Aging Of Immune System Research Articles

CGAS-STING pathway as a potential trigger of immunosenescence and inflammaging.

Aging is associated with an increased incidence of autoimmune diseases, despite the progressive decline of immune responses (immunosenescence). This apparent paradox can be explained by the age-related chronic low-grade systemic inflammation (inflammaging) and progressive dysregulation of innate signaling. During cellular aging, there is an accumulation of damaged DNA in the cell's cytoplasm, which serves as ubiquitous danger-associated molecule, promptly recognized by DNA sensors. For instance, the free cytoplasmic DNA can be recognized, by DNA-sensing molecules like cGAS-STING (cyclic GMP-AMP synthase linked to a stimulator of interferon genes), triggering transcriptional factors involved in the secretion of pro-inflammatory mediators. However, the contribution of this pathway to the aging immune system remains largely unknown. Here, we highlight recent advances in understanding the biology of the cGAS-STING pathway, its influence on the senescence-associated secretory phenotype (SASP), and its modulation of the immune system during sterile inflammation. We propose that this important stress sensor of DNA damage is also a trigger of immunosenescence and inflammaging.

MLKL deficiency protects against low-grade, sterile inflammation in aged mice

MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl–/– and Ripk3–/– mice on a congenic C57BL/6 J genetic background. We show that genetic deletion of Mlkl in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. -Seventeen-month-old Mlkl–/– female mice were also protected against age-related chronic sterile inflammation in connective tissue and skeletal muscle relative to wild-type littermate controls, exhibiting a reduced number of immune cell infiltrates in these sites and fewer regenerating myocytes. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans.

Immunosenescence and inflamm-ageing in COVID-19.

The destructive effects of coronavirus disease 2019 (COVID-19) on the elderly and people with cardiovascular disease have been proven. New findings shed light on the role of aging pathways on life span and health age. New therapies that focus on aging-related pathways may positively impact the treatment of this acute respiratory infection. Using new therapies that boost the level of the immune system can support the elderly with co-morbidities against the acute form of COVID-19. This article discusses the effect of the aging immune system against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the pathways affecting this severity of infection.

Abstract TP170: Heterochronic Parabiosis Lowers Microglia Activation And Myeloid Infiltration In Aged Parabiont

Introduction: Of the 795,000 people who suffer strokes annually, 75% are over the age of 65. Aging is a major risk factor for stroke. The risk of stroke doubles every decade after the age of 55. Aging leads to dramatic changes in peripheral myeloid cells and increases the activation state of microglia in the brain. Although age is an important determinant of stroke susceptibility and outcome, the contribution from the aged immune system remains unclear. Hypothesis: We hypothesize that aged mice (18-22 mo) parabionts paired with a young parabiont (2-3 mo) would have less microglia activation due to exposure to systemic factors from young mice when compared to aged mice paired with aged mice (18-22 mo). Methods: Young Pep-boy mice (haplotype CD45.1) were surgically paired with aged mice (haplotype CD45.2) for two months. The brains of these mice were then subjected to flow cytometry analysis. Brain single cell suspensions were isolated and immunophenotyped with a microglia specific panel. Results: Our results show that myeloid infiltration was decreased in the aged parabiont (paired with a young mouse) compared to its naïve counterpart (n=3-6/ grp, p = 0.0036). Microglia activation was assessed utilizing a homeostatic marker, P2RY12, and a microglia specific marker, Tmem119. Interestingly, the expression of Tmem119 on CD45 int CD11b + cells was significantly increased in the aged parabionts compared to aged, naïve mice (n=3-6/ grp, p =0.0006), however, P2RY12 trended upward in the aged parabiont (n=3/6 /grp, p =0.0742). This suggests that the shared circulation created between the heterochronic pair led to a reduction in immune activation in the aged parabiont. Thus, the young parabiont allows the aged parabiont access to rejuvenating factors through the shared flow of blood which reduced neuroinflammation. Conclusion: Future studies are needed to identify the specific factors contributing to reduced microglial activation and lowered infiltration of peripheral immune cells induced by pairing with young animals. Studies examining the immune response to stroke in young and aged parabionts are needed.

The ageing immune system and cancer

It is now well accepted that the immune system can protect from cancer, with checkpoint immunotherapy becoming standard of care for some cancers. However, immune function declines with age and most cancers emerge in the elderly. For example, mesothelioma emerges 30–40 years after exposure to asbestos, with most patients being greater than 60 years old. Studies in young (6–8 week old) mice that are equivalent to 14–16 year old humans have shown that several chemotherapeutic agents require a functional T cell response to elicit an effective anti-cancer outcome.

COVID-19 and the ageing immune system in an elderly patient : a case report

BackgroundThe severity of COVID-19 infection has an increasing trend in the elderly, which contributes to the high morbidity and mortality rates in this population. Aging itself is a prominent risk factor for severe disease and death from COVID-19. Case DescriptionThis case report a 71-year-old woman who complained of shortness of breath for 3 days before being admitted to the hospital. Bilateral consolidation and increased bronchovascular pattern were found on chest radiograph, and a positive SARS-COV2 nasopharyngeal swab PCR test result was noted. This patient was diagnosed with confirmed severe manifestation of COVID-19, community-acquired pneumonia and type 1 respiratory failure, as well as type II diabetes mellitus and suspicion of acute gastritis. The results of the geriatric status assessment were moderate functional status, risk of malnutrition, and moderate risk of deep vein thrombosis (DVT). This patient underwent treatment in accordance with the COVID-19 protocol along with management for geriatric status improvement. The patient was given permission to return home after 14 days of treatment, during which time her health had improved and her functional status had changed to moderate dependency. During follow-up, the patient continued to receive therapy. She is still being observed and future evaluations will be conducted. ConclusionThe increased susceptibility of the elderly to COVID-19 infection is caused by various factors. A burden of death and long-term disability brought on by this pandemic may be lessened by new or modified therapies that target aging-associated mechanisms. Therefore, COVID-19 case management in this population should be done with a comprehensive approach.

The ageing immune system as a potential target of senolytics.

Ageing leads to a sharp decline in immune function, precipitating the development of inflammatory conditions. The combined impact of these processes renders older individuals at greater risk of inflammatory and immune-related diseases, such as cancer and infections. This is compounded by reduced efficacy in interventions aiming to limit disease impact, for instance vaccines being less effective in elderly populations. This state of diminished cellular function is driven by cellular senescence, a process where cells undergo stable growth arrest following exposure to stressful stimuli, and the associated pro-inflammatory secretory phenotype. Removing harmful senescent cells (SnCs) using senolytic therapies is an emerging field holding promise for patient benefit. Current senolytics have been developed either to specifically target SnCs, or repurposed from cancer therapies or vaccination protocols. Herein, we discuss recent developments in senolytic therapies, focusing on how senolytics could be used to combat the age-associated diminution of the immune system. In particular, exploring how these drugs may be used to promote immunity in the elderly, and highlighting recent trials of senolytics in idiopathic pulmonary fibrosis and diabetic kidney disease. Novel immunotherapeutic approaches including chimeric antigen receptor T-cells or monoclonal antibodies targeting SnCs are being investigated to combat the shortcomings of current senolytics and their adverse effects. The flexible nature of senolytic treatment modalities and their efficacy in safely removing harmful SnCs could have great potential to promote healthy immune function in ageing populations.

Preoperative plasma vitamin D in patients with localized colorectal cancer: Age-dependent association with inflammation, postoperative complications, and survival.

Aging is often associated with low-grade chronic inflammation and a senescent immune system. Vitamin D is a regulator of immune function, and low plasma vitamin D is associated with poor health. The association between plasma vitamin D and inflammatory biomarkers and risk of postoperative complications and survival in patients with colorectal cancer (CRC) is unknown. Our aim was to investigate these associations and how they are influenced by age. Circulating vitamin D and the inflammatory biomarkers C-reactive protein (CRP), interleukin (IL)-6, and YKL-40 were measured in 398 patients with stage I-III CRC preoperatively. Older patients (≥70 years, n=208) were compared to younger patients (<70 years, n=190). The relation between vitamin D and complications and high inflammatory biomarker levels was presented by odds ratios ([OR], 95% confidence interval [CI]). Associations with survival were presented with hazard ratios ([HR], 95% CI). Plasma vitamin D was higher in older patients than in younger patients (75 vs. 67nmol/L, P=0.001). High vitamin D was associated with low plasma CRP in younger patients (OR=0.35, 95% CI 0.17-0.76), but not in older patients (OR=0.93, 0.49-1.76). High vitamin D in older patients with CRC was associated with reduced risk of major complications (OR=0.52, 0.28-0.95). This was not found in younger patients (OR=1.47, 0.70-3.11). Deficient vitamin D (<25nmol/L) was associated with short overall survival compared to sufficient (>50nmol/L) irrespective of age (HR=3.39, 1.27-9.37, P=0.02). For patients with localized CRC, high vitamin D levels before resection were associated with reduced risk of high inflammatory biomarkers for younger patients and reduced risk of major postoperative complications for older patients. Vitamin D deficiency was associated with reduced survival regardless of age.

Approaches of Reducing the Incidence of Arvi Among Elderly Patients

The article investigates approaches to reducing the incidence of acute respiratory viral infections among elderly patients. According to the author, in comparison with young people, respiratory viral infection in people over 65 years of age is associated with increased morbidity and mortality. Elderly patients may have severe lower respiratory tract infections, pneumonia, or exacerbation of chronic multimorbid conditions. Additional problems arise due to the fact that elderly patients often do not have fever or respiratory symptoms, but have atypical symptoms, including weakness, confusion and falls. This leads to a failure in diagnosis, an increase in morbidity, the appointment of additional drugs and further nosocomial spread. Currently, it is necessary to introduce sensitive and rapid diagnostics at the place of medical care to detect all viruses and treat infected elderly patients. This will make it easier to understand the true burden of respiratory viruses. To protect the aging immune system, it is now important to combine this with the development of expanded vaccination strategies and new antiviral therapeutics

Respiratory viral infections in the elderly: From the perspective of the aging immune system

&lt;p&gt;The susceptibility of the elderly to respiratory viral infections and the challenges posed by an aging population necessitate imperative development of advanced preventive and therapeutic strategies for elderly individuals. The clinical outcome of such infections is intricately determined by the complex interplay among viruses, host tissues, and immune cells. Elderly individuals exhibit a diminished efficacy of their immune system to clear viruses, consequently leading to prolonged viral insults, tissue damage, and an excessive activation of inflammatory cells. These ultimately result in worse clinical outcomes. Targeting the dysregulated antiviral immune responses has emerged as a potential approach to improve the prognosis of geriatric patients. It is noteworthy that the impacts of aging on antiviral immune responses are highly heterogenous. Thus, individualized patient assessment and management assume paramount importance. This review aims to summarize the current evidence elucidating the effects of aging on immune responses to respiratory viruses, with the ultimate goal of identifying knowledge gaps that can inform future research and enhance the management of elderly individuals.&lt;/p&gt;

MODELING OF IMMUNOSENESCENCE WITH AGING IN SYSTEMIC LUPUS ERYTHEMATOSUS

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting multiple systems and presenting with a wide range of clinical symptoms. Disease phenotype alters from childhood to old age. The possible reasons for these differences are genetic factors, changes in the hormonal status, and the aging immune system. As a result of the disease itself or as a side effect of medications, SLE patients often experience manifestations associated with aging like cardiovascular disease and infection susceptibility. Furthermore, immunosenescence, which commonly affects the elderly subjects, may result from the continued immune system activation during the natural history of SLE. In this study, we aimed to analyze the immunosenescence in SLE, the differences and similarities in SLE phenotype at different age groups, and possible reasons for these changes.

SEXUAL-DIMORPHISM IN HUMAN IMMUNE SYSTEM AGING

Abstract Differences in immune function and responses contribute to health- and life-span disparities between sexes. However, the role of sex in immune system aging is not well understood. Here, we characterize peripheral blood mononuclear cells from 172 healthy adults 22–93 years of age using ATAC-seq, RNA-seq and flow cytometry. These data reveal a shared epigenomic signature of aging including declining naïve T cells and increasing monocyte and cytotoxic cell functions. These changes are greater in magnitude in men and accompanied by a male-specific decline in B-cell-specific loci. Interestingly, genomic differences between sexes increase after age 65, with men having higher innate and pro-inflammatory activity and lower adaptive activity. In a separate cohort (n=39) we studied how older adults respond to two available pneumococcal vaccines: T-dependent Prevnar and T-independent Pneumovax. How older adults respond to these vaccines at the molecular and cellular level, and whether there are pre-vaccination predictors for vaccine responsiveness, is poorly understood. To address this, we characterized serum antibody responses and peripheral blood leukocyte composition using flow cytometry and transcriptional profiles using RNA-seq, in healthy older adults before and after vaccination. The vaccines induced comparable serological responses and increases in the number of ICOS+ T follicular helper cells. A shared plasmablast transcriptional signature (IGHG2, IGHA1, IGHA2) was induced by both vaccines ten days after vaccination, which is distinct from influenza vaccine responses. Importantly, the pre-vaccination (baseline) ratio of Th1/Th17 cells predicted responsiveness to Prevnar but not to Pneumovax. Interestingly, women had higher levels of Th1/Th17; and responded stronger to Prevnar compared to men. This study uncovered how older adults respond to different pneumococcal vaccines and demonstrated the significance of considering biological sex and the immune cell composition for precision vaccinology.

Investigating the potential of a prematurely aged immune phenotype in severely injured patients as predictor of risk of sepsis

BackgroundTraumatic injury elicits a hyperinflammatory response and remodelling of the immune system leading to immuneparesis. This study aimed to evaluate whether traumatic injury results in a state of prematurely aged immune phenotype to relate this to clinical outcomes and a greater risk of developing additional morbidities post-injury.Methods and findingsBlood samples were collected from 57 critically injured patients with a mean Injury Severity Score (ISS) of 26 (range 15–75 years), mean age of 39.67 years (range 20–84 years), and 80.7% males, at days 3, 14, 28 and 60 post-hospital admission. 55 healthy controls (HC), mean age 40.57 years (range 20–85 years), 89.7% males were also recruited. The phenotype and frequency of adaptive immune cells were used to calculate the IMM-AGE score, an indicator of the degree of phenotypic ageing of the immune system. IMM-AGE was elevated in trauma patients at an early timepoint (day 3) in comparison with healthy controls (p < 0.001), driven by an increase in senescent CD8 T cells (p < 0.0001), memory CD8 T cells (p < 0.0001) and regulatory T cells (p < 0.0001) and a reduction in naïve CD8 T cells (p < 0.001) and overall T cell lymphopenia (p < 0 .0001). These changes persisted to day 60. Furthermore, the IMM-AGE scores were significantly higher in trauma patients (mean score 0.72) that developed sepsis (p = 0.05) in comparison with those (mean score 0.61) that did not.ConclusionsThe profoundly altered peripheral adaptive immune compartment after critical injury can be used as a potential biomarker to identify individuals at a high risk of developing sepsis and this state of prematurely aged immune phenotype in biologically young individuals persists for up to two months post-hospitalisation, compromising the host immune response to infections. Reversing this aged immune system is likely to have a beneficial impact on short- and longer-term outcomes of trauma survivors.

Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity

The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Disrupted Lipid Homeostasis and Loss of IRF4 Impairs B-Cell and Plasma Cell Development in a Murine Model of Accelerated Aging

The aging immune system is characterized by increased bone marrow (BM) adiposity, myeloid skewing, impaired lymphocyte maturation, and loss of hematopoietic stem and progenitor cell (HSPC) regenerative capacity. Human systemic aging studies have found alterations in lipid and fatty acid metabolism, such as increased saturated fatty acid accumulation and decays in n-3 polyunsaturated fatty acid (PUFA) species leading to cellular membrane rigidity. However, the extent to which impaired fatty acid metabolism contributes to immune system aging and HSPC development is largely unexplored. In this study, we performed multi-omics studies to characterize BM aging phenotypes in a recently described mouse model that exhibits signs of accelerating aging in brain and eye tissues. This robust aging model expresses a mutant inactive form of the very long chain (VLC) PUFA elongation enzyme, Elongation of very long chain fatty acids protein 2 (ELOVL2), which is responsible for the elongation of 22-carbon PUFAs to 24-carbon PUFAs. These VLC-PUFAs are synthesized in vivo and are not readily available through dietary means. Previous studies using this mouse model demonstrated that Elovl2 DNA methylation-dependent and mutation-associated loss of function is a key driver of age-related defects in eye and brain tissues, however the hematopoietic system has not been characterized to date in this model. To investigate the extent to which impaired VLC-PUFA production in the setting of ELOVL2 enzymatic deficiency might also accelerate blood stem cell aging phenotypes, multi-omics studies were performed in murine BM samples from young (3 months old) and aged (18 months old) wild-type mice, compared with age-matched Elovl2 mutant mice. Total BM samples were subjected to lipidomics analyses, whole transcriptome RNA-sequencing (RNA-seq), and ATAC-seq analyses. Lipidomic profiling showed an almost complete depletion of direct and secondary products of ELOVL2 in BM isolated from mutant animals, suggesting significant changes in the biophysical properties of membranes in the cells. Gene set enrichment analyses (Reactome) of RNA-seq data revealed that pathways involving B cell receptor (BCR) signalling and immunoregulatory interactions between lymphoid and non-lymphoid cells were among the most differentially regulated in Elovl2 mutant mouse BM compared to age-matched controls. Key lymphoid lineage maturation markers (Cd19, Cd22, and Slamf7, among others) were downregulated in the BM of aged wild-type mice, and to a greater extent in Elovl2 mutant animals. This was accompanied by a significant downregulation of the lymphoid and plasma cell transcription factor, interferon-regulatory factor-4 (Irf4), in aged and Elovl2 mutant groups compared with young mice. In addition, phenotypic analyses of B cell lineage marker protein expression were performed by flow cytometry to confirm depletion of lymphoid cell populations and Irf4 expression in this model. Finally, ATAC-seq data revealed changes in DNA accessibility related to Elovl2 mutation, suggesting significant epigenetic changes in nuclear programs. These findings suggest that Elovl2 loss of function in a murine model of accelerated aging promotes diverse lipidomic, transcriptomic and chromatin alterations targeting lymphoid populations in murine BM, which may be mechanistically driven by a downregulation of Irf4. Together, these results provide insights into a functional link between disrupted lipid homeostasis and aging-related defects in lymphocyte maturation typified by loss of B-cell and plasma cell populations. Together, modulation of lipid catabolism pathways may provide a novel avenue for reversing a variety of age-related immune deficits including enhanced susceptibility to infection.

Immuno(T)herapy for age-related diseases.

During the last decade, the stimulation of T-cell function by the blockage of immunosuppressive checkpoints has experienced an outstanding impact in the treatment of cancer. Development of the chimeric antigen receptor T-cell technology has also emerged as a powerful alternative for patients suffering from oncological processes, especially those affected by hematological neoplasms. Recent evidence suggest that the use of immunotherapy could be extended to non-oncological diseases and could be especially relevant for age-associated disorders, opening exciting therapeutic options for a wide range of diseases of the elderly. Here we comment on the emergence of T-cell-based immunotherapies as feasible approaches that could revolutionize the future of GeroScience.

Immunosenescence in Neurological Diseases-Is There Enough Evidence?

The aging of the immune system has recently attracted a lot of attention. Immune senescence describes changes that the immune system undergoes over time. The importance of immune senescence in neurological diseases is increasingly discussed. For this review, we considered studies that investigated cellular changes in the aging immune system and in neurological disease. Twenty-six studies were included in our analysis (for the following diseases: multiple sclerosis, stroke, Parkinson's disease, and dementia). The studies differed considerably in terms of the patient groups included and the cell types studied. Evidence for immunosenescence in neurological diseases is currently very limited. Prospective studies in well-defined patient groups with appropriate control groups, as well as comprehensive methodology and reporting, are essential prerequisites to generate clear insights into immunosenescence in neurological diseases.

Effect of Ageing on The Immune System, A Review

The immune system's performance declines as we age, increasing our vulnerability to illnesses and perhaps lowering our quality of life. Stress and normal ageing both cause a decline in immune function. Social and psychological pressures are a regular component of life and the cause of significant events that alter direction. Throughout their lives, people are exposed to a variety of stressors, with effects that develop at various rates due to differences in stress exposure, stress buffering, stress reactivity, stress duration (recovery), and restorative mechanisms. The consequences of these processes on older persons' stress levels have been shown to mimic, aggravate, and possibly accelerate the immune system's ageing process. Therefore, it would be advantageous for aged people and less expensive for society to be able to renew the ageing immune system.

Immune system disruptions implicated in whole blood epigenome-wide association study of depression among Parkinson's disease patients

Although Parkinson's Disease (PD) is typically described in terms of motor symptoms, depression is a common feature. We explored whether depression influences blood-based genome-wide DNA methylation (DNAm) in 692 subjects from a population-based PD case-control study, using both a history of clinically diagnosed depression and current depressive symptoms measured by the geriatric depression scale (GDS). While PD patients in general had more immune activation and more accelerated epigenetic immune system aging than controls, the patients experiencing current depressive symptoms (GDS≥5) showed even higher levels of both markers than patients without current depressive symptoms (GDS<5). For PD patients with a history of clinical depression compared to those without, we found no differences in immune cell composition. However, a history of clinical depression among patients was associated with differentially methylated CpGs. Epigenome-wide association analysis (EWAS) revealed 35 CpGs associated at an FDR≤0.05 (569 CpGs at FDR≤0.10, 1718 CpGs at FDR≤0.15). Gene set enrichment analysis implicated immune system pathways, including immunoregulatory interactions between lymphoid and non-lymphoid cells (p-adj = 0.003) and cytokine-cytokine receptor interaction (p-adj = 0.004). Based on functional genomics, 25 (71%) of the FDR≤0.05 CpGs were associated with genetic variation at 45 different methylation quantitative trait loci (meQTL). Twenty-six of the meQTLs were also expression QTLs (eQTLs) associated with the abundance of 53 transcripts in blood and 22 transcripts in brain (substantia nigra, putamen basal ganglia, or frontal cortex). Notably, cg15199181 was strongly related to rs823114 (SNP-CpG p-value = 3.27E-310), a SNP identified in a PD meta-GWAS and related to differential expression of PM20D1, RAB29, SLC41A1, and NUCKS1. The entire set of genes detected through functional genomics was most strongly overrepresented for interferon-gamma-mediated signaling pathway (enrichment ratio = 18.8, FDR = 4.4e-03) and T cell receptor signaling pathway (enrichment ratio = 13.2, FDR = 4.4e-03). Overall, the current study provides evidence of immune system involvement in depression among Parkinson's patients.

Targeting metabolism through exercise and nutrition to rejuvenate an aging immune system

Dysregulated metabolism is a hallmark of the aging process. Immune function is tightly controlled by cellular metabolism, and emerging evidence indicates that aged immune cells have alterations in metabolism that may promote aging-related disease. Lifestyle interventions including diet and exercise are potent strategies for targeting metabolic dysfunction in aging, but to date, only a few studies have examined the ability of exercise or diet to regulate immunometabolism, despite their well-known positive effects on healthspan and lifespan. Utilizing lifestyle modification as precision medicine to target age-related diseases through modulating immunometabolism is promising, but a great deal of work remains. Keywords: Immunometabolism, exercise, diet, inflammaging, immunosenescence