

The strongest inverse associations appeared in the digestive tract. Each additional kilogram of birth weight corresponded to lower intestinal aging scores, with similar patterns in the esophagus and stomach. Beyond the gut, higher birth weight was linked to decelerated aging of the immune system, kidneys, liver, salivary glands, thyroid, adrenal glands, skin, and muscle. These findings align with a well-established body of developmental evidence. Low birth weight has previously been tied to impaired intestinal vascular development, reduced nephron endowment in the kidneys, hepatic fat accumulation, and diminished muscle mass—structural constraints established in utero that may quietly accelerate organ decline across the entire lifespan.

Breastfeeding told a more selective story. Being breastfed was associated with slower aging of the intestine and adrenal glands, but—somewhat unexpectedly—with accelerated aging of the thyroid. The intestinal finding is biologically plausible: breast milk is rich in human milk oligosaccharides and immune factors such as secretory IgA, which promote beneficial microbial colonization, strengthen the gut barrier, and suppress low-grade inflammation, all processes that counteract hallmark features of gut aging. The adrenal association may reflect long-term modulation of the hypothalamic–pituitary–adrenal axis, the body’s central stress-regulation system. The thyroid result, the authors caution, remains speculative; variability in iodine and thyroid hormone content of breast milk could theoretically impose metabolic load on the developing gland, but this interpretation requires further study.

Perhaps the most compelling finding emerged when the two exposures were combined. Participants who both weighed more at birth and had been breastfed showed the most favorable aging profiles of any group, with significantly reduced aging indices in the intestine, kidney, liver, adrenal gland, lung, and stomach. The magnitude of the intestinal effect was roughly double that of either exposure alone, hinting at an additive or synergistic relationship between prenatal and postnatal nutritional advantages. Conversely, low-birth-weight infants who were breastfed gained only modest protection, suggesting that breastfeeding can partially mitigate—but cannot fully compensate for—the developmental constraints of restricted fetal growth.

To probe the mechanisms behind these associations, the team conducted causal mediation analyses testing two candidate pathways: systemic inflammation, measured by C-reactive protein, and allostatic load, a composite index of cumulative physiological wear across ten metabolic, cardiovascular, and inflammatory biomarkers. Allostatic load emerged as the dominant mediator. For skin aging, 35.3 percent of the birth weight benefit was attributable to lower cumulative stress burden, with substantial mediation also seen for the adrenal glands (30.5 percent) and thyroid (19.8 percent). Moderate contributions appeared for the salivary glands, kidneys, and intestines, while C-reactive protein mediated a smaller 4.8 percent of the liver effect. Notably, neither mediator explained the breastfeeding associations, suggesting that infant feeding may act through earlier developmental or localized biological pathways rather than chronic stress accumulation.

The study also revealed that early-life advantages do not operate in a social vacuum. Interaction analyses showed that breastfeeding’s protective effects were stronger in women, particularly for brain, pituitary, arterial, and adipose aging, hinting at sex-specific modulation involving lifelong hormonal milieu. The benefits of both exposures were most pronounced among individuals with higher body mass index and, paradoxically, among those living in more favorable socioeconomic circumstances as measured by the Townsend Deprivation Index. This pattern resonates with the cumulative advantage framework in life-course epidemiology: early biological endowment appears to compound over time when paired with supportive later-life environments, while adverse social and behavioral contexts may erode the protective legacy of good early nutrition.

Sensitivity analyses bolstered the robustness of the findings. Adding medication use to the models left the results virtually unchanged, and mutually adjusting for both perinatal exposures preserved the significance of nine of the eleven birth weight associations and the intestinal benefit of breastfeeding. Restricted cubic spline analyses confirmed that the birth weight relationships were approximately linear across the observed range. Still, the authors acknowledge important limitations. Both exposures were self-reported decades after the fact, introducing potential recall bias that would likely bias results toward the null. Breastfeeding was captured as a simple yes-or-no question, precluding analysis of duration or exclusivity, and proteomic aging indices, while scalable, may not fully capture the structural and functional deterioration visible on imaging or histopathology.

Even with these caveats, the study delivers a provocative message: the trajectory of biological aging is shaped, at least in part, by nutritional conditions in the earliest days of life. By integrating developmental origins theory, population-scale proteomics, and mediation analysis within a single framework, the research reframes organ aging not as a process that begins in middle age, but as the culmination of exposures accumulated across the entire life course. If confirmed in prospective cohorts with granular perinatal data, these findings could elevate early-life nutrition—from maternal-fetal health through infant feeding—into a central pillar of healthy-aging policy, alongside the familiar levers of diet, exercise, and smoking cessation pursued in adulthood.

Subject of Research: Associations of birthweight and breastfeeding with proteome-based organ-specific biological aging in the UK Biobank

Article Title: Birthweight and Breastfeeding Shape Patterns of Biological Aging Across Adult Organs

Article References: Wei, W., Qi, X., Cheng, B., Zhao, B., He, D., Hui, J., Feng, J., Cheng, S., Yang, X., Pan, C., Gou, Y., Wen, Y., Liu, H., Jia, Y., Liu, L., & Zhang, F. (2026). Birthweight and Breastfeeding Shape Patterns of Biological Aging Across Adult Organs. Aging Cell, 25(10), Article e70762. https://doi.org/10.1111/acel.70762

Image Credits: AI Generated

DOI: 10.1111/acel.70762

Keywords: biological aging, birth weight, breastfeeding, UK Biobank, proteomics, organ aging, Developmental Origins of Health and Disease, allostatic load, inflammation, life-course epidemiology, Aging Cell, early-life nutrition