Environmental conditions have a substantial influence on the rate of human aging. People living at high altitudes generally have shorter life expectancy than those residing at lower elevations, and prolonged hypoxia has been associated with accelerated biological aging. However, little was previously known about how extreme altitudes affect the immune system, particularly among individuals who permanently live above 5,000 meters.
Chinese researchers analyzed blood immune cells from healthy individuals residing at different elevations, including inhabitants of high-altitude regions of Tibet. The results showed that chronic hypoxia is associated with profound remodeling of the immune system.
High-altitude residents exhibited increased numbers of neutrophils, exhausted T cells, regulatory T cells, age-associated B cells, and memory immune cells. At the same time, the number of naïve T and B cells declined. These alterations are considered hallmarks of immune aging.
A key mechanism linking long-term residence at high altitude to accelerated organismal aging appears to be the development of chronic inflammation resulting from immune system remodeling.
To validate these findings, the researchers reproduced high-altitude conditions in mice. Exposure to hypoxia equivalent to approximately 5,000 meters above sea level induced similar immune alterations and signs of aging across multiple organs. Age-associated immune cells accumulated near intestinal epithelial cells, contributing to intestinal damage and aging.
To assess the effects of altitude, the researchers analyzed single-cell sequencing data from more than 1 million human and mouse cells collected from populations living at sea level and up to 5,070 meters. Compared with lowland residents, high-altitude populations displayed similar age-independent patterns of gene activity associated with inflammation and aging.
High Altitude Promotes Neutrophil Expansion and Aging
Residents of extreme high-altitude environments exhibited a marked increase in neutrophils, innate immune cells closely linked to inflammation and age-related changes. These cells showed activation of genes involved in inflammatory responses, interferon signaling, oxidative stress, and the NF-κB signaling pathway – processes also associated with aging. Particularly prominent at high altitude was the accumulation of pro-inflammatory neutrophil subpopulations that lost immune surveillance functions and adopted an effector phenotype that promotes aging.
Mouse experiments confirmed the human findings. Exposure to conditions corresponding to an altitude of 5,000 meters led to neutrophil accumulation in multiple organs, particularly pro-inflammatory and interferon-responsive neutrophil subsets.
Previous studies have shown that both short-term and long-term exposure to high altitude increases oxidative stress and inflammatory burden, thereby accelerating aging and increasing disease susceptibility. In the present study, both acute and chronic hypoxia promoted the accumulation of pro-inflammatory neutrophils and systemic oxidative stress in mice and humans.
High Altitude Alters Communication Between Immune Cells
Disrupted intercellular communication is a hallmark of aging. At high altitude, interactions between senescent neutrophils and exhausted T cells were enhanced, while interactions between proliferating naïve T cells and effector memory T cells were weakened.
In addition, CXCL/CCL chemokine signaling activity increased, and inflammatory signals originating from neutrophils became progressively stronger with age. Previous research has shown that elevated CXCL8 expression may promote the recruitment of immune cells to senescent cells, thereby further amplifying systemic inflammation.
Mouse experiments confirmed the human findings. In addition to enhanced inflammatory signaling, aging mice exhibited alterations in extracellular matrix components, growth factors, and cell adhesion molecules. These changes may accelerate systemic aging by disrupting tissue homeostasis, affecting stem cell activity, and intensifying inflammatory responses.
High Altitude Promotes Immunosenescence
A pro-inflammatory state characterizes age-related immune dysfunction, while chronic inflammation accelerates immune cell aging. This further impairs immune function, reducing the body’s ability to eliminate senescent cells and inflammatory molecules, creating a vicious cycle of inflammation and aging.
High-altitude residents accumulated age-associated B cells and memory B cells, and the abundance of these populations increased with age. These cells displayed enhanced resistance to hypoxia, hallmarks of aging, and impaired autophagy.
Similar alterations were observed among monocytes. High-altitude residents exhibited a predominance of monocyte subpopulations characterized by pro-inflammatory profiles, cellular senescence, and defective autophagy.
Furthermore, the number of naïve T cells declined, whereas the populations of exhausted and regulatory T cells increased. These changes indicate immune remodeling and immunosenescence driven by chronic high-altitude hypoxia.
Mouse experiments confirmed the findings observed in humans. Exposure to high-altitude conditions promoted the accumulation of age-associated B cells, memory B cells, plasma cells, and pro-inflammatory monocytes.
At the same time, multiple organs exhibited defects in autophagy, cell-cycle regulation, and antigen presentation. Mice also showed reduced numbers of naïve T cells and increased proportions of regulatory T cells, effector T cells, and pro-inflammatory Th17 cells.
High-Altitude Environments Cause Intestinal Barrier Dysfunction in Mice
Mice exposed to high-altitude conditions exhibited reduced numbers of endothelial cells and fibroblasts, particularly in the ileum and colon, indicating impaired vascular integrity and tissue repair capacity.
In addition, intestinal and hepatic epithelial cells displayed features of accelerated aging, including defects in autophagy, cell-cycle regulation, DNA repair, and intercellular junction function. Simultaneously, the cellular composition of the intestine shifted, with increased proportions of secretory cells and decreased proportions of tuft cells, reflecting intestinal aging.
High-Altitude Conditions Enhance Interactions Between Age-Associated Immune Cells and Intestinal Secretory Epithelial Cells in Mice
Under high-altitude hypoxic conditions, senescent immune cells accumulated near intestinal epithelial cells, which are responsible for nutrient absorption, mucosal lubrication, and maintenance of the intestinal barrier.
These findings indicate that chronic hypoxia strengthens interactions between aging immune cells and intestinal secretory cells, potentially accelerating age-related intestinal damage.
High-Altitude Hypoxia Promotes Chronic Inflammation and Tissue Damage, Creating Conditions for Accelerated Aging
Residence at high altitude was associated with increased neutrophil numbers and enhanced activity of genes involved in inflammatory and interferon responses. These changes were observed even in Tibetans who are genetically adapted to hypoxic environments.
Mouse experiments confirmed that chronic hypoxia increases oxidative stress, disrupts mitochondrial function, enhances cell death, and causes tissue damage in the heart and lungs, all of which may accelerate aging-related processes.
Reference
High altitude–mediated immune remodeling accelerates aging
