A researcher's guide to studying sex differences in immune aging.

Mice are widely used as models for studying immune system aging due to their biological and physiological similarities with humans. Both species experience immune system aging, characterized by immunosenescence and “inflammaging” ( Box 3 )[ 7 ], as well as age-related changes in glucose metabolism and energy balance[ 18 ]. Although there are differences in lifespan patterns between the two species – for example, human females consistently outlive males across populations, whereas sex-differences in lifespan are less robust in mice and vary significantly by strain[ 19 ] – the fundamental drivers of sex-differences in immune aging can still be effectively modeled in animals. In this section, we discuss the naturally aged intact mouse model and other complementary models that address its limitations, aiming to provide researchers with practical guide to the available tools for studying sex-differences in immune system aging. Naturally aged ‘intact’ mice, which preserves the unmanipulated aging process, provides a critical baseline for comparing aging mechanisms between humans and mice and for studying how sex-differences influence these processes[ 20 ]. However, important limitations exist. For example, while women experience an abrupt loss of estrogen production during menopause, female mice undergo a more gradual hormonal decline without a distinct menopausal transition[ 21 ]. Moreover, the intricate nuances of estrogen’s long-term effects on immune cells, including potential epigenetic modifications induced during puberty and reproductive years, complicate the study of menopause and its impact on immune aging[ 22 ]. These complexities highlight the challenges in fully modeling menopause in mice and emphasize the need for careful interpretation when comparing findings across species. Despite these differences, naturally aged intact mice share many similarities with humans in immune aging, making them a valuable model. Both species possess similar immune cells, including T cells, B cells, macrophages, neutrophils, dendritic cells, and NK cells, which perform analogous functions[ 23 ]. In adaptive immunity, aged mice, like humans, exhibit a decline in T cell function, including reduced proliferation and T cell receptor repertoire diversity, consistent with T cell immunosenescence[ 24 ]. Both species experience a decrease in naive T cells and an accumulation of memory T cells[ 24 ], alongside diminished B cell function and impaired antibody responses[ 25 ]. On the innate side, macrophages and neutrophils in aging mice and humans exhibit decreased phagocytic activity and impaired pathogen clearance[ 26 , 27 ]. Aging also affects dendritic cells in both species, reducing their ability to process and present antigens effectively, which compromises the initiation of adaptive immune responses[ 28 ]. Furthermore, NK cells in both mice and humans show a decline in cytotoxic activity with age, reducing their effectiveness in targeting infected or transformed cells[ 29 ]. These similarities make mice an invaluable model for understanding the mechanisms of immune aging. Research into sex-differences in immune system aging using naturally aged intact mice has historically been limited. However, recent studies have begun to explore the impact of sex on immune system aging using mouse models[ 30 – 35 ]. For instance, longitudinal studies have shown that, aging males mice exhibit higher percentages of neutrophils and Ly6C high classical monocytes, while female mice have more T cells (both CD4 + and CD8 + subsets), eosinophils and NK cells[ 34 ]. Additionally, female mice exhibited greater immune decline after vaccination with a universal influenza vaccine[ 35 ]. Sex-differences extend to innate immunity. For example, female mice neutrophils have been shown to significantly increase in NETosis induction capabilities with age, whereas male neutrophils exhibited no change[ 30 ]. Aged female mice microglia exhibited a more pronounced AKT-mTOR-HIF1α-driven shift to glycolysis[ 31 ]. Consistently, C3a production and detection were also elevated in aged female vs. male mice microglia[ 31 ]. In the aging mouse hippocampus, female microglia were more likely than male microglia to adopt disease-associated and senescent phenotypes, even in the absence of pathology[ 32 ]. Lastly, a recent study discovered that aging in both male and female mice led to increased expression of dendritic cell-like monocyte signature genes and MHCII, and CD74 proteins in classical monocytes[ 33 ]. Together, these findings emphasize the importance of considering sex as a biological variable in immune aging research and highlight the utility of naturally aged intact mice for uncovering these differences. While naturally aged intact mice provide critical baseline data, they have limitations. Additionally, naturally aged intact mice are limited in their ability to address certain mechanistic questions, such as disentangling the effects of hormonal vs . chromosomal influences on immune system aging – an area where other models can provide complementary insights ( Figure 2 ). In the following sections, we explore these alternative models, highlighting their development and utility in advancing our understanding of immune aging, particularly as it relates to sex-differences ( Table 1 ). Gonadectomy models in rodents are invaluable for exploring the role of gonadal hormones, if any, on lifelong and/or aging-specific sex-dimorphic phenotypes in the immune system. Ovariectomy (OVX) mouse model, in which ovaries are surgically removed, induces acute loss of estrogen and progesterone, enabling manipulation of estrogen and other ovarian hormones signaling to examine its physiological effects[ 36 ]. OVX offer the strength of consistent and reproducible reduction of circulating estrogens, but surgical stress or complications, which may influence immune responses, are a significant weakness[ 37 ]. Nevertheless, studies have demonstrated that both OVX in mice[ 38 ] and oophorectomy in humans[ 39 ] result in elevated levels of IL-6, a potent proinflammatory cytokine. These parallels underscore the translational relevance of OVX mouse models for studying the impact of oophorectomy on immune system aging. To assess the effects of androgen signaling, the most common surgical model is bilateral orchiectomy (ORX), removing both testes[ 40 ]. This surgery drastically reduces circulating androgen levels[ 40 ]. Since testes produce more than testosterone, including numerous paracrine and autocrine factors, replacing these components is crucial to pinpoint the specific influence of androgen signaling on immune system aging or other studied phenotypes[ 41 ]. As with OVX, ORX offers the strength of reliably reducing circulating androgens, but its weakness lies in the potential for surgical stress or complications. Androgens are known to have immunosuppressive effects, which can impact infection risk and immune responses. Interestingly, castration has been associated with improved lifespan and healthspan in both humans and mice[ 42 ]. These findings suggest a conserved role for androgen depletion in promoting health and longevity while highlighting the need to further investigate both the protective and immunosuppressive effects of androgens, particularly in the context of immune aging. Chemical and drug-based approaches provide versatile tools for exploring the role of sex hormones in immune system aging. By manipulating hormone production or signaling, these models allow researchers to investigate the contribution of estrogen, progesterone, and/or androgen signaling on sex-differences in the aging immune system. The VCD (4-vinylcyclohexene diepoxide) model mimics menopause-like conditions by selectively depleting primordial and primary ovarian follicles[ 43 ]. This progressive follicular depletion closely mirrors the gradual decline in ovarian function and estrogen production seen in human menopause[ 43 ]. While the VCD model effectively mirrors hormonal changes, its potential cytotoxic effects may introduce off-target effects on the immune system. VCD-induced ovarian failure in mice parallels findings in postmenopausal women, such as reduced populations of T regulatory cells[ 44 ]. Despite its limitations, the VCD model holds promise for investigating immune aging and translational research. Aromatase inhibitors (AI), such as anastrozole and letrozole, block the conversion of androgens to estrogens, reducing circulating estrogen levels without the confounding influence of surgery[ 45 ]. However, this approach has potential off-target effects on enzymes involved in steroidogenesis or other metabolic processes[ 46 ]. Since AIs block the conversion of androgens to estrogens, their administration leads to drastic reduction of estrogen levels in mice[ 47 ]. This reduction is accompanied by increased circulating androgen levels due to inhibited aromatase activity[ 47 ]. Thus, it represents an extreme model for hormonal changes observed after menopause, which could be initiated in middle-age for mice to mimic menopausal symptoms. Both in humans[ 48 ] and mouse models[ 49 ], AI treatment has been shown to increase inflammation markers (i.e. MCP-1 abundance and NFκB activity). AIs provide a useful model for studying estrogen depletion. Estrogen supplementation models are widely used to examine the effects of estrogen signaling[ 50 ], especially in contexts where endogenous estrogen production has waned ( i.e . aging, menopause). Estrogen supplementation mouse models closely mirror hormonal conditions observed in hormone supplementation therapy for menopausal women; however, potential inconsistencies in estrogen levels due to differences in metabolism and clearance rates among individual mice can complicate standardization and data interpretation[ 51 ]. Estrogen supplementation is usually paired with OVX, so as to precisely determine the impact of estrogen on sex-dimorphic processes (since the ovary also secretes progesterone and androgens)[ 50 ]. Notably, both estrogen supplementation in mice and hormone supplementation therapy in menopausal women lead to reduced IL-6 production[ 52 ]. Selective estrogen receptor modulators (SERMs) provide nuanced control of estrogen signaling by targeting specific estrogen receptor (ER) subtypes[ 53 ]. Different SERMs modulate specific estrogen receptors: tamoxifen primarily modulates ER alpha (ERα), raloxifene acts on both ERα and ER beta (ERβ), clomiphene also targets ERα and ERβ, and bazedoxifene selectively modulates ERα[ 53 ]. These SERMs can be used to study sex-differences in immune system aging by selectively modulating ER activity. Androgen supplementation can be an invaluable tool in biomedical research to facilitate precise investigation into the effects of androgens, such as testosterone, dihydrotestosterone (DHT), and dehydroepiandrosterone (DHEA)[ 54 ]. Androgen supplementation in both humans and mouse models increases neutrophil and monocyte numbers, making it a valuable model for studying the effect of testosterone therapy, which is used in human conditions such as hypogonadism, aging-related testosterone decline, and delayed puberty[ 55 ]. However, prolonged androgen use carries risks such as carcinogenesis[ 56 ], which can alter immune system function. Pharmacological interventions targeting androgen signaling, including antiandrogens (e.g., flutamide), 5α-reductase inhibitors (e.g., finasteride), and gonadotropin-releasing hormone agonists/antagonists (e.g., leuprolide), disrupt androgen production or receptor[ 57 ]. Androgen signaling modulation mouse models are powerful for studying both AR-independent and AR-dependent effects of androgens, but they may not uniformly block all androgen signaling actions across different tissues and cell types[ 58 ] which requires special consideration in immune-related studies. Genetic mouse models provide powerful tools to investigate the mechanisms driving sex-differences in immune system aging. These models allow researchers to manipulate sex chromosome complement, hormone receptor pathways, or hormone production to untangle the complex interplay between gonadal hormones and sex chromosomes. The Four Core Genotype (FCG) model is widely used to study the effect of sex chromosome complement in immunology and aging research[ 59 ]. This model involves the deletion of Sry from the Y chromosome and the insertion of an Sry transgene on chromosome 3 in a C57BL/6 background[ 60 ]. The FCG model produces four types of animals: (a) XX females with ovaries (XXO), (b) XY males with testes (XYT), (c) XY females with ovaries (XYO), and (d) XX males with testes (XXT)[ 60 ]. Additionally, FCG mice can be gonadectomized to eliminate gonadal hormone effects, allowing researchers to determine whether hormonal effects are organizational or activational. The strength of the FCG mouse model is that it allows for the uncoupling of sex chromosomes and sex hormones. However, it is important to note that the model involves an X-Y translocation, leading to increased expression of the autoimmune master regulator Tlr7 , which can produce confounding results in immune-focused studies[ 61 ]. The XY* mouse model investigates the effects of X chromosome ploidy or the presence of a Y chromosome[ 62 ]. This model involves mating XY* males, which have an aberrant Y chromosome pseudoautosomal region, with XX females[ 63 ]. The resulting progeny consist of four types: XX and XO females with ovaries, and XY and XXY males with testes[ 63 ]. The XY* mouse model is valuable for uncovering the effects of sex chromosomes, particularly the Y chromosome, on sex-differences[ 62 ]; however, developmental abnormalities arising from sex chromosome aneuploidy can complicate the interpretation of experimental results. Importantly, the XY* model holds immense possibilities to study how sex chromosomes drive sex-dimorphism during aging and its effects on the immune system. ERKO (estrogen receptors knockout) mouse models are pivotal in studying the effects of the estrogen signaling pathway[ 64 ]. These models are generated by genetically engineering mice to knock out or mutate one or both of the classical ER genes, specifically ERα and ERβ, either throughout the entire body or in specific tissues or cell types[ 64 ]. ERKO mouse models are powerful for highlighting the function of classical ER signaling, the primary mode of estrogen effect[ 64 ]; however, they may overlook the ability of estrogens to modulate immune responses through non-classical, ER-independent mechanisms[ 65 ]. ERKO mouse models present a valuable opportunity to look at the effect of classical ER signaling in immune system aging. ArKO (aromatase knockout) mouse models are crucial for studying both ER-dependent and independent signaling mechanisms[ 66 ]. Aromatase is an enzyme that converts androgens to estrogens, and ArKO mice are generated by genetically engineering mice to lack or have a nonfunctional mutation in the aromatase gene, resulting in an absence of estrogen production[ 66 ]. ArKO mouse models provide a non-invasive method to significantly reduce circulating estrogen levels[ 66 ], but they also lead to an increase in androgen levels[ 67 ], which are known to modulate the immune system and could confound experimental results. Nonetheless, ArKO mouse models are a viable option to elucidate the role of estrogen signaling (or lack thereof) during the aging process of the immune system. For studying androgen signaling, ARKO (Androgen receptor knockout) mice disrupt androgen receptor function globally or in specific tissues model being particularly prominent[ 68 ]. ARKO mouse models effectively highlight the function of androgen receptor signaling, the primary mode of androgen effect; however, they do not take into account how androgens can modulate immune responses through androgen receptor-independent mechanisms[ 13 ]. The inducible Foxl2 knockout model in adult XX females offers a unique system for studying sex-dimorphic phenotypes and the activational effects of sex hormones[ 69 ]. Inducible deletion of Foxl2 in adult XX females leads to adult somatic ovary-to-testis transdifferentiation (aOTT)[ 69 ]. This reprogramming results in male-like levels of circulating testosterone in XX aOTT animals[ 69 ]. The aOTT mouse model is valuable for uncoupling the effects of sex chromosomes from the activational effects of sex hormones; however, the use of tamoxifen for induction can influence the immune system, such as by shifting the balance towards a Th2 response[ 70 ]. The Steroidogenic Factor 1 knockout (SF-1 KO) model eliminates gonadal hormone production entirely, allowing for the study of sex chromosome-driven differences independent of gonadal hormones[ 71 ]. SF-1, encoded by the Nr5a1 gene, is essential for the development of gonads and adrenal glands[ 71 ]. SF-1 KO male and female mice are born without gonads or adrenal glands, thus lacking endogenous gonadal steroids entirely[ 71 ]. To prevent death from adrenal deficiency, newborn SF-1 KO pups must receive daily corticosteroid injections for 6–7 days, followed by adrenal transplantation at days 7–8[ 71 ]. The SF-1 KO mouse model is useful for revealing sex chromosome-driven differences by eliminating sex hormone production[ 71 ]; however, the requirement for corticosteroid injections can affect immune responses and inflammatory processes. Moreover, the SF-1 KO model is seldom employed in long-term aging studies beyond 6 months of age, highlighting the need for extended research to determine its suitability for aging studies[ 72 ].

Sex-differences shape the immune system across lifespan, influencing its function, aging, and susceptibility to disease. These differences are driven by a complex interplay of biological factors, such as genetics and hormones, as well as cultural and societal influences, including lifestyle and healthcare access. In this section, we explore the foundational biological drivers of sex-differences, followed by an examination of how societal and environmental factors further modulate immune responses. We then discuss sex-specific characteristics of the adult human immune system, highlighting key differences in innate and adaptive immunity. Finally, we address how these sex-differences evolve with age, focusing on the processes of immunosenescence and inflammaging, and their implications for health in older adults. Together, these insights provide a comprehensive understanding of the lifelong impact of sex on the human immune system. Building on the foundational role of sex-differences in shaping immune function and aging, we begin by examining the biological drivers of these differences. Sex-differences in biology, encompassing physical, behavioral, and physiological variations between males and females, arise from a complex interplay of chromosomal sex and gonadal hormonal influences that shape the development and function of an organism [ 8 ] ( Box 1 ). In mammals, biological sex is determined primarily by sex chromosome complement (i.e. XY vs. XX), and, secondarily, by gonadal identity (i.e. testes vs. ovaries, leading to a predominance of estrogens or androgens)[ 8 ]. While biological sex establishes the foundational differences in immune system function and aging, gender adds an additional layer of complexity[ 9 ]. Gender, referring to the societal and culturally constructed roles, behaviors, and expectations assigned to individuals based on their perceived sex, can significantly impact immune system aging[ 9 ]. While biological sex-differences are key, gender also influences immune health through factors such as access to healthcare, nutrition, and environmental exposures[ 9 ]. Gender-related behaviors, such as alcohol consumption, smoking, and physical labor, also differ between men and women, impacting immune health across the lifespan[ 9 ]. Economic conditions and dietary practices further shape immune function, with women in low-income regions more likely to experience malnutrition and micronutrient deficiencies, which can compromise immune health in older age[ 9 ]. Although gender plays an important role in immune system aging, its complex societal and cultural dimensions make it difficult to model in animals. Therefore, this review focuses on providing models to study the biological drivers of immune system aging. Sex-differences in chromosome complement and hormonal production play a critical role in shaping the immune system[ 10 ], which is a complex network of cells and molecules that work together to defend the body against infections and maintain overall health[ 11 ]. The immune system is typically divided into two main branches: the innate immune system and the adaptive immune system , each composed of specialized cells that collaborate to provide immune defense[ 11 ] ( Box 2 ). In the innate immune system, macrophages and neutrophils act as first responders[ 11 ]. Macrophages engulf and digest pathogens, while also acting as antigen-presenting cells to activate adaptive immunity[ 11 ]. Neutrophils are quick to arrive at infection sites, where they engulf bacteria and release enzymes to kill pathogens[ 11 ]. Other key cells in the innate immune system include natural killer (NK) cells, which play a crucial role in early defense and signaling[ 11 ]. Together, these cells of the innate immune system provide the first line of defense, rapidly detecting and responding to pathogens, and setting the stage for the activation of the adaptive immune response[ 11 ]. The other major branch of the immune system is the adaptive immune system, which involves lymphocytes such as B cells and T cells[ 11 ]. B cells produce antibodies that neutralize pathogens, while T cells have subtypes with specific roles: helper T cells activate other immune cells, cytotoxic T cells kill infected cells, and regulatory T cells maintain immune tolerance to prevent autoimmunity[ 11 ]. These lymphocytes, along with signaling molecules like cytokines and chemokines, coordinate to generate a precise and effective immune response, ensuring the body’s ability to maintain homeostasis and combat infections[ 11 ]. Sex-differences in immune function have been well-documented in humans, with distinct patterns emerging between males and females[ 10 ]. In general, females mount stronger immune responses than males, which may help explain why autoimmune diseases like lupus and multiple sclerosis are more common in females[ 10 ]. This heightened immune reactivity is likely influenced by genetic factors, such as higher X-linked immune gene dosage, and estrogen’s immune-activating effects[ 10 ]. Interestingly, with age, the prevalence and severity of autoimmune conditions tend to worsen in both men and women due to accumulated immune dysfunction and tissue damage[ 12 ]. In contrast, androgens exert an immunosuppressive effect, often leading to reduced immune responsiveness in males[ 13 ]. These sex-differences in immune function contribute to varying susceptibilities to disease[ 10 ]. For instance, men are more likely to experience severe outcomes in conditions like sepsis, while women are at greater risk for autoimmune diseases[ 10 ]. These sex-specific differences in immune function become even more pronounced with aging, influencing the immune system’s ability to respond to infections and diseases in older adults[ 14 ]. Aging brings significant changes to the immune system, primarily characterized by immunosenescence and ‘inflammaging’[ 15 , 16 ]. Immunosenescence refers to the gradual decline in immune function, reducing effectiveness and responsiveness, which makes the body more susceptible to infections and diseases[ 15 ]. Additionally, chronic low-grade inflammation, or ‘inflammaging,’ results from persistent immune activation, contributing to tissue damage and exacerbating age-related conditions[ 16 ]. Immune dysfunction plays a pivotal role in age-related diseases, such as Alzheimer’s disease, where neuroinflammation accelerates neuronal damage, and cardiovascular disease, where inflammation contributes to the formation of plaques in blood vessels[ 15 , 16 ]. In age-related diseases, Alzheimer’s is more prevalent in females, possibly due to estrogen’s role in brain health, while cardiovascular disease initially affects more males but rises in females after menopause due to hormonal shifts[ 3 ]. Differences in immune aging also impact vaccine responsiveness in older adults, with implications for tailoring vaccination strategies to improve efficacy[ 15 ]. These patterns reflect complex sex-based interactions among genetics, hormones, and aging. Together, these processes are central to the aging immune system and have important implications for health in older adults[ 15 , 16 ] ( Box 3 ). The impact of aging on the human immune system has been well documented and appreciated within the scientific community[ 17 ], but the investigation into human immune system aging with an emphasis on differences between biological sexes is just now becoming a significant focus of research[ 9 , 14 ]. Interestingly, studies now show that sex-differences are pervasive in both the adaptive and innate immune systems during aging[ 9 , 14 ]. However, it is important to note that although sex-differences in human immune system aging are reported for all cell types studied, these effects are unique to individual cell types[ 9 , 14 ] ( Figure 1 and Box 2 ).

In the U.S., all 56 verified supercentenarians (individuals over 110) are women ( https://gerontology.fandom.com/wiki/List_of_supercentenarians_from_the_United_States ), reflecting the broader trend where females consistently outlive males. Women generally have lower death rates than men for most leading causes of death, despite improvements in life expectancy for both sexes[ 1 ]. However, women experience greater frailty and co-morbidities with age, a phenomenon known as the ‘male-female health-survival paradox’[ 2 ]. This longevity advantage, alongside age-related dysfunctions in systems like immunity, underscores the significant role of biological sex in health and aging (see Glossary) across species[ 3 , 4 ], distinct from gender , which relates to societal and cultural roles. Yet, despite the clear influence of biological sex on aging and health trajectories, these differences are still largely ignored in clinical and preclinical research[ 5 ]. Although the National Institutes of Health (NIH) implemented a policy for including sex as a biological variable (SABV) into research designs, analyses, and reporting to address the overrepresentation of men and male animals in biomedical research, a considerable body of NIH-funded research ignores the effects of sex either in the design or reporting of research data[ 5 ]. Ignoring this important facet of biology is likely to result in unequal efficacy and safety of treatments, as demonstrated by the large excess of female-biased adverse events of FDA-approved drugs[ 6 ]. Incorporating biological sex-differences into health research is a low-cost, immediate approach to achieving more precise, effective medical treatments. While the push for precision medicine often focuses on genetic variation, addressing sex-based disparities in health and disease throughout the lifespan represents an essential, underutilized step toward truly personalized healthcare. In this review, we explore the multifaceted drivers of sex-differences in immune system function and aging, highlighting both biological and societal influences. We begin by examining the biological drivers, such as genetic and hormonal differences, that underlie sex-specific immune responses. We then address cultural and societal factors, including lifestyle and healthcare disparities, which can modulate these immune differences. Next, we delve into the distinct features of the adult human immune system, discussing how sex and age shape each innate and adaptive immune cell type differently. We also examine sex-specific trajectories in immune system aging, with a focus on the dual phenomena of immunosenescence —the gradual decline in immune function with age—and inflammaging , the chronic low-grade inflammation that increases over time and contributes to age-related diseases[ 7 ]. To gain deeper mechanistic insights, we discuss the utility of a plethora of mouse models , including surgical models (e.g., ovariectomy), chemically treated models (e.g., 4-vinylcyclohexene diepoxide), and genetic models (e.g., estrogen receptor knockout mice), as powerful tools for studying these processes. By offering researchers a range of models and approaches to dissect the biological contributors to immune aging, this review aims to support advancements in personalized medicine , enabling the development of sex- and age-specific strategies to improve immune health.

For the majority of scientific history, biological sex was overlooked as a critical variable, with males often serving as the default in both human and animal studies. This oversight has left significant gaps in our understanding of sex-specific biology and medicine (see Outstanding Questions ). As this review highlights, integrating sex-differences into immune aging research is essential for advancing precision medicine and addressing these gaps (see Clinician’s Corner ). Immune aging is shaped by both hormonal and chromosomal contributions, which must be studied in an integrated way. Testosterone treatment, for example, has been shown to enhance antiviral cytokine production and memory T cell function, pointing to potential applications for hormone supplementation therapy in mitigating immune aging[ 73 ]. However, the long-term effects of such interventions on immune regulation and disease susceptibility in aged populations remain unclear. Similarly, estrogen decline during menopause has been linked to increased inflammation and a higher risk of autoimmune diseases, highlighting the need to better understand its role in immune aging. Meanwhile, chromosomal dynamics add further complexity. Y chromosome loss in aging males is associated with increased risks of aging-associated diseases, while X chromosome inactivation and mosaicism in females introduce unique challenges in immune regulation[ 74 , 75 ]. Together, these hormonal and chromosomal factors represent a critical frontier for understanding sex-specific aging processes. Addressing these challenges requires selecting appropriate research models. Preclinical models must balance physiological relevance with the ability to test specific hypotheses. The catalog of mouse models presented in this review provides an essential resource for studying hormonal and chromosomal contributions to immune aging. By choosing the most suitable models, researchers can generate insights that bridge the gap between animal studies and human applications. Emerging technologies such as organoid systems and in vitro models that mimic sex-specific immune responses offer promising tools to complement traditional animal studies. These platforms, combined with computational modeling and multi-omics analyses, can help uncover the molecular drivers of sex-specific differences in aging. Incorporating sex as a variable in clinical trials, particularly for vaccines and immunomodulatory therapies, is also critical for translating preclinical insights into personalized interventions. In conclusion, understanding sex-specific immune aging is not only fundamental to advancing basic biology but also pivotal for the future of personalized medicine. By embracing sex as a fundamental variable, leveraging innovative models, and translating findings into actionable therapies, we can improve health outcomes for all individuals. This review serves as both a resource and a call to action, urging researchers to integrate sex-differences into their studies and push the boundaries of what is known about immune aging.