Exposure to high altitude: a potential driver of accelerated biological aging

High-altitude areas are characterized by lower oxygen levels, reduced atmospheric pressure, and intense ultraviolet radiation. Recently, there has been increasing attention to the impact of high-altitude environments on human health, particularly with the growing influx of people to these areas for purposes such as tourism, work, and sports training [1]. Although humans have evolved mechanisms to adapt to high-altitude conditions, recent studies indicate that prolonged residence in these regions may accelerate aging and contribute to related health issues. These studies offer valuable insights into the effects of high-altitude environments on aging, highlighting their multidimensional impact on health, which could have significant consequences for populations living in these areas (Fig. 1). This article summarizes recent relevant research, analyzes the conclusions drawn in their articles, and discusses the argument that high-altitude exposure may accelerate biological aging, as well as its potential public health implications.

1 Multidimensional analysis of the relationship between high altitude and aging

1.1 High-altitude exposure accelerates biological aging: Evidence from traditional epidemiology

A recent study utilized data from the West China Natural Population Cohort Study (WCNPCS) and the West China Health and Aging Trend (WCHAT) cohorts in western China to explore the association between long-term high-altitude (> 1500 m) exposure and accelerated aging, with the aim of understanding its multidimensional impact on aging [2]. The study specifically employed the Klemera-Doubal biological age (KDM-BA) and PhenoAge algorithms, which assess aging based on clinical and biological markers. The findings revealed that individuals living at high altitudes generally exhibited a biological age greater than their actual age. In the WCNPCS cohort, biological age increased by 0.85 years, while in the WCHAT cohort, it increased by 0.71 years. These results suggest that residents of high-altitude areas tend to have higher biological ages compared to those living at lower altitudes, and this accelerated biological aging remained significant even after controlling for factors such as age, gender, smoking, and chronic diseases. This indicates that living at high altitudes accelerates the aging process. Furthermore, the study found that smokers experienced a more pronounced acceleration of biological aging in high-altitude areas, suggesting that the combined effects of high-altitude environments and smoking may further exacerbate aging. Smoking is a known contributor to aging, and its synergistic effect with hypoxic conditions underscores the complexity of the aging process in high-altitude regions.

In addition to accelerated biological aging, high-altitude exposure is associated with various multidimensional aging-related changes. These include cognitive decline, depression, anxiety, gastrointestinal disorders, muscle atrophy, and frailty [2]. These findings align with earlier research, which indicates that high-altitude exposure may impair both cognitive and physical health in older adults. The link between high-altitude exposure and cognitive decline is particularly concerning. Previous studies have demonstrated that hypoxia can affect brain function, leading to memory loss and decreased cognitive performance [3]. This may result from reduced oxygen supply, which impairs neural function and accelerates cognitive decline [4,5]. Moreover, residing at high altitudes negatively impacts mental health, further accelerating unhealthy aging [6]. Additionally, the high prevalence of frailty and muscle atrophy at high altitudes is worrisome, as these conditions are common among older adults and directly affect their ability to live independently and maintain a good quality of life. Reduced physical activity, metabolic changes, and oxygen deficiency may accelerate muscle atrophy and strength loss, leading to functional decline.

1.2 The Ethiopian Paradox: slow chronological aging, fast biological aging?

A study conducted in Ethiopia offers a unique perspective by examining both macro indicators (such as disease burden, disability-adjusted life years (DALYs), and life expectancy) and micro biological markers (such as facial photoaging and immune cell aging) [7]. Surprisingly, regions at high-altitude ( > 1500 m) in Ethiopia showed lower risk exposure, lighter disease burden, and longer life expectancy. These findings are consistent with previous research from Tibet, China, where individuals aged 60 years and above exhibited a lower disease burden compared to those in other regions in China [8]. However, facial aging analysis using artificial intelligence tools revealed that biological aging accelerates with increasing altitude. The aging pattern shows a complex trend: replicative aging increases, while DNA damage-induced aging decreases.

This seemingly paradoxical phenomenon suggests that different components of aging—such as systemic and cellular, or functional and molecular—may respond differently to high-altitude stressors. While chronic ultraviolet exposure may contribute to photoaging, reductions in inflammation and lower incidence of metabolic diseases may counterbalance other aging pathways.

2 Underlying mechanisms

2.1 Hypobaric hypoxia as a dual-edged sword

The most prominent feature of high-altitude environments is low-pressure hypoxia. This condition induces the production of reactive oxygen species (ROS), leading to cellular damage and even cell death, which is believed to be associated with premature aging [9]. Prolonged exposure to hypoxic environments triggers adaptive changes in high-altitude residents, primarily regulated at the cellular level by the hypoxia-inducible factor (HIF) family [10]. Among these, the dysregulation of HIF-1α is a key change and is associated with several pathological processes, including aging [11]. Additionally, studies have shown that hypoxic patients exhibit shortened telomeres and accelerated cellular aging [12]. However, some studies suggest that moderate low-pressure hypoxia exposure (e.g., in mid-altitude regions) may slow the aging process [13–15]. The physiologic responses to mild hypoxic stress associated with living at moderate altitudes (1500–2000 m) provide protective effects through adaptive mechanisms, safeguarding against many hypoxia-related diseases [14]. Wu et al. stratified the study population and found that altitudes of 1000–2000 m and > 2000 m accelerated biological aging [2]. In contrast, epidemiological evidence from Burtscher and colleagues shows that people living at moderate altitudes have lower overall and age-specific mortality. This is particularly true for those aged 50 to 89 [16]. Additionally, they exhibit healthier aging profiles compared to people living at lower altitudes. Based on these differing findings, it is reasonable to suggest that although exposure to moderate altitudes (1000–2000 m) may accelerate certain biological aging processes, it does not necessarily lead to worse health outcomes in later life or higher mortality rates among the elderly. These differences may be attributed not only to lifestyle and environmental factors but also to physiologic adaptations triggered by intermittent hypoxic exposure. Therefore, the biological signs of aging observed at moderate altitudes may not directly translate into diminished late-life health, suggesting a more complex relationship between altitude, aging, and longevity. And that seems to confirm Ethiopian findings [7].

2.2 Role of genetics and epigenetics

One of the most significant aspects of the relationship between high-altitude exposure and aging is the role of genetic and epigenetic factors. High-altitude residents have enhanced survival capabilities in hypoxic environments through genetic adaptations. Genes such as EPAS1 and EGLN1 regulate the body’s response to hypoxia, improving oxygen transport and utilization [10,17]. However, while genetic adaptations provide survival advantages, they may interact with environmental stressors and influence the aging process. Recent studies indicate that epigenetic changes, which are modulations in gene expression without altering the DNA sequence, may play a crucial role in the aging process at high altitudes (~4100 m) [17].

The study employed the Best Linear Unbiased Prediction model to quantify the deviation between an individual’s epigenetic age and their actual age, based on age acceleration residuals (AAR). The results revealed that the AAR for Han Chinese individuals migrating to high altitudes was significantly higher by 1.3 years compared to native Tibetan populations and low-altitude Han Chinese, while no significant difference was observed between Tibetans and low-altitude Han Chinese. This suggests that high-altitude residency may accelerate aging. These epigenetic changes may be influenced by factors such as oxygen levels, ultraviolet radiation, and lifestyle, which accelerate aging in high-altitude residents. Interestingly, the accelerated aging in these individuals appeared to be independent of the duration of high-altitude exposure, suggesting that epigenetic changes in high-altitude environments may occur rapidly, potentially observable within a few years. This finding underscores the need for further research into the molecular mechanisms of high-altitude aging and whether lifestyle interventions can reverse or mitigate these changes.

The phenomenon of high-altitude exposure accelerating epigenetic aging has also been observed in the Andean population [18]. This study primarily focuses on the high-altitude population of the Andean Quechua people. The research team divided the Andean Quechua into three study groups: 1) High-altitude Quechua (HAQ)—individuals who have been exposed to high-altitude environments throughout their lives, born, raised, and residing in high-altitude regions; 2) Migrant Quechua (MQ)—individuals born in the Peruvian highlands (> 3000 m) and later migrated to low-altitude regions (150 m) for long-term residence; 3) Low-altitude Quechua (LAQ)—individuals whose parents and both sets of grandparents have highland Quechua ancestry, but they were born and raised in low-altitude regions (150 m). The study used the degree of epigenetic aging (ΔDNAmAge) to describe the difference between epigenetic age and chronological age. The results showed that the ΔDNAmAge of HAQ was significantly higher than that of LAQ. This finding differs from the study by Cheng et al., where there was no difference in AAR between high-altitude Tibetan populations and low-altitude Han populations. This may be due to the more complete high-altitude adaptation in the Tibetan population, while adaptation to high altitudes in the Andean region is still ongoing [19,20].

2.3 Metabolic functions

The effects of high-altitude living environments on human metabolism and the aging process represent a complex and multidimensional field of study. Research has shown that living at high altitudes can lead to increased oxidative stress and inflammatory responses, thereby causing damage to liver and kidney functions [21]. In addition, high-altitude environments affect blood pressure regulatory mechanisms, potentially resulting in elevated blood pressure levels, especially among elderly populations [22]. In high-altitude regions, the low oxygen concentration prompts the body to regulate metabolism by enhancing oxygen delivery and modifying tissue oxygen utilization. This regulation occurs primarily through the HIF pathway at the cellular level, which promotes glycolytic capacity while suppressing oxidative metabolism [23]. Such metabolic adaptations influence not only energy metabolism but are also closely linked to lipid metabolism. Studies have found that indigenous populations in high-altitude areas exhibit lower rates of obesity and diabetes, likely due to their unique metabolic regulatory mechanisms developed through long-term adaptation to hypoxia [24]. Furthermore, individuals who have migrated from lowlands to live long-term at high altitudes also experience significant metabolic changes. Research indicates that these populations often display elevated levels of dyslipidemia and inflammatory markers in high-altitude environments, potentially increasing their risk of cardiovascular diseases [25].

2.4 Involvement of the gut microbiota

The low-pressure and hypoxic conditions characteristic of high-altitude environments can induce profound alterations in the gut microbial community. Although such changes may represent an adaptive physiologic response to extreme environments, they may simultaneously increase associated health risks [26]. The composition and functionality of the gut microbiota are closely linked to the host’s aging process. Previous studies have shown that elderly individuals with a healthy gut microbiome tend to exhibit a “younger” biological state, whereas dysbiosis may accelerate aging even in younger individuals [27]. A recent study focusing on high-altitude residents further elucidated the specific connections between physiologic aging and gut microbiota [28]. This study performed fecal metagenomic analysis on 105 individuals who had relocated to high-altitude regions before the age of 20. This analysis revealed that prolonged residence at high altitudes significantly reduced gut microbiota diversity and markedly increased the Firmicutes to Bacteroidetes (F/B) ratio, a known marker of aging. Notably, the abundance of the beneficial bacterium Akkermansia muciniphila, known for its anti-aging potential, began to decline significantly from the age of 25 among high-altitude residents, whereas this reduction occurred only after the age of 38 in lowland populations. These findings suggest that high-altitude environments may accelerate the aging process of the gut microbiota by approximately 13 years. Based on these results, the study identified Akkermansia muciniphila as a potential biomarker of aging and emphasized the urgent need to develop targeted interventions aimed at maintaining gut microecological health in high-altitude populations.

3 Public health implications

The accelerated aging observed in high-altitude residents raises important public health concerns, particularly as more people visit high-altitude areas for work, sports, or tourism. However, the effects of moderate altitudes seem to present a more nuanced picture. Evidence suggests that exposure to moderate altitudes may offer certain health benefits [15]. From a public health perspective, this distinction is crucial for designing appropriate health interventions. For moderate altitudes, interventions could focus on promoting physical activity, encouraging balanced diets, and supporting regular health screenings to ensure these populations maintain healthy aging processes. For high-altitude residents, however, more targeted interventions may be necessary, such as promoting antioxidant-rich diets, tailored physical activities based on oxygen availability, and smoking cessation, which could help mitigate the risks associated with accelerated aging [2]. Moreover, healthcare systems in these regions may need to focus on screening for cognitive decline, depression, and muscle atrophy—conditions more prevalent at higher altitudes but less so at moderate altitudes. Public health policies should also consider the impact of genetics and environmental factors when crafting strategies to promote healthy aging in both high- and moderate-altitude regions.

Exposure to high altitudes has been shown to accelerate biological aging, with significant impacts on physical, mental, and social health. While the combination of environmental stressors, genetic adaptations, and epigenetic changes contributes to this accelerated aging process, moderate altitudes (1000–2000 m) seem to offer health advantages, potentially slowing certain aging processes and promoting healthier aging outcomes. As interest in high-altitude living and tourism grows, understanding the differential impacts of various altitude ranges will be key to developing targeted public health strategies. Further research into the molecular mechanisms of aging in these regions could provide valuable insights into mitigating the effects of high-altitude exposure and improving the health and well-being of these populations.

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