bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.64898/2026.07.24.740585

Early and current environments exert distinct effects on immune function in the Orang Asli

Brassington, L.·Arner, A. M.·Rodenberg, G.·Ryan, N.·Song, D.·A/P Tan Boon Huat, T. B. T.·Kraus, V. B.·Huebner, J. L.·bin Mohd Sayed, I.·Lim, Y. A.·Venkataraman, V. V.·Wallace, I. J.·Kraft, T. S.·Lea, A. J.
View original source ↗Export metadata ↓

Abstract

Humans evolved in environments characterized by subsistence foraging and hunting, high levels of physical activity, and regular and diverse pathogen exposure. Industrialization has rapidly altered these environments, leading to increased metabolic and inflammatory disease risk. These observations have motivated studies of how industrialization shapes immune function, but whether industrialization alters immune biology through developmental embedding of early-life environments or ongoing plastic responses to current conditions remains poorly understood. To address this gap, we worked with the Orang Asli--the Indigenous peoples of Peninsular Malaysia--who currently span a gradient from subsistence horticulture, foraging, and hunting to industrialized, urban environments with substantial inter-individual variation in life course experiences. Leveraging continuous measures of both early-life and current lifestyle, we found that current lifestyle exerts stronger effects on adult immune gene expression than early-life conditions, impacting 1,428 as compared to 223 genes, respectively. Early-life associated genes were enriched for pathways regulating adaptive immunity, particularly T cell development and differentiation, consistent with higher predicted T cell abundance and circulating IL-8 in urban-born individuals. In contrast, current exposure to urban, industrialized conditions was linked to innate immune and inflammatory activation, including dendritic cell abundance, metabolic pathway upregulation, and elevated CRP. Finally, consistent with lower rates of immune disorders in non-industrial settings, current exposure to this lifestyle was associated with up-regulation of genes involved in Th1/Th2 differentiation. Together, these results emphasize that industrialized immune profiles reflect both early-life developmental embedding and ongoing environmental responses, highlighting the importance of considering exposures across the life course. Significance statementHumans evolved in environments with high levels of physical activity, subsistence-based diets, and constant pathogen exposure. Rapid industrialization has dramatically changed these conditions, coinciding with rising rates of non-communicable diseases with inflammatory underpinnings. Our study with the Orang Asli, the Indigenous peoples of Peninsular Malaysia, tests how exposure to industrialization across the life course shapes immune variation. We find that early-life environments leave lasting marks on adaptive immune function particularly T cells, while industrialized adult lifestyle influences innate immune activity and inflammation. These results clarify how different stages of life contribute to immune remodeling and point to a mechanistic link between industrialization and disease risk, highlighting the importance of both early-life and current environments in shaping later life health.

Explore related subjects

geneticsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Brassington, L., Arner, A. M., Rodenberg, G., Ryan, N., Song, D., A/P Tan Boon Huat, T. B. T., Kraus, V. B., Huebner, J. L., bin Mohd Sayed, I., Lim, Y. A., Venkataraman, V. V., Wallace, I. J., Kraft, T. S., Lea, A. J.. 2026-07-30. Early and current environments exert distinct effects on immune function in the Orang Asli. https://doi.org/10.64898/2026.07.24.740585

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗
bioRxiv2026

Temporal control of mitochondrial mutagenesis reveals the fate of mtDNA mutations with age

Mutations in the mitochondrial genome (mtDNA) play a critical role in the aging process and a wide variety of age-related diseases. However, it remains unclear when the mutations that drive physiological decline arise. To answer this question, we generated a new mouse model in which mitochondrial mutagenesis can be confined to a defined window of time. Surprisingly, we found that mutations that arise during the first two months of life are sufficient to drive a wide variety of age-related pathologies, and that the severity of this pathology is broadly regulated by distinct, tissue-specific selective pressures that control the fate of mtDNA mutations with age. Further, we found that selection against deleterious variants can be modulated by manipulation of mitochondrial fusion in vitro and in vivo. These observations raise the possibility that in some tissues, the pace of aging is pre-determined by events that occur early in life and that interventions targeting mitochondrial fusion may be able to slow down or reverse the expansion of these pathogenic variants. These results carry far-reaching implications for strategies aimed at preventing or delaying age-related decline.

genetics↗
bioRxiv2026

Innate immune stress pathway activation underlies heterochromatin dysfunction pathology

Heterochromatin loss disrupts nuclear architecture, gene regulation and repetitive element silencing, and is associated with diverse human diseases. However, mechanisms linking heterochromatin dysfunction to pathological phenotypes remain unclear. Using genetic interaction screening and genomic analyses in C. elegans, we identify secondary activation of the Intracellular Pathogen Response (IPR), an innate immune stress pathway, as a major contributor to heterochromatin mutant phenotypes. Constitutive IPR activation phenocopies slow growth and indirect transcriptional changes observed in these mutants. Depletion of genetic enhancers further increased, whereas suppressor RNAi attenuated IPR activation, with direct heterochromatin targets remaining substantially deregulated. Notably, many suppressors encode active chromatin components, and mild reduction of RNA polymerase II activity ameliorates growth defects in C. elegans HP1 mutants and human HP1-deficient cells. Our findings reveal secondary stress response activation as an important mechanism linking heterochromatin dysfunction to pathology and identify transcriptional dampening as a potential therapeutic strategy for mitigating these effects.

genetics↗