Transcription Factor Analysis to Investigate Immunosenescence in Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is linked to various signs of advanced aging, such as premature immunosenescence which occurs due to decline in regenerative ability of T cells. RA T cells develop a unique aggressive inflammatory senescent phenotype with an imbalance of Th17/T regulatory (Treg) cell homeostasis and presence of CD28- T cells. The phenotypic analysis and characterization of T cell subsets become necessary to ascertain if any functional deficiencies exist within with the help of transcription factor (TF) analysis. These subset-specific TFs dictate the functional characteristics of T-cell populations, leading to the production of distinct effector cytokines and functions. Examining the expression, activity, regulation, and genetic sequence of TFs not only aids researchers in determining their importance in disease processes but also aids in immunological monitoring of patients enrolled in clinical trials, particularly in evaluating various T-cell subsets [Th17 (CD3+CD4+IL17+RORγt+) cells and T regulatory (Treg) (CD3+CD4+CD25+CD127-FOXP3+) cells], markers of T-cell aging [aged Th17 cells (CD3+CD4+IL17+RORγt+CD28-), and aged Treg cells (CD3+CD4+CD25+CD127-FOXP3+CD28-)]. In this context, we propose and outline the protocols for assessing the expression of TFs in aged Th17 and Treg cells, highlighting the crucial aspects of this cytometric approach.

Evaluating the Efficacy of Immune Checkpoint Inhibitors in Elderly Patients: A Systematic Review and Meta-analysis.

In this chapter, we outline the steps for designing and conducting a rigorous systematic review and meta-analysis, focusing on the efficacy of immune checkpoint inhibitors (ICIs) in elderly patients. ICIs have improved survival rates in advanced cancers, yet their effectiveness in older populations remains unclear. We detail the essential processes involved in both systematic reviews and meta-analyses. We can evaluate the efficacy of ICIs in elderly patients with advanced cancer, examining outcomes such as overall survival and progression-free survival.

Polyphenol Treatment of Peripheral Blood Mononuclear Cells from Individuals of Different Ages.

Human peripheral blood mononuclear cells (PBMCs) have been largely utilized to assess the cytotoxic, immunomodulatory, and anti-inflammatory properties of both synthetic and natural compounds. Within the latter category, polyphenols from dietary sources have been extensively analyzed. PBMCs represent a feasible in vitro model to study polyphenol hallmarks and activity according to quantitative and qualitative differences in immune responses in individuals of different age. In this chapter, we propose a method for PBMC treatment with polyphenols and analysis designed on age-dependent qualitative and quantitative variability in immune cell performance.

Analysis of Cytokine-Inducible SH2-Containing Protein (CISH) in the Study of Immunosenescence.

The aging immune system undergoes significant changes, leading to a state known as immunosenescence. Understanding the molecular mechanisms underlying immunosenescence is crucial for developing targeted interventions to enhance immune functions in older individuals. This bio-protocol review focuses on the application of quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for the mRNA quantification of cytokine-inducible SH2-containing protein (CISH), an immune regulator overexpressed in T-cell responses from older adults. We outline a comprehensive protocol for the quantitative assessment of CISH mRNA expression, providing a valuable tool for researchers investigating immunosenescence.

TEMRA in kidney transplant recipients: new crossroads.

Immunosenescence, the age-related dysregulation of innate and adaptive immunity, impairs immune response and increases inflammation, leading to higher infection and cardiovascular risks, particularly outside the field of transplantation. In kidney transplant recipients (KTRs), conditions like CMV infection, old age, uremia, smoking, and diabetes, linked to poor outcomes, are associated with enhanced immunosenescence. Recent studies highlight the pathogenic role of cytotoxic T cells, particularly terminally differentiated effector memory T cells that re-express CD45RA (TEMRA), in graft dysfunction. A higher proportion of circulating CD8+ TEMRA cells is observed in KTRs with chronic rejection. In antibody-mediated rejection, they invade the graft by superior chemotactic properties and binding to HLA-antibodies through FcγRIIIa (CD16). Also in microvascular inflammation without DSA, and even in patients without rejection but faster decline of kidney function, intra-graft CD8+ TEMRA cells were instrumental. CD8+ TEMRA cells may explain the unresolved dismal graft outcomes associated with donor age and CMV-serostatus mismatching, and could become a novel therapeutic target in KTRs.

Deciphering the impact of TERT/telomerase on immunosenescence and T cell revitalization.

Immunosenescence impacts both the innate and adaptive immune systems, predominantly affecting certain immune cell types. A notable manifestation of immunosenescence is the diminished efficacy of adaptive immunity. The excessive senescence of immune cells, particularly T cells, leads to marked immune deficiency, consequently escalating the risk of infections, tumors, and age-associated disorders. Lymphocytes, especially T cells, are subject to both replicative and premature senescence. Telomerase reverse transcriptase (TERT) and telomerase have multifaceted roles in regulating cellular behavior, possessing the ability to counteract both replicative and premature senescence in lymphocytes. This review encapsulates recent advancements in understanding immunosenescence, with a focus on T cell senescence, and the regulatory mechanisms involving TERT/telomerase. Additionally, it comprehensively discusses strategies aimed at inhibiting immunosenescence by augmenting TERT/telomerase activity.

Effect of a Multifactorial Weight Loss Intervention on HDL Cholesterol Efflux Capacity and Immunosenescence: A Randomized Controlled Trial.

OBJECTIVE: Life expectancy and obesity prevalence are increasing worldwide, leading to an increase in the prevalence of cardiovascular disease. High-density lipoprotein (HDL) functionality and immunosenescence play key roles in cardiovascular disease, longevity, and quality of aging. Both molecular hallmarks of aging are impacted by obesity and metabolic syndrome and can be modulated by lifestyle. We aimed to evaluate the effect of a lifestyle intervention focused on an energy-reduced Mediterranean diet (erMedDiet), physical activity (PA), and behavioral support on HDL cholesterol efflux capacity (CEC) and immunosenescence. METHOD: CEC and immunosenescent T cells were determined in 60 participants from the control group (CG) and 56 from the intervention group (IG) of the PREDIMED-Plus trial at baseline and after 1 and 3 years of follow-up. PREDIMED-Plus is a randomized, controlled, parallel-group trial with an IG of erMedDiet, PA promotion, and behavioral support for weight loss and a CG of usual primary care advice. The sample included 116 volunteers from the PREDIMED-Plus-IMDEA subsample of the PREDIMED-Plus trial. Men aged 55 to 75 years and women aged 60 to 75 years with a body mass index between 27 and 40 kg/m2 and metabolic syndrome were included. RESULTS: Participants within the IG had significantly improved CEC (2.42% and 10.69% after 1 and 3 years of follow-up) and a decreased in senescent T cell profile (-3.32% ± 12.54% and -6.74% ± 11.2%, p < 0.001, after 1 and 3 years of follow-up). Baseline obesity status impacted the response to the intervention. CONCLUSIONS: A weight loss intervention program with erMedDiet and PA ameliorated senescence markers.

Immunosenescence and Inflammaging: Mechanisms and Role in Diseases.

Age-related changes initiate a cascade of cellular and molecular alterations that lead to immune system dysfunction or abnormal activation, predisposing individuals to age-related diseases. This phenomenon, commonly referred to as immunosenescence, highlighting aging-associated progressive decline of the immune system. Moreover, mounting evidence suggests that immunosenescence contributes to a related pathological phenomenon known as inflammaging. Inflammaging refers to chronic, low-grade, and systemic inflammation associated with aging, occurring despite the absence of overt stimuli. In the body, inflammation is typically activated in response to overt stimuli such as bacterial/microbial invasion or a pathological state, however, inflammaging occurrence and its underpinning mechansisms seem to be independent and in the absence of such stimuli. Despite recent advancements in molecular characterization and the scrutiny of disease relevance, these two interconnected concepts have remained largely unexplored and unrecognized. In this comprehensive review, we aim to shed light on the mechanistic and cellular aspects of immunosenescence and inflammaging, as well as their pivotal roles in the pathogenesis of aging-related diseases, including cancer, infections, dementia, and neurodegenerative disorders.

IL-10 deficiency aggravates cell senescence and accelerates BLM-induced pulmonary fibrosis in aged mice via PTEN/AKT/ERK pathway.

BACKGROUND: Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. METHODS: Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-ß-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. RESULTS: The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-ß-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. CONCLUSIONS: IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF.

The Aging Immune System: A Critical Attack on Ischemic Stroke.

Ischemic stroke caused by cerebrovascular embolism is an age-related disease with high rates of disability and mortality. Although the mechanisms of immune and inflammatory development after stroke have been of great interest, most studies have neglected the critical and unavoidable factor of age. As the global aging trend intensifies, the number of stroke patients is constantly increasing, emphasizing the urgency of finding effective measures to address the needs of elderly stroke patients. The concept of "immunosenescence" appears to explain the worse stroke outcomes in older individuals. Immune remodeling due to aging involves dynamic changes at all levels of the immune system, and the overall consequences of central (brain-resident) and peripheral (non-brain-resident) immune cells in stroke vary according to the age of the individual. Lastly, the review outlines recent strategies aimed at immunosenescence to improve stroke prognosis.

Innate immune response in acute critical illness: a narrative review.

BACKGROUND: Activation of innate immunity is a first line of host defense during acute critical illness (ACI) that aims to contain injury and avoid tissue damages. Aberrant activation of innate immunity may also participate in the occurrence of organ failures during critical illness. This review aims to provide a narrative overview of recent advances in the field of innate immunity in critical illness, and to consider future potential therapeutic strategies. MAIN TEXT: Understanding the underlying biological concepts supporting therapeutic strategies modulating immune response is essential in decision-making. We will develop the multiple facets of innate immune response, especially its cellular aspects, and its interaction with other defense mechanisms. We will first describe the pathophysiological mechanisms of initiation of innate immune response and its implication during ACI. We will then develop the amplification of innate immunity mediated by multiple effectors. Our review will mainly focus on myeloid and lymphoid cellular effectors, the major actors involved in innate immune-mediated organ failure. We will third discuss the interaction and integration of innate immune response in a global view of host defense, thus considering interaction with non-immune cells through immunothrombosis, immunometabolism and long-term reprogramming via trained immunity. The last part of this review will focus on the specificities of the immune response in children and the older population. CONCLUSIONS: Recent understanding of the innate immune response integrates immunity in a highly dynamic global vision of host response. A better knowledge of the implicated mechanisms and their tissue-compartmentalization allows to characterize the individual immune profile, and one day eventually, to develop individualized bench-to-bedside immunomodulation approaches as an adjuvant resuscitation strategy.

Fasting and calorie restriction modulate age-associated immunosenescence and inflammaging.

Aging is a multifaceted process impacting cells, tissues, organs, and organ systems of the body. Like other systems, aging affects both the adaptive and the innate components of the immune system, a phenomenon known as immunosenescence. The deregulation of the immune system puts elderly individuals at higher risk of infection, lower response to vaccines, and increased incidence of cancer. In the Western world, overnutrition has increased the incidence of obesity (linked with chronic inflammation) which increases the risk of metabolic syndrome, cardiovascular disease, and cancer. Aging is also associated with inflammaging a sterile chronic inflammation that predisposes individuals to age-associated disease. Genetic manipulation of the nutrient-sensing pathway, fasting, and calorie restriction (CR) has been shown to increase the lifespan of model organisms. As well in humans, fasting and CR have also been shown to improve different health parameters. Yet the direct effect of fasting and CR on the aging immune system needs to be further explored. Identifying the effect of fasting and CR on the immune system and how it modulates different parameters of immunosenescence could be important in designing pharmacological or nutritional interventions that slow or revert immunosenescence and strengthen the immune system of elderly individuals. Furthermore, clinical intervention can also be planned, by incorporating fasting or CR with medication, chemotherapy, and vaccination regimes. This review discusses age-associated changes in the immune system and how these changes are modified by fasting and CR which add information on interventions that promote healthy aging and longevity in the growing aging population.

Anogenital Warts in Geriatrics: Immunosenescence and New Sexual Contacts? A Case Report.

Introduction: Anogenital warts (AGW) are sexually transmitted infections (STIs) caused by the human papillomavirus (HPV), particularly types 6 and 11. The highest incidence of AGW occurs in the age group of 15-24 years. However, as life expectancy increases, there is a significant rise in the geriatric population worldwide. This demographic shift is directly proportional to the increasing number of STIs cases within the geriatric group. Cases: A case of AGW was reported in a 75-year-old man who had a history of erectile dysfunction medication use and recent sexual contact. During the physical examination, a hyperpigmented plaque with a verrucous surface was observed at the base of the penis. The results of the histopathological examination were consistent with the characteristics of AGW. In addition, HPV genotyping, through polymerase chain reaction (PCR) showed the presence of HPV type 6. Discussion: The aging process leads to a decline in immune function among geriatric individuals, which causes susceptibility to infections, including STIs. Moreover, the geriatric population has a different level of susceptibility to STIs compared to younger individuals. Factors such as physiological changes, decreased sexual function, low awareness of STIs, and having multiple sexual partners further increase the risk of STIs in this age group. Conclusion: Sexual intercourse is an important component of the human life. However, the natural decline in sexual function due to the aging process often occurs with advancing age. As a result, many geriatrics seek various solutions in order to maintain sexual function and activity in old age. Since STIs can occur at any age, early detection and education are essential, particularly for the geriatric population.

Botanical Bioflavonoid Composition from Scutellaria baicalensis- and Acacia catechu-Protected Mice against D-Galactose-Induced Immunosenescence, and Cyclophosphamide Induced Immune Suppression.

Oxidative stress and chronic inflammation create a perpetual cycle in the elderly, where impaired immune function amplifies susceptibility to oxidative damage, and oxidative stress further weakens the immune response. This cycle is particularly detrimental to the respiratory system of the elderly, which is an easy target for constant exogenous harmful attacks during cold/flu season or under heavy air pollution. Herbal medicines that protect respiratory function are seen as safer alternatives to conventional therapies; however, there is limited availability of scientifically validated, safe, and effective natural supplements for these conditions. In this study, we evaluated a standardized bioflavonoid composition, UP446, that contains bioactives from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu as a natural and nutritional supplement for its antioxidative and immunoregulatory effects in oxidative stress-accelerated aging and chemically induced immune suppression mouse models. Immunosenescence was induced through the repeated subcutaneous inoculation of D-galactose (D-Gal) at a dose of 500 mg/kg/day in CD-1 mice. UP446 was administered orally at doses of 100 mg/kg and 200 mg/kg starting in the fifth week of immunosenescence induction. This study lasted a total of ten weeks. All mice received a quadrivalent influenza vaccine 2 weeks before termination. Whole blood, serum, spleen homogenate, and thymus tissues were processed for analysis. Cyclophosphamide (Cy)-induced immunosuppression was triggered by three consecutive injections of cyclophosphamide at 80 mg/kg/day, followed by the oral administration of UP446 for 18 days at doses of 100 mg/kg and 200 mg/kg. Blood was collected from each animal at necropsy, and serum was isolated for IgA and IgG ELISA analysis. UP446 was found to improve immune response, as evidenced by the stimulation of innate (NK cells) and adaptive immune responses (T cells and cytotoxic T cells), an increase in antioxidant capacity (glutathione peroxidase), the preservation of vital immune organs (the thymus), and a reduction in NFκB. UP446 also increased serum levels of IgA and IgG. The findings presented in this report demonstrate the antioxidative, anti-inflammatory, and immune-regulatory activities of UP446, suggesting its potential use in respiratory conditions involving immune stress due to aging, oxidative stress, and/or pathogenic challenges.

DAMPs in immunosenescence and cancer.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released by cells in response to injury or stress, recognized by host pattern recognition receptors that assess the immunological significance of cellular damage. The interaction between DAMPs and innate immune receptors triggers sterile inflammation, which serves a dual purpose: promoting tissue repair and contributing to pathological conditions, including age-related diseases. Chronic inflammation mediated by DAMPs accelerates immunosenescence and influences both tumor progression and anti-tumor immunity, underscoring the critical role of DAMPs in the nexus between aging and cancer. This review explores the characteristics of immunosenescence and its impact on age-related cancers, investigates the various types of DAMPs, their release mechanisms during cell death, and the immune activation pathways they initiate. Additionally, we examine the therapeutic potential of targeting DAMPs in age-related diseases. A detailed understanding of DAMP-induced signal transduction could provide critical insights into immune regulation and support the development of innovative therapeutic strategies.

Senescence-Associated T cells in Immunosenescence and Diseases.

Age-related changes in the immune system, referred to as immunosenescence, appear to evolve with rather paradoxical manifestations, a diminished adaptive immune capacity, and an increased propensity for chronic inflammation often with autoimmunity, which may underlie the development of diverse disorders with age. Immunosenescent phenotypes are associated with the emergence of unique lymphocyte subpopulations of both T and B lineages. We report that a CD153+ PD-1+ CD4+ T-cell subpopulation with severely attenuated T-cell receptor (TCR)-responsiveness, termed senescence-associated T (SAT) cells, co-evolve with potentially autoreactive CD30+ B cells, such as spontaneous germinal center B cells and age-associated B cells, in aging mice. SAT cells and CD30+ B cells are reciprocally activated with the aid of the interaction of CD153 with CD30 in trans and with the TCR complex in cis, resulting in the restoration of TCR-mediated proliferation and secretion of abundant proinflammatory cytokines in SAT cells and the activation and production of autoantibodies by CD30+ B cells. Besides normal aging, the development of SAT cells coupled with counterpart B cells may be robustly accelerated and accumulated in the relevant tissues of lymphoid or extra-lymphoid organs under chronic inflammatory conditions including autoimmunity and may contribute to the pathogenesis and aggravation of the disorders. This review summarizes and discusses recent advances in the understanding of SAT cells in the contexts of immunosenescent phenotypes, autoimmune and chronic inflammatory diseases and provides a novel therapeutic clue.

Elevated IL-15 levels in systemic lupus erythematosus: potential pathogenesis insight and therapeutic target.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by persistent immune cell activation and the overproduction of autoantibodies, affecting various organs such as joints, kidneys, and skin. Interleukin-15 (IL-15) is a pleiotropic cytokine that modulates immune cells of the innate and adaptive immune systems, playing a crucial role in the development of inflammatory and protective immune responses. However, the role of IL-15 in SLE pathogenesis and the therapeutic effects of IL-15 blockade on SLE remain unknown. In this study, we conducted flow cytometry analysis and identified a significant increase in the frequencies of IL-15+ and IL-15R+ cells in peripheral blood CD4+ T cells, CD8+ T cells, dendritic cells (DCs), monocytes, and natural killer (NK) cells of patients with SLE compared to healthy controls (HCs). Besides, we found elevated levels of serum IL-15 in SLE patients compared to HCs. Furthermore, we evaluted the effectiveness of IL-15 mAb treatment in a chronic graft-versus-host disease (cGVHD) mouse model of SLE. We observed that the IL-15 mAb treatment effectively reduced the frequencies of CD4+CD44hiCD62LloPD-1+CD153+ senescent CD4+ T cells, B220+CD11c+T-bet+ age-associated B cells (ABCs), Tfh cells, and germinal center (GC) B cells, alleviated lupus-associated manifestations such as serum anti-double-stranded DNA antibody (anti-dsDNA) and kidney injury in the SLE mouse model of cGVHD. These findings provide compelling preclinical evidence suggesting the pathogenic role of IL-15 in SLE and the therapeutic potential of IL-15 blockade in the treatment of SLE.

Rapid progression of CD8 and CD4 T cells to cellular exhaustion and senescence during SARS-CoV2 infection.

Risk factors for the development of severe COVID-19 include several comorbidities, but age was the most striking one since elderly people were disproportionately affected by SARS-CoV-2 infection. Among the reasons for this markedly unfavorable response in the elderly, immunosenescence and inflammaging appear as major drivers of this outcome. A finding that was also notable was that hospitalized patients with severe COVID-19 have an accumulation of senescent T cells, suggesting that immunosenescence may be aggravated by SARS-CoV-2 infection. The present work was designed to examine whether these immunosenescence changes are characteristic of COVID-19 and whether it is dependent on disease severity using cross-sectional and longitudinal studies. Our cross-sectional data show that COVID-19, but not other respiratory infections, rapidly increased cellular senescence and exhaustion in CD4 and CD8 T cells during early infection. In addition, longitudinal analyses with patients from Brazil and Portugal provided evidence of increased frequencies of senescent and exhausted T cells over a 7-d period in patients with mild/moderate and severe COVID-19. Altogether, the study suggests that accelerated immunosenescence in CD4 and especially CD8 T-cell compartments may represent a common and unique outcome of SARS-CoV2 infection.

Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function.

Chaperone-mediated autophagy (CMA) is a selective form of autophagy that contributes to the maintenance of cellular homeostasis. CMA activity declines with age in most tissues and systems, including the immune system, due to a reduction in levels of lysosome-associated membrane protein type 2A (LAMP2A), an essential CMA component. In this study, we show that overexpressing a copy of hLAMP2A within T cells since middle-age can prevent some of their age-associated loss of function. Our data support the idea that preserving LAMP2A expression with age through genetic means leads to enhanced proliferative responses, decreased number of regulatory T cell populations, and down-regulated expression of inhibitory receptors by T cells. During aging, elevated numbers of these immunosuppressive T cell populations significantly contribute to the age-associated downregulation of T cell responses. Using comparative proteomics, we confirm that preservation of CMA activity in old mice prevents age-related changes in both the resting and the activated T cell proteome. We also explore the effect of using first-in-class small molecule activators of CMA and demonstrate improved T cell response upon their administration to old mice. We conclude that sustaining CMA activity constitutes a potentially viable therapeutic approach to improving T cell function with age.

Inflammaging: The Next Challenge-Exploring the Role of Gut Microbiota, Environmental Factors, and Sex Differences.

The term 'inflammaging' has been coined to describe the chronic state of inflammation derived from ongoing cycles of tissue damage and the subsequent immune responses. This inflammatory status contributes to the decline of organs and physiological functions, accelerates the aging process, and increases the risk of age-related illnesses and death. During aging, the gut microbiota (GM) undergoes significant changes, including a decreased diversity of species, a decline in beneficial bacteria, and a rise in proinflammatory ones, resulting in persistent low-grade inflammation. Moreover, environmental factors, such as diet and medications, contribute to age-related changes in GM and immune function, preventing or promoting inflammaging. This narrative review aims to clarify the underlying mechanisms of inflammaging and to specifically investigate the influence of GM and several environmental factors on these mechanisms, while also exploring potential differences related to sex. Moreover, lifestyle and pharmacological interventions will be suggested to promote healthy aging.