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Thymic involution

Thymic involution refers to the progressive, age-dependent atrophy of the thymus gland, characterized by a reduction in thymic size, loss of thymic epithelial cells, and diminished production of naive T lymphocytes, which collectively impair adaptive immunity.^[1] This process begins shortly after birth in humans, with a rapid decline of approximately 3% per year until middle age (around 35–45 years), after which the rate slows to less than 1% annually, resulting in the thymic epithelial space shrinking to under 10% of its original volume by age 70.^[2] By puberty, the thymus reaches its peak involution, marked by the replacement of functional thymic stroma with adipose and fibrous tissue, peaking around this developmental stage and continuing throughout adulthood.^[3] The mechanisms driving thymic involution are multifaceted, involving hormonal influences such as elevated sex steroids (androgens and estrogens) that promote thymic atrophy via receptor-mediated signaling, alongside disruptions in the thymic stromal microenvironment, including reduced expression of key transcription factors like Foxn1 and altered cytokine profiles (e.g., decreased IL-7 but increased pro-inflammatory IL-6).^[1] Additional contributors include age-related changes in thymic epithelial cells (TECs), such as downregulated cell cycle genes and upregulated senescence-associated pathways, as well as the expansion of non-productive fibroblasts and adipocytes that disrupt thymocyte development and T-cell receptor diversity.^[1] Genetic factors, including loci like Cdkn2a, and extrinsic stressors like glucocorticoids further accelerate this degeneration, leading to inefficient negative selection of autoreactive T cells.^[3] Functionally, thymic involution results in a profound reduction in naive T-cell output—over 95% by age 70—shifting the peripheral T-cell pool toward memory cells and decreasing T-cell receptor repertoire diversity from approximately 2 × 10^7 unique receptors before age 60 to as few as 200,000 after age 70, which heightens susceptibility to infections, autoimmunity, and malignancies in the elderly.^[3] This decline also complicates immune reconstitution following events like chemotherapy or transplantation, though interventions such as sex steroid ablation or cytokine therapies (e.g., IL-7) show promise in partially reversing these effects by enhancing thymopoiesis.^[2] Overall, thymic involution represents a hallmark of immunosenescence, underscoring the thymus's critical role in maintaining lifelong T-cell homeostasis.^[1]

Overview

Definition

The thymus is a primary lymphoid organ situated in the anterior mediastinum, anterior to the heart and between the lungs, where it plays a crucial role in the maturation and education of T cells derived from bone marrow progenitors.^[4] Within the thymic microenvironment, immature T cells undergo positive selection to ensure recognition of self-major histocompatibility complex (MHC) molecules and negative selection to eliminate autoreactive clones, thereby establishing central tolerance and a functional T-cell repertoire essential for adaptive immunity.^[4] Thymic involution refers to the progressive atrophy and functional decline of the thymus, marked by a reduction in thymic epithelial cells (TECs), which are vital for supporting T-cell development, alongside increased infiltration by adipocytes and the gradual replacement of functional lymphoid tissue with adipose and connective tissue.^[5] This process diminishes the organ's capacity for naive T-cell production, contributing to age-associated immune dysregulation.^[1] A 1985 morphometric study of human thymic tissue documented post-pubertal shrinkage of the thymic epithelium occurring independently of puberty-related hormonal influences.^[6] Thymic involution proceeds in a two-phase model: an initial involutionary phase at the end of postnatal growth, around age 1 in humans, characterized by stabilization of thymic volume after early expansion; followed by an age-dependent phase from adolescence onward, involving ongoing replacement of epithelial and lymphoid components with adipose tissue.^[7] Thymic size can be quantified using the thymic index, defined as the ratio of thymus weight to body weight, which peaks at birth and subsequently declines sharply.^[7] In humans, this leads to an approximately 95% reduction in thymic size by age 60, reflecting extensive adipose infiltration and loss of functional tissue.^[8]

Types

Thymic involution is broadly classified into two primary types: age-related (chronic) involution and acute (stress-induced) involution, distinguished by their onset, triggers, and potential for reversibility.^[8] Age-related involution represents a gradual, lifelong process that commences in early life and progresses with intrinsic aging factors, while acute involution involves rapid, transient shrinkage in response to external stressors.^[1] These categories highlight the thymus's dual vulnerability to endogenous developmental changes and exogenous challenges, with implications for T-cell production across species.^[9] Age-related involution begins as early as one year of age in humans and around 4–6 weeks in mice, driven by factors such as hormonal shifts (e.g., androgens and estrogens) and progressive stromal remodeling.^[1] This chronic process leads to a substantial reduction in thymic size and cellularity, often dropping to less than 5% of peak levels in aged individuals, and is largely irreversible without targeted interventions like Foxn1 overexpression or sex hormone ablation.^[1] It is universal among mammals, reflecting an evolutionarily conserved aspect of immune maturation where the thymus transitions from a high-output organ in youth to a diminished structure in adulthood.^[8] In contrast, acute involution occurs rapidly—often within days—triggered by external stressors such as infections (e.g., viral pathogens like HIV or influenza, bacterial agents like Salmonella typhimurium), glucocorticoid surges during physiological stress, chemotherapy, or malnutrition.^[9] This type features massive apoptosis of double-positive cortical thymocytes, resulting in up to 80–90% loss of these cells without significant damage to the thymic stroma, and is typically reversible upon removal of the stressor, allowing partial regeneration through mechanisms like IL-7 signaling.^[9] It is prevalent in 70–90% of cases involving severe infections or post-chemotherapy scenarios, as evidenced by thymic volume reductions in 90% of pediatric cancer patients after initial treatment cycles.^[10] The distinctions between these types lie in their pathological signatures: age-related involution entails permanent loss of thymic epithelial cells (TECs) through mechanisms like epithelial-mesenchymal transition, leading to fibrosis and adipose infiltration that disrupt the stromal microenvironment, whereas acute involution spares TECs and focuses on transient thymocyte depletion via apoptosis.^[8] This differential impact underscores why chronic forms progressively impair T-cell output over decades, while acute episodes allow quicker functional recovery.^[1] In chronic infections such as HIV, sustained stressors can accelerate overall thymic decline, bridging aspects of both acute and age-related involution. Recent research as of 2025 has further elucidated mechanisms, including age-related defects in thymic epithelial cells that limit regeneration after injury, and emerging therapeutic approaches like RANKL administration to restore thymic function and improve T-cell immunity in aging.^[11]^[12]

Mechanisms

Age-related thymic involution involves the progressive loss of thymic epithelial cells (TECs), including both cortical TECs (cTECs) and medullary TECs (mTECs), which are essential for supporting T-cell development and selection. This reduction impairs the thymic microenvironment's ability to nurture thymocytes, leading to diminished T-cell output over time. A key driver is the age-dependent decline in expression of the transcription factor Foxn1, which is critical for TEC differentiation and maintenance; reduced Foxn1 levels accelerate TEC deterioration and contribute to the onset of involution.^[13] Parallel to TEC loss, the thymic stroma undergoes adipogenesis and epithelial-mesenchymal transition (EMT), where functional epithelial tissue is replaced by adipose tissue. This process is mediated by suppression of Wnt signaling pathways, which normally inhibit fat accumulation,^[14] coupled with upregulated activity of peroxisome proliferator-activated receptor gamma (PPARγ), promoting adipocyte differentiation in the thymic niche.^[15] Hormonal changes significantly influence these cellular dynamics. Post-puberty elevations in sex steroids, such as androgens and estrogens, directly inhibit TEC proliferation and induce thymic atrophy by altering epithelial cell signaling and survival. Concurrently, the age-related decline in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) exacerbates this atrophy, as these factors are necessary for maintaining thymic structure and function; their reduction disrupts anabolic processes in TECs. Oxidative stress further accelerates involution through the accumulation of reactive oxygen species (ROS), which trigger cellular senescence in TECs via p16^INK4a-mediated pathways, leading to irreversible cell cycle arrest and functional decline. Additionally, microRNAs such as miR-181a-5p play a regulatory role by modulating TEC proliferation and survival; its dysregulation in aged TECs interferes with signaling cascades like TGF-β, promoting thymic demise.^[1] Genetic factors underpin these mechanisms, including the progressive decline in E2F3 transcription factor activity, which regulates cell cycle genes in TECs and whose downregulation during early involution reduces proliferative capacity. Dysregulation of the mTORC1/TSC1 pathway also contributes, as TSC1-dependent inhibition of mTORC1 is required for TEC survival and homeostasis; age-associated perturbations lead to apoptosis and stromal disruption. Gender differences modulate the pace of these processes, with males experiencing faster involution due to heightened androgen sensitivity in TECs.^[16] Recent studies (as of 2024) highlight age-related defects in thymic epithelial cells that further limit organ function and regenerative capacity after injury.^[11]

Stress-Induced Mechanisms

Stress-induced thymic involution represents an acute, adaptive response to environmental pressures, characterized by rapid thymic atrophy that is typically reversible upon stressor removal. This process contrasts with chronic age-related changes by engaging fast-acting pathways that prioritize short-term immune modulation over long-term structural decline. External stressors such as psychological strain, infection, or therapeutic interventions trigger these mechanisms, resulting in pronounced reductions in thymic cellularity and output of naive T cells. A primary pathway involves glucocorticoid-mediated apoptosis, where stress hormones like cortisol (or corticosterone in rodents) bind to glucocorticoid receptors predominantly expressed on double-positive (CD4+CD8+) thymocytes in the thymic cortex. This binding activates pro-apoptotic signaling, leading to substantial apoptosis in double-positive cortical thymocytes, with up to 90% cell death within 48-72 hours of acute stress exposure.^[17]^[18] The selective targeting of these immature cells minimizes peripheral immune disruption while temporarily halting T-cell production, as evidenced in models of restraint stress where endogenous glucocorticoid elevation directly correlates with thymic weight loss and apoptosis.^[19] Cytokine storms further exacerbate involution by promoting damage to thymic epithelial cells (TECs) and inhibiting lymphopoiesis. Pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), released during infections or systemic inflammation, induce TEC apoptosis and disrupt the thymic stromal architecture essential for T-cell maturation.^[20]^[9] More recently, interleukin-33 (IL-33) has been implicated in accelerating naive T-cell dysfunction akin to aging phenotypes, with elevated IL-33 levels during severe infections driving thymic atrophy and impaired host defense through altered gene expression in recent thymic emigrants.^[21] Chemotherapy agents, such as cyclophosphamide, contribute to stress-induced involution by targeting rapidly dividing cells, including double-positive thymocytes and autoimmune regulator (AIRE)-expressing medullary TECs (mTECs). This leads to acute depletion of thymic cellularity and disruption of negative selection, where self-reactive T cells are normally eliminated, potentially allowing escape of autoreactive clones during recovery.^[22] Full restoration of AIRE+ mTECs and thymic function typically requires 7-10 days post-treatment, highlighting the transient yet impactful nature of this atrophy.^[23] Infectious agents, including viruses like HIV, bacteria, and parasites, induce acute thymic involution (ATI) either through direct thymic invasion or indirect inflammatory cascades. Pathogens exploit ATI as a virulence strategy, reducing naive T-cell output and impairing adaptive immunity; for instance, HIV targets thymic progenitors, while protozoan parasites like Toxoplasma gondii destroy thymic epithelium via cytokine-mediated mechanisms.^[24]^[9] This pathological form of ATI is classified as an acute type, distinct from gradual age-related processes.^[25] Reversibility of stress-induced involution relies on transient upregulation of the transcription factor FOXN1 in TECs, which drives regeneration of the thymic stroma and resumption of T-cell production without the permanent epigenetic alterations seen in aging. Unlike age-related involution, this recovery can restore near-normal thymic architecture within weeks, supported by progenitor cell proliferation and reduced apoptosis upon stressor cessation.^[9]^[26]

Developmental Progression

Early Life Stages

In the neonatal period, the thymus undergoes rapid growth immediately following birth, expanding to support the establishment of a diverse naive T-cell repertoire essential for immune system priming against pathogens. This growth phase, which peaks in cellularity around 6 months of age, facilitates high output of naive T cells to populate peripheral lymphoid tissues and provide broad immune surveillance.^[27] Early signs of involution emerge as soon as the first year of life, characterized by an initial reduction in thymic epithelial cells (TECs), which begins to limit overall thymic function without yet substantially altering thymocyte subset proportions.^[28] During childhood and extending into puberty, the thymus continues to mature but experiences a progressive decline in the thymic index—a measure of thymic size relative to body weight—with reductions estimated at approximately 3% per year, leading to a 20-30% overall size decrease by age 10 based on autopsy studies. This early decline is influenced by maternal factors such as prenatal nutrition and exposures like acetate levels, as well as postnatal elements including breastfeeding duration and early environmental insults, which can modulate thymic development and function.^[1] Adipose tissue replacement remains minimal during this stage, distinguishing it from later adult involution, and the process maintains relatively stable proportions of developmental T-cell intermediates despite reduced total output.^[29] Mouse models provide valuable insights into these patterns, with thymic involution commencing at 4-6 weeks of age, paralleling the human timeline when adjusted for lifespan differences and enabling mechanistic research into early TEC dynamics.^[1] Human autopsy data corroborate a gradual size reduction in the first decade, with thymic volume decreasing from postnatal peaks without dramatic shifts in architecture until puberty accelerates the process.^[30] These early life stages are critical for generating a foundational T-cell repertoire diversity that largely persists into adulthood, as the thymus establishes central tolerance and naive T-cell pools before involution curtails further production.^[7]

Adulthood and Senescence

Following puberty, thymic involution accelerates, with the organ shrinking at a rate of approximately 3% of its mass per year in humans until middle age, after which the decline slows to about 1% annually.^[7] This progressive loss involves a marked reduction in thymic epithelial cells and overall cellularity, leading to substantial replacement by adipose tissue. By age 60, functional thymic tissue constitutes less than 10% of its youthful volume, predominantly infiltrated by fat, which further impairs T-cell production.^[1] In the senescent phase, typically beyond 70 years, the thymus undergoes near-complete atrophy, resulting in thymic output of naïve T cells dropping to less than 1% of levels observed in youth.^[31] This severe functional decline correlates with inflammaging, a state of chronic low-grade systemic inflammation driven by accumulated proinflammatory signals in the thymic microenvironment.^[32] The process exacerbates immune dysregulation, as the diminished production of new T cells limits the diversity and responsiveness of the adaptive immune system. In mice, caloric restriction implemented from early adulthood delays age-related involution by inhibiting thymic adipogenesis and preserving epithelial integrity, thereby extending functional thymic output by up to several months compared to ad libitum-fed controls.^[15] A key biomarker of this progressive loss is the decline in recent thymic emigrants (RTEs), quantified through T-cell receptor excision circles (TREC) levels in peripheral blood, which decrease exponentially from adulthood onward, reflecting reduced thymic export of naïve T cells.^[33] TREC concentrations, often exceeding 10,000 copies per million T cells in youth, fall to below 1,000 in senescence, providing a direct measure of thymic output impairment.^[31]

Consequences

Immune System Impacts

Thymic involution significantly impairs T-cell mediated immunity by reducing the production of naive T cells, leading to a decline in thymopoiesis and the formation of oligoclonal T-cell pools with limited diversity. This process results in a marked decrease in recent thymic emigrants (RTEs), shifting the peripheral T-cell compartment toward a memory-biased population that exhibits elevated exhaustion markers, such as PD-1 and Tim-3 expression, and diminished responses to novel antigens. Quantitatively, T-cell receptor excision circle (TREC) levels, a marker of thymic output, fall approximately 100-fold by age 60, reflecting a profound reduction in naive T-cell generation.^[31]^[34]^[35] The loss of medullary thymic epithelial cells (mTECs) during involution further disrupts central tolerance by diminishing AIRE-mediated expression of tissue-specific antigens, which impairs negative selection and allows autoreactive T cells to escape into the periphery. This defective clonal deletion increases the output of self-reactive T cells, contributing to a breakdown in immune self-tolerance. In the periphery, the decreased influx of RTEs exacerbates this issue, promoting chronic T-cell activation and oligoclonal expansions that limit the adaptive immune repertoire's ability to mount effective responses.^[36]^[34] Thymic atrophy intersects with inflammaging, where reduced thymic output contributes to the accumulation of senescent cells that secrete pro-inflammatory cytokines like IL-6 and TNF-α, thereby linking involution to broader immunosenescence. Overall, thymic output significantly declines by middle age, correlating with increased susceptibility to varicella-zoster virus reactivation due to weakened T-cell mediated control of latent infections. These impacts collectively diminish immune surveillance and adaptability, underscoring involution's role in age-related immune decline.^[34]^[37]

Health Implications

Thymic involution contributes to increased susceptibility to infections in the elderly by reducing T-cell diversity, thereby heightening risks for pathogens such as cytomegalovirus (CMV) and influenza.^[38]^[39] This diminished naive T-cell output exacerbates age-related immune decline, leading to higher morbidity and mortality rates from infectious diseases, with thymic function failure serving as an independent predictor of mortality in older adults.^[40] For instance, CMV infection accelerates immune aging and is associated with elevated mortality in the elderly population.^[41] Impaired thymic tolerance due to involution is linked to the development of late-onset autoimmune diseases, including rheumatoid arthritis and type 1 diabetes, where defective negative selection of autoreactive T cells promotes self-reactivity.^[42]^[43] In rheumatoid arthritis, incomplete thymic involution correlates with persistent thymic activity that may sustain autoimmune responses.^[44] Similarly, disruptions in thymic expression of self-antigens like insulin contribute to autoreactive T-cell escape in type 1 diabetes.^[45] Regarding cancer, chemotherapy-induced acute thymic involution raises the risk of second primary malignancies by compromising immune surveillance; epidemiologic data indicate a cumulative incidence of approximately 6.8% for second primary malignancies over 30 years post-diagnosis in pediatric cancer survivors.^[46] The decline in naive T-cell production from thymic involution also underlies reduced vaccine efficacy in aged populations, with poor T-cell responses leading to 40-60% lower antibody titers following vaccination compared to younger individuals.^[47] This manifests as suboptimal protection against preventable diseases like influenza, where immunosenescence limits the generation of effective humoral immunity.^[48] In the context of chemotherapy, acute thymic involution delays T-cell reconstitution for months post-treatment, prolonging immunosuppression and increasing vulnerability to opportunistic infections.^[49] Recent research highlights IL-33-driven thymic involution as a mechanism linking severe infections to accelerated T-cell aging, where elevated IL-33 during post-infection states induces naive T-cell dysfunction and senescence-like phenotypes, further impairing host defense.^[21] Recent studies also link thymic involution to impaired thymic regeneration following acute injuries and heightened severity of infections like COVID-19 in the elderly.^[11]^[50] This process underscores the broader clinical burden of thymic involution in amplifying disease risks across infectious, autoimmune, and oncologic contexts.

Evolutionary Perspectives

Selective Pressures

One prominent evolutionary hypothesis for the persistence of thymic involution is the trade-off theory, which posits that the process reallocates metabolic resources from the energy-demanding maintenance of thymic function and T-cell production to reproductive efforts following puberty. This reallocation would have conferred a fitness advantage in ancestral environments characterized by high extrinsic mortality from infections, predation, and resource scarcity, where early reproduction maximized lifetime reproductive success despite later immune compromise. Mathematical modeling supports this view by linking the exponential decline in thymic output to increased disease incidence with age, aligning the timing of involution with peak reproductive years in short-lived populations. Experimental evidence from prepubertal gonad manipulation in fish models further indicates that investments in gonadal development directly modulate thymic size and function via energetic trade-offs, suggesting a conserved mechanism across vertebrates.^[51] Pathogen-driven selection may also favor acute thymic involution as a rapid adaptive response to infection, temporarily suppressing excessive T-cell activation and cytokine storms to mitigate immunopathology and improve short-term survival. Recent computational models demonstrate that scheduling thymic contraction during acute pathogen exposure optimizes immune resource allocation, favoring innate responses over adaptive ones when inflammation could otherwise be lethal, especially against diverse microbial threats prevalent in evolutionary history.^[52] Evidence from animal models underscores the balancing act of these pressures; for instance, genetic knockouts or transgenes that delay involution, such as Foxn1 overexpression in mice, enhance T-cell output and extend markers of immune vigor into later life.^[53]^[54] This suggests stabilizing selection maintaining involution as an equilibrium between immune longevity and other vulnerabilities. However, the adaptive nature of thymic involution remains debated, with some researchers viewing it primarily as a maladaptive consequence of aging processes rather than a directly selected trait.

Comparative Aspects

Thymic involution is a conserved process across mammalian species, characterized by age-related atrophy of the thymus gland, though the timing and pace vary significantly. In mice, involution begins as early as 4–6 weeks of age, with substantial reduction in thymic cellularity by 9 months, reflecting a rapid progression relative to their short lifespan.^[1] In contrast, humans exhibit a slower trajectory, with initial signs appearing around 1 year of age and gradual decline over decades, marked by an exponential reduction in T-cell production with a half-life of approximately 16 years.^[1]^[55] This universal pattern in mammals, observed from rodents to primates and including species like sheep, underscores a shared evolutionary feature despite differences in longevity and metabolic rates.^[56] Exceptions among long-lived mammals highlight divergent adaptations that mitigate involution. Naked mole rats (Heterocephalus glaber), known for their exceptional longevity and cancer resistance, display no significant thymic atrophy up to 11 years of age—roughly midlife for this species—and possess additional ectopic cervical thymi alongside the primary mediastinal thymus, supporting prolonged thymopoiesis.^[57] This extended thymic function correlates with maintained T-cell output, potentially contributing to their robust immune surveillance and low cancer incidence.^[58] Such features suggest that in species with enhanced longevity, evolutionary pressures may favor delayed involution to sustain adaptive immunity against chronic threats. In non-mammalian vertebrates, thymic involution is notably less pronounced, indicating mammalian-specific evolutionary pressures. Birds exhibit variable thymic regression among species, but generally lack complete involution prior to puberty, with only slight age-related changes that permit lifelong T-cell production.^[59] Similarly, reptiles such as lizards and snakes show minimal permanent atrophy; in temperate species, any involution is often seasonal and reversible, allowing reconstitution of T-cell populations upon environmental shifts, as seen in hibernation-like states.^[60]^[61] These patterns contrast with the irreversible adipose replacement in mammalian thymic tissue, implying that the pronounced involution in mammals may relate to unique life history traits like extended post-reproductive lifespan and increased pathogen exposure in social groups.^[59] Experimental interventions reveal conserved metabolic pathways influencing involution across species. Caloric restriction (CR), a 30–40% reduction in energy intake, delays thymic atrophy in rodents by preserving thymic epithelial integrity and enhancing T-cell output, as demonstrated in mice where CR prevents premature decline in thymopoiesis.^[62] This effect extends to nonhuman primates, such as rhesus monkeys, where long-term CR attenuates immune senescence markers, including reduced terminal differentiation of T cells and sustained thymic function, suggesting shared nutrient-sensing mechanisms like those involving IGF-1 and mTOR pathways.^[63]^[64] These findings imply evolutionary conservation of metabolic links to thymic maintenance, applicable from short-lived rodents to longer-lived primates. For research purposes, rodent models, particularly mice, facilitate rapid investigation of involution due to their accelerated timeline—completing significant atrophy within months—yet this overestimates the pace compared to humans, where functional decline spans 50–60 years from peak output.^[2]^[55] While mouse systems excel in dissecting molecular events, such as Foxn1 downregulation, interspecies differences necessitate validation in primates or humanized models to translate findings accurately to the protracted human context.^[1] This comparative lens underscores selective trade-offs in thymic function, as explored in evolutionary analyses.

Interventions

Regeneration Strategies

Growth factors have emerged as key agents in preclinical models of thymic regeneration, targeting thymic epithelial cells (TECs) to counteract involution. Keratinocyte growth factor (KGF, also known as FGF7) promotes the proliferation of TECs and reduces their apoptosis, thereby enhancing postnatal T-cell development and supporting thymic architecture in aged or stressed models.^[65] Similarly, interleukin-22 (IL-22) facilitates the recovery of medullary TECs (mTECs) following stress-induced damage, driving endogenous thymic regeneration through pathways that preserve TEC survival and function after depletion of double-positive thymocytes.^[66] Hormonal modulation via sex steroid ablation represents another preclinical strategy to reverse thymic involution. Administration of luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide (Lupron), induces chemical castration that temporarily restores thymic size and cellularity in aged mice, with histological evidence of regenerated cortical and medullary compartments observed within months of treatment.^[67] This approach yields partial reversal of age-related atrophy through enhanced thymopoiesis and reduced stromal disruption.^[68] Genetic approaches focus on rejuvenating TECs by targeting key regulatory genes. Overexpression of the transcription factor Foxn1 via gene therapy in aged mice promotes the differentiation and proliferation of TEC progenitors, leading to substantial regrowth of thymic architecture and improved T-cell production in both sexes.^[69] Pharmacological interventions offer non-invasive options to stimulate thymopoiesis and delay atrophy. Analogs of ghrelin and leptin, which act through opposing yet complementary pathways, enhance thymic cellularity and architecture in aged mice, with ghrelin infusions increasing recent thymic emigrant output and leptin boosting progenitor expansion selectively in older models.^[70] mTOR inhibitors like rapamycin also show promise in preclinical settings by delaying age-related thymic atrophy through modulation of TEC metabolism and survival, although chronic dosing requires careful titration to avoid transient involution.^[71] Stem cell therapies, particularly mesenchymal stem cell (MSC) infusions, have demonstrated regenerative potential in aged animal models by reconstituting the thymic stroma. Intravenous administration of bone marrow-derived MSCs in senescent mice or nonhuman primates promotes TEC recovery and stromal remodeling, resulting in increased naive T-cell output and partial restoration of thymic function through paracrine effects on the microenvironment.^[72]

Therapeutic Applications

Therapeutic applications of thymic regeneration strategies aim to restore T-cell production in clinical settings where thymic involution exacerbates immune deficiencies, such as post-chemotherapy lymphopenia, age-related immunosenescence, and infection-triggered autoimmunity. In cancer therapy, recombinant interleukin-7 (IL-7, e.g., CYT107) has been investigated as an adjunct to accelerate T-cell reconstitution following chemotherapy-induced lymphopenia. A randomized, double-blind, placebo-controlled trial in critically ill patients with sepsis (a model relevant to post-chemotherapy immunosuppression) demonstrated that IL-7 administration increased CD4+ and CD8+ T-cell counts while decreasing secondary hospital-acquired infections by over 40% compared to placebo, thereby mitigating infection risks associated with thymic dysfunction.^[73] Similarly, in metastatic breast cancer patients, pre-chemotherapy IL-7 dosing enhanced naïve and memory T-cell subsets by up to 148% for CD4+ cells, with no reported febrile neutropenia or severe hematological toxicities during treatment.^[74] For aging interventions, keratinocyte growth factor (KGF, or palifermin) has shown promise based on preclinical data and trials in transplant settings to support thymic recovery, potentially improving vaccine responses. Administration of recombinant KGF promotes thymic epithelial cell proliferation and naïve T-cell output, with preclinical data indicating sustained thymopoiesis in aged models that could enhance immune responses to vaccines.^[75] Human trials, such as NCT01233921, evaluated KGF's pharmacodynamics on thymic recovery post-stem cell transplantation in adults, including older patients, supporting its role in countering thymic dysfunction in such contexts.^[76] In autoimmunity management, targeting IL-33 signaling has emerged as a strategy to prevent infection-induced thymic involution and associated T-cell aging. A 2022 study revealed that IL-33 drives medullary thymic epithelial cell overproduction, leading to naïve T-cell dysfunction and impaired infection control, with implications for autoimmune exacerbation during severe infections like sepsis.^[77] Blocking IL-33 or its receptor ST2 restored thymic balance and T-cell function in models, suggesting therapeutic inhibition could mitigate post-infection autoimmunity by preserving thymic output and preventing premature T-cell senescence. Despite these advances, challenges persist in translating thymic regeneration therapies to the clinic, including off-target effects and ethical considerations. KGF, while effective for epithelial regeneration, can promote tumor growth in epithelial cancers by enhancing proliferation and inhibiting apoptosis, necessitating careful patient selection to avoid exacerbating malignancies.^[78] In pediatric applications for congenital immunodeficiencies like athymia, ethical issues arise around informed consent in vulnerable populations, equitable access to experimental therapies such as thymus transplantation, and the limits of commercializing pediatric research products.^[79] Looking to the future, combination therapies integrating stem cells with growth factors are under investigation in ongoing clinical trials to enhance thymic regeneration efficacy. For instance, protocols combining hematopoietic stem cell transplantation with factors like IL-7 or KGF aim to synergistically restore thymic stroma and T-cell production, as explored in expanded pilot studies like TRIIM-X.^[80] Recent preclinical advances as of 2025 include exogenous RANKL administration to reinvigorate thymic function and improve T-cell immunity during aging, as well as the role of recirculating regulatory T cells in mediating regeneration through amphiregulin following damage.^[81]^[82] Additionally, induced pluripotent stem (iPS) cell-derived models for human thymus organogenesis offer new platforms for studying and potentially generating thymic tissue.^[83] Monitoring efficacy relies on biomarkers such as T-cell receptor excision circles (TRECs), which quantify recent thymic emigrants and provide a direct measure of thymic output in response to interventions.^[84] These multimodal approaches, supported by preclinical evidence of improved immune reconstitution, offer promising directions for addressing thymic involution in diverse clinical contexts.^[85]

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Nov 24, 2021 · Thymic adipogenesis is recognized as a notable feature of thymic involution. The thymic stromal space shrinks to be replaced by adipose tissue ...<|control11|><|separator|>
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IL-33 induces thymic involution-associated naive T cell aging and ...
Nov 12, 2022 · Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant ...
[22]
A Proposed Link Between Acute Thymic Involution and Late ...
Jul 1, 2022 · Acute thymic involution as a result of cytoreductive chemotherapy leads to delayed recovery of T cells, with imminent consequences in the ...
[23]
(PDF) Ablation and Regeneration of Tolerance-Inducing Medullary ...
Cyclophosphamide and dexamethasone caused more extensive ablation of thymocytes and stromal cells but again severely depleted tolerance-inducing mTEC(high).
[24]
Infection-Associated Thymic Atrophy - PMC - PubMed Central
Thymic atrophy occurs with age (physiological thymic atrophy) or as a result of viral, bacterial, parasitic or fungal infection (pathological thymic atrophy).
[25]
The Thymus Is a Common Target Organ in Infectious Diseases
Jun 30, 2006 · A variety of infectious agents—including viruses, protozoa, and fungi—invade the thymus, raising the hypothesis of the generation of central ...
[26]
Postnatal Involution and Counter-Involution of the Thymus - PMC
May 12, 2020 · Stressed-induced thymic involution results in decreased naïve T cell output and ... Foxn1 expression and age-associated thymic involution. It has ...
[27]
Conventional and Computational Flow Cytometry Analyses Reveal ...
Aug 3, 2020 · Our work shows that the early phase of human thymic involution mainly limits the overall T cell output since no obvious changes in thymocyte subsets could be ...
[28]
Thymus Size and Age-related Thymic Involution - PubMed Central
Age-related thymic involution is characterized by a progressive regression in thymus size and a diminishment of thymic structure.Missing: definition | Show results with:definition
[29]
Evaluation of age-related thymic changes using computed ... - NIH
Aug 12, 2022 · The CT attenuation values were stable from birth to puberty, decreased after puberty, and were stable again in the late 50s and beyond. The ...
[30]
The involution of the ageing human thymic epithelium is ... - PubMed
This begins in the first year of life, reaches a maximum from 10 to 25 years, then declines again. Adipose tissue replaces the lymphocytic perivascular space ...
[31]
Measuring thymic output across the human lifespan
Feb 13, 2025 · During adulthood, thymic involution continues at a slower rate, maintaining a low but relatively stable T cell output. However, by middle ...
[32]
Contributions of Age-Related Thymic Involution to ... - PubMed Central
Jan 20, 2020 · Age-related thymic involution is characterized by a reduction in thymic size and thymocyte numbers as well as overt remodeling of the thymic ...
[33]
Immune Profile Predicts Survival and Reflects Senescence in a ...
Sep 25, 2014 · Here, we tested if age and survival, two aspects associated with longevity, are linked to immune parameters in an 8 g bat species.Missing: delayed | Show results with:delayed
[34]
Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an ...
Oct 3, 2022 · TRECs are an established proxy for thymic output, which is reduced following thymic involution and is reflected by decreases in new thymic ...
[35]
Contributions of Age-Related Thymic Involution to ...
Jan 20, 2020 · Effects of castration on thymocyte development in two different models of thymic involution. J Immunol. 2005;175(5):2982–93. Article CAS ...Missing: phase | Show results with:phase<|separator|>
[36]
Diversity and clonal selection in the human T-cell repertoire - PNAS
A decline in the diversity of the T-cell receptor repertoire owing to thymic involution has been implicated as causing defective immune responses in the ...
[37]
Thymic Involution Perturbs Negative Selection Leading to ...
Thymic involution results in the release of autoreactive T cells that become activated shortly after reaching the periphery and produce low levels of ...Thymic Involution Perturbs... · Thymic Involution Results In... · Thymic Involution Does Not...<|control11|><|separator|>
[38]
Primary immune responses are negatively impacted by persistent ...
In this model of T-cell ageing independent of chronological age, the combination of reduced thymic output (i.e. due to thymectomy) and chronic immune activation ...
[39]
Impact of Aging and Cytomegalovirus on Immunological Response ...
Jul 17, 2017 · This review focuses on the impact of aging and CMV on immune cell function, the response to influenza infection and vaccination.
[40]
Why the elderly appear to be more severely affected by COVID‐19 ...
Jul 15, 2020 · CMV has been shown to accelerate immune ageing by affecting peripheral blood T cell phenotypes and increasing inflammatory mediated cytokines ...
[41]
Thymic function and survival at advance ages in nursing home ...
Apr 10, 2023 · Thymic function failure is an independent predictor of mortality among elderly nursing home residents. sjTREC represents a biomarker of effective ageing.
[42]
Cytomegalovirus infection is associated with increased mortality in ...
Aug 7, 2025 · High CMV antibody titer in the elderly has been linked to increased mortality ... influenza vaccination in the elderly. Article. Jul 2008.
[43]
Immune tolerance and the prevention of autoimmune diseases ...
Mar 20, 2024 · This review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic ...
[44]
Review Modeling human T1D-associated autoimmune processes
Here, we review the gaps filled by these models in understanding the intricate involvement and regulation of the immune system in human T1D pathogenesis.
[45]
Incomplete thymic involution in systemic sclerosis and rheumatoid ...
The aim of this study was to evaluate the prevalence and correlates of radiological incomplete involution of the thymus in SSc and RA patients.Original Article · Abstract · IntroductionMissing: cancer | Show results with:cancer
[46]
Beyond the Hormone: Insulin as an Autoimmune Target in Type 1 ...
Insulin is not only the hormone produced by pancreatic β-cells but also a key target antigen of the autoimmune islet destruction leading to type 1 diabetes.<|separator|>
[47]
A Proposed Link Between Acute Thymic Involution and Late ...
Epidemiologic data suggest that cancer survivors tend to develop a protuberant number of ad-verse late effects, including second primary malignancies (SPM), ...
[48]
lessons learned from mouse models of aging - PMC - PubMed Central
This review describes key findings regarding age-related defects in T-cell function and discusses the impact these defects have on vaccine efficacy and ...Missing: titers | Show results with:titers
[49]
Insights into vaccines for elderly individuals: from the impacts of ...
Apr 10, 2024 · There is a loss of naïve T cells in elderly individuals caused by thymic involution. ... to direct immune-polarization and vaccine efficacy ...
[50]
Prepubertal gonad investment modulates thymus function
Mar 31, 2021 · This observation suggests that the reproduction-related changes in the thymus result from an energy trade-off with the reproductive system, as ...
[51]
Overexpression of Foxn1 attenuates age-associated thymic ... - NIH
Our data indicate that manipulation of Foxn1 expression in the thymus ameliorates thymopoiesis in aged mice and offer a strategy to combat the age-associated ...
[52]
FOXN1 compound heterozygous mutations cause selective thymic ...
Sep 30, 2019 · In mouse models, hypomorphic mutations in murine Foxn1 result in thymic involution as the mice age, contributing to reduced T cell output (42, ...
[53]
Thymic involution and rising disease incidence with age - PNAS
Feb 5, 2018 · This framework provides mechanistic insight into cancer emergence, suggesting that age-related decline in T cell output is a major risk factor.
[54]
Why does the thymus involute? A selection-based hypothesis
This phenomenon – known as 'thymic involution' – occurs in many mammalian species, from sheep [9] to mice [10] to humans 6, 7, but as yet has no satisfactory ...
[55]
Ectopic cervical thymi and no thymic involution until midlife in naked ...
Oct 1, 2021 · We show that naked mole rats display no thymic involution up to 11 years of age. Furthermore, we found large ectopic cervical thymi in addition to the ...
[56]
Evolution of T cells in the cancer-resistant naked mole-rat - Nature
Apr 11, 2024 · Ectopic cervical thymi and no thymic involution until midlife in naked mole rats. Aging Cell 20, e13477 (2021). Article CAS PubMed PubMed ...
[57]
Why Does the Thymus Involute? - jstor
There are no birds, reptiles, amphi- bians or chondrichthyans that are known to show complete involution before puberty, and involution is generally slight ...
[58]
Lizard and Snake Immune System - WikiVet English
In temperate species thymic involution and splenic follicle regression occur seasonally. Antibody production is temperature dependent. The immune system ...
[59]
Understanding the vertebrate immune system: insights from the ...
Mar 1, 2010 · Hibernating mammals also show thymic involution in the winter, and thus both reptiles and hibernating mammals must reconstitute their T cell ...Lymphoid tissues · Innate immunity · Cell-mediated immunity · Humoral immunity
[60]
and diet-associated changes in murine thymus - ScienceDirect
Interestingly, many changes associated with thymic aging are either muted or almost completely reversed in mice on caloric-restricted diets. These studies ...
[61]
Immune senescence in aged nonhuman primates - PMC
Most of our current understanding of immune senescence stems from clinical and rodent studies. More recently, the use of nonhuman primates (NHPs) to investigate ...
[62]
Calorie Restriction Attenuates Terminal Differentiation of Immune Cells
Jan 12, 2017 · ... delayed in calorie-restricted (CR) mice. ... Weindruch R. The retardation of aging by caloric restriction: studies in rodents and primates.
[63]
Keratinocyte growth factor (KGF) enhances postnatal T-cell ... - NIH
Here, we report that KGF induces in vivo a transient expansion of both mature and immature thymic epithelial cells (TECs) and promotes the differentiation of ...
[64]
Interleukin-22 drives endogenous thymic regeneration in mice - NIH
Here we detail a framework of thymic regeneration centred on IL-22 and triggered by depletion of CD4+CD8+ double positive (DP) thymocytes.
[65]
Reversal of Age-related Thymic Involution by an LHRH Agonist in ...
Testosterone levels were still low at 6 months after injection when TREC levels returned to baseline, suggesting that LHRH agonist had a direct effect on thymus ...
[66]
The role of sex steroids and gonadectomy in the control of thymic ...
This review will examine the endocrinology of thymic atrophy—the impact of sex steroids on the immune system and the use of gonadectomy to enhance immune ...Missing: TEC | Show results with:TEC
[67]
The Molecular Balancing Act of p16INK4a in Cancer and Aging - NIH
Long term p16INK4a expression pushes cells to enter senescence, an irreversible cell cycle arrest that prevents the growth of would-be cancer cells, but also ...Missing: CRISPR | Show results with:CRISPR
[68]
Ghrelin promotes thymopoiesis during aging - PMC - PubMed Central
Ghrelin's regulatory counterpart, leptin, enhances thymopoiesis in aged, but not young, mice. We have previously demonstrated that, similar to their opposing ...Missing: analogs | Show results with:analogs
[69]
Metabolic Regulation of Thymic Epithelial Cell Function - Frontiers
Mar 2, 2021 · In this review, we will consider the integration of three aspects of metabolic regulation: mTOR signaling, the redox status of the cell, and autophagy.
[70]
Bone marrow mesenchymal stem cells improve thymus and spleen ...
Jun 19, 2020 · BMSCs can be used as seed cells for cell therapy because of homing to damaged tissues, repairing tissues and regulating immune system [5, 6].Missing: output | Show results with:output
[71]
Manu Shankar-Hari et al. - Insight.Jci.org
Feb 4, 2025 · IL-7 is a lymphocyte growth factor that has unfailingly been demonstrated to cause a dose-dependent increase in CD4 and CD8 T cells in numerous ...
[72]
https://www.aging-us.com/article/103186/text
[73]
Thymic Rejuvenation and Aging - PMC - NIH
Jul 4, 2013 · Thymic function gradually starts to decrease from the first year of life [4]. With age there is an expansion of the perivascular space and a ...
[74]
IL-33 induces thymic involution-associated naive T cell aging and ...
Nov 12, 2022 · We demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging- ...Missing: cytokine storms TNF-
[75]
Keratinocyte Growth Factor Expression and Activity in Cancer
Jun 21, 2006 · Thus, it is possible that KGF treatment might result in enhanced growth or metastasis of epithelial tumors. Furthermore, in addition to having ...Keratinocyte Growth Factor... · Fgf S Ignalingin C Ancer · E Xpression Of Kgf And I Ts...
[76]
Thymus Regeneration and Future Challenges - PMC
Jan 29, 2020 · These mesenchymal cells might be important to the maintenance of the thymic microenvironment since it is already known that mesenchymal ...
[77]
Thymus Regeneration, Immunorestoration, and Insulin Mitigation ...
The TRIIM-X trial is an expanded pilot clinical study that will evaluate a personalized combination treatment regimen for thymus regeneration.Missing: KGF enhancement
[78]
T cell receptor excision circles as a tool for evaluating thymic ...
Jun 19, 2019 · In clinical practice, T cell receptor excision circles (TRECs) are considered a direct and reliable measure of the thymic function.
[79]
Strategies for thymus regeneration and generating thymic organoids
This review describes several strategies to treat thymic impairment, including endogenous regeneration by growth factor administration, cellular and stem cell ...