УДК 542.934:572.7:577.17.049:611:428:612.67

Age-related changes in peripheral lymphatic organs with regard to their topographic location

Веременко Анастасия Сергеевна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Горчаков Владимир Николаевич – доктор медицинских наук, профессор Научно-исследовательского института Клинической и экспериментальной лимфологии – филиала Института цитологии и генетики Сибирского отделения Российской академии наук.

Левченко Ирина Дмитриевна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Вергунова Екатерина Евгеньевна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Тумас Артем Сергеевич – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Платонова Полина Яновна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Бекенева Ксения Алексеевна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Шаймарданова Диана Рамильевна – студент Института медицины и психологии имени Зельмана Новосибирского государственного университета.

Abstarct: In this study, the focus is on examining the age-related changes in the structural and functional parameters of lymph nodes in rats of different age groups. The primary attention is given to the analysis of the structure of lymphatic nodes based on their location. In young rats, specific characteristics were observed in the cortical and medullary zones of the nodes, including variations in the sizes of functional areas. These unique features of structural composition are crucial for determining the functional specialization of lymph nodes, based on their location in the body. With the aging of rats, significant structural transformations in the lymph nodes are observed, including a reduction in the volume of lymphoid tissue, an increase in the proportion of connective tissue, and a decrease in the volume of structural-functional zones. It is noteworthy that the degree of these changes depends on the location of the lymph nodes and their belonging to either the somatic or visceral group, underscoring the importance of anatomical-topographical specificity for their functionality. This study not only reveals structural and functional modifications in the lymph nodes but also forms the basis for a deep understanding of the aging processes in peripheral lymphoid organs. The results can serve as a foundation for developing new approaches to the correction and optimization of the functioning of these organs, which is of great significance for improving the quality of life of the aging population and for developing effective strategies in the field of medicine and gerontology.

Аннотация: В этом исследовании акцент сделан на изучение изменений, связанных с возрастом, в структурно-функциональных параметрах лимфатических узлов у крыс различных возрастных групп. Основное внимание уделяется анализу структуры лимфатических узлов в зависимости от их расположения. У молодых крыс были обнаружены специфические характеристики в кортикальных и медуллярных зонах узлов, включая различия в размерах функциональных областей. Эти уникальные особенности структурной композиции имеют ключевое значение для определения функциональной специализации лимфоузлов, основываясь на их местоположении в организме. Со старением крыс наблюдаются значительные структурные преобразования в лимфоузлах, включающие уменьшение объема лимфоидной ткани, увеличение доли соединительной ткани и уменьшение объема структурно-функциональных зон. Заметно, что степень этих изменений зависит от места расположения лимфоузлов и их принадлежности к соматической или висцеральной группе, подчеркивая значимость анатомо-топографической специфики для их функционирования. Это исследование не только раскрывает структурные и функциональные модификации в лимфатических узлах, но и лежит в основе для глубокого понимания процессов старения в периферических лимфоидных органах. Результаты могут послужить основой для разработки новых подходов к коррекции и оптимизации работы этих органов, что имеет большое значение для улучшения качества жизни стареющего населения и для развития эффективных стратегий в области медицины и геронтологии.

Keywords: ageing, lymph nodes, regional specificity, morphofunctional parameters.

Ключевые слова: старение, лимфоузлы, региональная специфика, морфофункциональные параметры.

Introduction

As humans age, their bodies experience significant changes, especially in the lymphatic system, an essential part of our immune defense. This system includes lymph nodes and vessels that are key in fighting infections and foreign substances. The lymph nodes undergo structural changes such as vitrification, fat deposition, and a decrease in some small blood vessels [1]. These changes affect the lymph nodes' structure and the immune cells within, leading to less efficient lymphatic drainage and a weaker immune response. Older adults particularly see a decrease in the number of follicular dendritic cells, which are crucial for holding onto immune complexes, resulting in a weaker antibody-specific immune response, a major concern for those over 65 [2,3].

Animal studies show that lymph nodes change structurally as they age and respond differently to external stimuli, varying by region due to factors like antigen exposure and hormonal influences [4]. These findings are key to understanding how well bodies can fight infections and cancers.

In 2023, Gödde et al. discovered significant transformations in the pelvic region's lymph nodes with age, including the accumulation of fatty tissue and calcifications [1]. This has important implications for cancer progression and treatment.

Sonar et al., in 2023, studied elderly mice and found a decline in their immune functions, primarily due to changes in T-cells caused by aging [1]. This highlights the aging process's negative effect on the immune system.

Ural and colleagues' 2022 research focused on how inhaled particles like dust and smoke affect our lymph nodes, particularly in the bronchopulmonary region. They found that aging, combined with environmental factors, significantly affects the lymph nodes' structure and function [1].

Using advanced MRI technology, Muraoka and his team studied the cervical lymph nodes in the neck and found a significant decline in the "apparent diffusion coefficient" in healthy nodes with age, which is important for disease detection and diagnosis [1].

Cakala-Jakimowicz et al. in 2021 noted several changes in aging lymph nodes, including size reduction, thickening of the outer layer, and shrinking lymphoid nodules. These changes lead to immunosenescence, reducing the body's ability to fight infections and immune-related diseases [1].

Lastly, Kenney et al.'s 2023 study used single-cell RNA sequencing to examine the effects of aging on the immune system in elderly mice. They found that aging leads to changes in gene expression in lymph node cells, linking aging to increased oxidative stress and mitochondrial function impairments [1].

These studies collectively provide significant insights into how aging affects lymph nodes and the immune system, highlighting their importance in disease understanding and treatment strategies.

Research materials

In our comprehensive study, the primary focus was to scrutinize the traits of three distinct lymph node clusters in Wistar rats. These clusters were specifically targeted, encompassing nodes near the anal region, within the intestinal area, and those in the respiratory system. This selection aligned with core tenets of ecological lymphology, reflecting key insights from pivotal research in this domain. The subjects of our study were male Wistar rats, methodically sorted into two age-based groups to reflect different human life stages.

The correlation with human ages was illustrated using 5-month-old rats as equivalents of humans aged 16 to 20 years, while rats aged 1.5 years were compared to humans aged 75 years. This analogy was based on a life expectancy ratio, employing a 1.7 coefficient as a comparative benchmark [5].

Our experimental design segmented the rats into three groups: a baseline control group, a set of younger rats, and a collection of older rats, with each group comprising 10 rats. To ensure a consistent and controlled environment, each rat was provided constant access to food and water throughout the experiment.

For a detailed analysis of the lymph nodes, we employed advanced light microscopy techniques, utilizing two high-end microscope models: the Leica DM 750 and the Mic-med-2, each equipped with a ScanMicro scanning attachment for precise observation.

This setup enabled an in-depth examination of the lymphatic structures. We adopted a technique to trace the lymphatic pathways in these rats, involving injections of ink or Evans blue dye as per the protocol suggested by V.N. Gorchakov [6]. This approach allowed us to visually map the intricate networks within the lymphatic system. We approximated the lymph node volume by treating them as ellipsoids, providing a reliable estimate of their size.

For histological analysis, we adhered to rigorous standards and protocols [7,8]. These methods were chosen for their proven reliability, simplicity, and their ability to consistently yield high-quality results, making them ideal for our research objectives.

This comprehensive study embarked on an in-depth exploration of the lymphatic system in juvenile rodents, with a keen focus on their lymphatic nodules. These nodules, resembling small, kidney-shaped entities, are pivotal components of the body's immune defense mechanism. The research meticulously examined each region within these nodules, given their distinct and critical roles in orchestrating immune responses.

At the heart of this investigation was a detailed comparative analysis of the nodules' external and internal segments. The external part, constituting approximately two-thirds (66%) of the nodule's total structure, was meticulously contrasted with the internal section, which comprised about one-third (34%). This study particularly highlighted the variations in the proportions of these sections based on the nodules' anatomical locations. For instance, notable differences were observed in the cortical to cerebrum ratios across various types of nodes, such as the inguinal nodes located in the groin area (1.98), the tracheobronchial nodes found in the chest (2.34), and the intestinal nodes situated in the abdominal region (2.47). These differences underscored a more densely packed structure in the cortical areas, suggesting a specialized adaptation based on their locations within the body.

A significant element of this research was the thorough examination of the thymus-independent zone present within the lymph nodes. This zone is crucial for the generation of antibodies, a fundamental aspect of the immune response. Intriguingly, the size of this area exhibited variability among different types of lymph nodes. The study noted a fairly consistent size in the inguinal and tracheobronchial nodes, ranging between 41.18%-43.40%. However, this zone was comparatively smaller in the mesenteric nodes, measuring about 32.97%.

Another key focus was the identification of lymphoid nodules with germinal centers within the lymph nodes. These nodules are indicative of an active immune cell presence. Notably, these nodules were found to be larger in the tracheobronchial nodes, which hinted at a more robust and vigorous immune activity in these specific regions.

In terms of juvenile rodents, the study observed a pronounced difference in the size of the brain tissue areas across various lymph nodes. The inguinal nodes demonstrated a larger brain tissue area (26.87±1.65%), as did the tracheobronchial nodes (25.56±0.86%), compared to their counterparts in the mesenteric nodes (17.08±0.52%). This observation sheds light on the diverse functional roles that different lymph nodes play within the lymphatic system.

Additionally, the research delved into the sinus system of the lymphatic glands, a system critical for the filtration and retention of substances within the body. This system's size was found to vary among different glands, with the tracheobronchial glands exhibiting the smallest sinus system. This variation reflects the diverse roles these glands play in lymphatic transport and immune function.

Moreover, the study meticulously investigated the structural and functional zones of lymph nodes in various bodily regions. For example, the tracheobronchial nodes were found to have a more developed internodal cortex and a higher number of lymphoid nodules with germinal centers, yet they exhibited smaller cerebral lymphatic sinuses. In contrast, the inguinal nodes featured a larger paracortical area, fewer lymphoid nodules with germinal centers, and a moderately-sized cerebral lymphatic sinus. Such detailed findings contribute significantly to our understanding of the lymphatic system's functionality and adaptability.

The study also pointed out the unique architecture of mesenteric nodes, which showcased a significant cerebral lymphatic sinus region. Their internodal cortex and lymphoid nodule areas, including generative centers, were of average size. On the other hand, the tracheobronchial nodes presented a distinct architecture with a prominent thymus-independent zone, lymphoid nodules, and medullary strands, yet minimal sinus areas. The inguinal nodes were characterized by a well-developed sinus system and a predominant paracortical zone that is dependent on the thymus. These findings offer substantial insights into the lymphatic system's complexity and underscore its vital role in the immune response.

Furthermore, this study provides a novel perspective on the functional categorization of lymph nodes, unveiling how their primary roles are intricately shaped by the development and size of the sinus system. The inguinal nodes were found to primarily support drainage functions, while the tracheobronchial nodes played a crucial role in immunity. The mesenteric nodes, interestingly, were observed to perform a combination of these functions, highlighting the multifaceted nature of the lymphatic system.

This in-depth research not only enhances our comprehension of the lymphatic system in juvenile rodents but also sets the foundation for understanding the adaptability and functionality of this system in various physiological conditions. The meticulous attention to detail in this study, particularly in the analysis of the different lymph nodes and their respective roles, offers a valuable contribution to the field of immunology and lymphatic research.

The research undertaken to understand the nuances of lymph node structure and function in rodents, both young and old, has led to a series of intriguing discoveries, particularly regarding the differentiation in the composition of these critical immune system components. A key finding from this extensive study was the variation in the proportion of cortical to medullary tissue among different types of lymph nodes. For instance, in mesenteric nodes, this ratio was notably higher at approximately 41%, compared to inguinal nodes, which exhibited a ratio of around 34%. This significant disparity not only underscores the distinct structural identities of lymph nodes depending on their bodily location but also highlights the unique way each type of lymph node adapts to its specific environmental demands and functional necessities.

As the research delved deeper into the age-related changes in these lymphatic structures, it became evident that older rats exhibited considerable alterations in both their visceral and somatic lymph nodes. These changes were manifold and included a reduction in the overall size of the lymphoid tissue, which is crucial for the efficient functioning of the immune system. Additionally, there was an increase in connective tissue within these nodes, which could imply a compensatory mechanism or a sign of aging-related degradation. Furthermore, the study observed a decrease in the area occupied by secondary lymphoid nodules, suggesting a decline in the lymph nodes' ability to generate an effective immune response in older rats.

One of the most striking changes noted was the enlargement of the capsulo-trabecular basis in the lymph nodes of older rats. This enlargement was particularly evident in the thickening of the capsule and trabeculae across various lymph node groups. The extent of this change was most pronounced in the intestinal and tracheobronchial nodes, where a 2.2 to 2.4-fold increase was observed compared to the inguinal nodes. This significant structural alteration could be indicative of various physiological changes occurring as the rats age, potentially impacting the lymphatic drainage and immune surveillance capabilities of these nodes.

In terms of the cortical substance, aged rats demonstrated varying structural compositions depending on the location of the lymph node. Mesenteric nodes, for instance, had the smallest internodal cortex area, highlighting their unique structural and functional adaptations. In contrast, inguinal and tracheobronchial nodes had larger internodal cortex areas, with inguinal nodes showing a notable increase of 1.3 times in older rats. However, this size decreased by 2.1 times in mesenteric nodes, indicating a dynamic change in the structural organization of these lymph nodes with age. The paracortical area, which is significant for T-cell mediated immune responses, remained relatively stable across different lymph node groups in older rats, but it was observed to be larger in inguinal nodes compared to others.

Furthermore, the research brought to light significant changes in the lymph nodes of aged rats in terms of lymphoid nodules with germinal centers. Inguinal nodes experienced a 1.4-fold decrease, mesenteric nodes a 1.9-fold reduction, and tracheobronchial nodes a more pronounced decrease of 2.3 times. These changes have far-reaching implications for the operational functionality of the lymph nodes, with a noticeable shift in the ratio of secondary to primary lymphoid nodules. This shift signifies a decline in their proliferative capacity, which could have critical implications for the overall immune competence of older rats.

When examining the cerebral mass volume in older rats, the study uncovered remarkable data. The cerebral mass in mesenteric nodes of these older rats increased significantly, to about 34.8%, which is almost 1.6 times the size found in inguinal and tracheobronchial nodes. This increase is double that observed in younger rats, suggesting a marked age-related change in the immunological activity within these nodes. However, the cerebral mass volumes in the inguinal and tracheobronchial nodes of older rats were approximately 21.62% and 22.11% respectively, showing minimal deviation from the values noted in younger rats.

Additionally, the size of the thymus-independent zone, which is crucial for B-cell mediated or humoral immunity, was found to be fairly consistent in both inguinal (around 32.73%) and tracheobronchial (approximately 34.84%) nodes. However, a significant expansion in this zone was observed in the mesenteric nodes of older rats, where it occupied around 44.85% of the node. This expansion indicates a possible increase in humoral immune activity in these nodes as the rats age.

An analysis of the spatial distribution of thymus-dependent (T-zone) and thymus-independent (B-zone) areas within lymph nodes also revealed interesting variations based on their location in the body. Inguinal and tracheobronchial nodes predominantly exhibited a T-zone, with coefficients of around 1.41 and 1.12 respectively. This is indicative of a robust T-cell mediated immune response in these nodes. Conversely, the mesenteric nodes had a coefficient of about 0.64, pointing to a more pronounced humoral (B-cell mediated) immune response in these nodes. This distribution underscores the lymph nodes' ability to adapt and specialize according to their specific location and the demands placed upon them by the body's immune system.

The comprehensive study undertaken to explore age-related transformations in the lymph nodes of rats is a testament to the ever-evolving nature of biological systems. Focusing primarily on the structural and functional aspects of these lymph nodes, the research uncovers a myriad of intricate changes that occur as the rats mature. A pivotal aspect of this study is the observation of a decrease in the size of lymphoid nodules that possess germinal centers, a crucial component of the immune response mechanism.

Delving into the specifics, the investigation reveals that this reduction is not uniform across all lymph node types. In inguinal nodes, the shrinkage is quantified at about 1.4 times their original size. This trend becomes more pronounced in mesenteric nodes, which contract by approximately 1.9 times. However, it is in the tracheobronchial nodes where this phenomenon is most significant, with a contraction of an astounding 2.3 times their initial size. This pattern underscores a potential decline in the functional efficiency of these lymph nodes, a critical consideration in the context of age-related immune response.

In addition, the study sheds light on the variations in the ratio of secondary to primary lymphoid nodules. This ratio is a key indicator of cell proliferation rates within these organs. The research meticulously quantifies these ratios, revealing a gradual decline across different nodes: inguinal nodes exhibit a ratio of 1.10±0.03, mesenteric nodes at 0.91±0.03, and tracheobronchial nodes at a lower 0.69±0.03. These figures suggest a decreasing trend in cell proliferation rates with age, which could have significant implications for the overall immune capabilities of the organisms.

Another critical observation made in the study is the alteration in the size of the sinus system within these lymph nodes as the rats age. In older rats, the inguinal nodes' sinus system expands by 1.8 times compared to their younger counterparts. This expansion contrasts with the tracheobronchial and mesenteric nodes, which experience a reduction in size by 1.2 and 1.9 times, respectively. When analyzed in relation to the overall lymph node area, the sinus system occupies a considerable portion, ranging from 9.04% to 14.29% of the area. The inguinal nodes, in particular, show a substantial cerebral lymphatic sinus area of 12.5±0.51%, which is markedly larger – between 2 to 3.3 times – than those in the mesenteric and tracheobronchial nodes.

The research also brings to light significant disparities in the thymus-independent zone, a region integral to B-cell mediated humoral immunity. In older rats, this zone is notably larger in the mesenteric lymph nodes, encompassing 44.85±3.16% of the area. This contrasts with the inguinal and tracheobronchial nodes, where the areas are almost equal, at 32.73±2.14% and 34.84±2.48% respectively. On the other hand, the thymus-dependent zone, which is indicative of the T-cell immune response, is more pronounced in the inguinal and tracheobronchial nodes, with ratios of 1.41±0.04 and 1.12±0.04, respectively. The mesenteric nodes, with a lower ratio of 0.64±0.02, seem to favor a more robust humoral immune response.

In terms of overall architecture and functionality, the study concludes that with aging, rats' lymph nodes undergo significant transformations that impact their draining and depositing capabilities. The mesenteric lymph nodes in older rats demonstrate the least cortical-brain index, internodal cortex area, and thymus-dependent zone, primarily consisting of brain substance and the sinus system. Conversely, the tracheobronchial nodes exhibit elevated values in these areas, with a predominance of the thymus-dependent zone and narrow lymphatic sinuses. The inguinal lymph nodes, while presenting a lower connective tissue content, show a higher paracortical area and cerebral lymphatic sinus indices. This represents a unique morphological variant that balances both thymus-dependent and thymus-independent zones with expansive lymphatic sinuses.

These findings collectively suggest that the structural modifications in lymph nodes due to aging have profound implications for the functional capacity of these organs within various regions of the lymphatic system. The insights garnered from this study not only enhance our understanding of the aging process in the context of the lymphatic system but also open up avenues for further research into age-related immune response mechanisms.

Lymph nodes, integral elements of the lymphatic system, are pivotal in maintaining fluid equilibrium and facilitating essential immune responses. Their efficacy is not uniform but varies significantly depending on the specific lymphatic region they are associated with. This variation is a well-established fact, extensively backed by scientific literature and studies [9,10]. These nodes serve as critical junctures in the lymphatic flow and are reflective of the unique immune characteristics inherent to the body's distinct lymphatic areas [11,12]. It is crucial to acknowledge that the geographical positioning of these nodes within an organism, coupled with the age of the subject, exerts a profound influence on their structural integrity and compositional makeup [13,14].

Focusing on the inguinal lymph nodes, which are particularly accessible and thus a frequent subject of study [15,16], we find that they play a key role in the lower body's lymphatic system. This includes areas like the external genitalia and parts of the abdomen. In younger specimens, these nodes are distinguished by their abundance of secondary lymphoid follicles, each marked by a well-defined germinal center. This is a clear indication of their vigorous participation in immune system activities [17,18]. Additionally, the paracortical regions of these nodes often display signs of hyperplasia, indicative of an amplified T-cell mediated immune response [13,19].

As animals progress in age, there are marked and observable structural alterations in these lymph nodes. A trend towards reduction in size is noted, accompanied by a thickening of the external capsule. Concurrently, there is a discernible degeneration in the lymphoid tissues and a concurrent increase in connective tissue presence [20,21]. These changes are indicative of a gradual decline in functional capacity, pointing towards a less robust immune system in the older specimens. Turning our attention to the mesenteric lymph nodes, which are predominantly associated with the lymphatic drainage of the intestines [13], it is observed that in younger animals, these nodes usually possess numerous secondary lymphoid clusters. Interestingly, primary nodules are somewhat rarer in these nodes [19,20]. Furthermore, the size of the paracortical area in these nodes displays significant fluctuation, ranging anywhere from 7% to 28% [19,22,23]. This variability could be indicative of different stages in immune development and responsiveness.

The tracheobronchial lymph nodes, strategically positioned near the tracheal bifurcation, play a critical role in the bronchopulmonary system [24]. These nodes are characterized by a pronounced ratio of cortical to medullary tissue [25], underscoring their primary function in initiating immune responses against airborne pathogens. Notably, the expansion of regions such as the paracortical zone, the medullary cords, and lymphoid follicles equipped with germinal centers, serves to highlight their indispensable role in the orchestration of immune responses.

Our investigative efforts focusing on young rats have shed light on the distinctive characteristics and structural divergences among various groups of lymph nodes. These differences are reflective of their unique functional roles and morphotypes. The structure of the medullary cords within these lymph nodes, for instance, is seen to be significantly influenced by their bodily location [26,27]. There exists a range of perspectives in various studies regarding the microanatomical and cytoarchitectural changes that lymph nodes undergo with advancing age [28,29]. Generally, it is observed that older lymph nodes tend to exhibit a reduction in size, diminished cortical material, and an increase in connective tissue stroma, among other age-related changes [28,29].

Moreover, the occurrence of sclerolipomatous atrophy, a commonly observed condition in lymph nodes, is also noted [30]. These alterations have a significant impact on the orientation of lymph nodes, whether towards immune functionality or drainage efficiency. With the onset of aging, lymph nodes exhibit a marked decrease in their compartmental sizes and a reduction in the sinus system. This reflects the functional limitations that emerge as a consequence of aging. This comprehensive understanding of the structure and function of lymph nodes, as influenced by both age and location, is of paramount importance in pushing the boundaries of medical research and enhancing clinical practices.

Conclusions

This study on the lymphatic systems of young and old rodents reveals how aging impacts immune function. It initially examines the structural differences in the lymph nodes of young rodents, highlighting variations in their cortex and medulla based on location. The research then analyzes lymph nodes from various body regions, noting unique structural features and the presence of a thymus-independent zone crucial for antibody production.

Key findings include a decrease in the size of lymphoid nodules with germinal centers in older rodents, indicating reduced immune capabilities with age. The study also observes size variations in the medullary regions of different lymph nodes and changes in the lymph nodes' drainage functions due to aging.

In summary, the research provides vital insights into the aging process's effects on the lymphatic system and immune response, highlighting the system's adaptability and the evolving nature of lymph nodes in different anatomical areas.

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