Inflammaging, immunosenescence, and cardiovascular aging: insights into long COVID implications.

Aging leads to physiological changes, including inflammaging-a chronic low-grade inflammatory state with significant implications for various physiological systems, particularly for cardiovascular health. Concurrently, immunosenescence-the age-related decline in immune function, exacerbates vulnerabilities to cardiovascular pathologies in older individuals. Examining the dynamic connections between immunosenescence, inflammation, and cardiovascular aging, this mini-review aims to disentangle some of these interactions for a better understanding of their complex interplay. In the context of cardiovascular aging, the chronic inflammatory state associated with inflammaging compromises vascular integrity and function, contributing to atherosclerosis, endothelial dysfunction, arterial stiffening, and hypertension. The aging immune system's decline amplifies oxidative stress, fostering an environment conducive to atherosclerotic plaque formation. Noteworthy inflammatory markers, such as the high-sensitivity C-reactive protein, interleukin-6, interleukin-1ß, interleukin-18, and tumor necrosis factor-alpha emerge as key players in cardiovascular aging, triggering inflammatory signaling pathways and intensifying inflammaging and immunosenescence. In this review we aim to explore the molecular and cellular mechanisms underlying inflammaging and immunosenescence, shedding light on their nuanced contributions to cardiovascular diseases. Furthermore, we explore the reciprocal relationship between immunosenescence and inflammaging, revealing a self-reinforcing cycle that intensifies cardiovascular risks. This understanding opens avenues for potential therapeutic targets to break this cycle and mitigate cardiovascular dysfunction in aging individuals. Furthermore, we address the implications of Long COVID, introducing an additional layer of complexity to the relationship between aging, immunosenescence, inflammaging, and cardiovascular health. Our review aims to stimulate continued exploration and advance our understanding within the realm of aging and cardiovascular health.

Inhibitory immune checkpoints suppress the surveillance of senescent cells promoting their accumulation with aging and in age-related diseases.

The accumulation of pro-inflammatory senescent cells within tissues is a common hallmark of the aging process and many age-related diseases. This modification has been called the senescence-associated secretory phenotype (SASP) and observed in cultured cells and in cells isolated from aged tissues. Currently, there is a debate whether the accumulation of senescent cells within tissues should be attributed to increased generation of senescent cells or to a defect in their elimination from aging tissues. Emerging studies have revealed that senescent cells display an increased expression of several inhibitory immune checkpoint ligands, especially those of the programmed cell death protein-1 (PD-1) ligand-1 (PD-L1) proteins. It is known that the PD-L1 ligands, especially those of cancer cells, target the PD-1 receptor of cytotoxic CD8+ T and natural killer (NK) cells disturbing their functions, e.g., evoking a decline in their cytotoxic activity and promoting their exhaustion and even apoptosis. An increase in the level of the PD-L1 protein in senescent cells was able to suppress their immune surveillance and inhibit their elimination by cytotoxic CD8+ T and NK cells. Senescent cells are known to express ligands for several inhibitory immune checkpoint receptors, i.e., PD-1, LILRB4, NKG2A, TIM-3, and SIRPα receptors. Here, I will briefly describe those pathways and examine whether these inhibitory checkpoints could be involved in the immune evasion of senescent cells with aging and age-related diseases. It seems plausible that an enhanced inhibitory checkpoint signaling can prevent the elimination of senescent cells from tissues and thus promote the aging process.

The human colon: Evidence for degenerative changes during aging and the physiological consequences.

BACKGROUND: The incidence of constipation increases among the elderly (>65 years), while abdominal pain decreases. Causes include changes in lifestyle (e.g., diet and reduced exercise), disease and medications affecting gastrointestinal functions. Degenerative changes may also occur within the colo-rectum. However, most evidence is from rodents, animals with relatively high rates of metabolism and accelerated aging, with considerable variation in time course. In humans, cellular and non-cellular changes in the aging intestine are poorly investigated. PURPOSE: To examine all available studies which reported the effects of aging on cellular and tissue functions of human isolated colon, noting the region studied, sex and age of tissue donors and study size. The focus on human colon reflects the ability to access full-thickness tissue over a wide age range, compared with other gastrointestinal regions. Details are important because of natural human variability. We found age-related changes within the muscle, in the enteric and nociceptor innervation, and in the submucosa. Some involve all regions of colon, but the ascending colon appears more vulnerable. Changes can be cell- and sublayer-dependent. Mechanisms are unclear but may include development of "senescent-like" and associated inflammaging, perhaps associated with increased mucosal permeability to harmful luminal contents. In summary, reduced nociceptor innervation can explain diminished abdominal pain among the elderly. Degenerative changes within the colon wall may have little impact on symptoms and colonic functions, because of high "functional reserve," but are likely to facilitate the development of constipation during age-related challenges (e.g., lifestyle, disease, and medications), now operating against a reduced functional reserve.

Probiotic-Reduced Inflammaging in Older Adults: A Randomized, Double-Blind, Placebo-Controlled Trial.

The disparity between increased lifespan and healthy aging, marked by prevalent "inflammaging", highlights the global challenge in care of older persons. This study explored the anti-inflammatory effects of Lactiplantibacillus plantarum HEAL9 (LpHEAL9), alone or combined with berries, on older volunteers with chronic low-grade inflammation (LGI). It was a randomized, double-blind, placebo-controlled trial, with a total of 66 volunteers (> 70 years old), randomly assigned, and equally distributed, to placebo, LpHEAL9 or LpHEAL9 + Berries group. After a 2-week run-in period, participants underwent a 4-week dietary intervention. Intake of LpHEAL9 showed a trend towards reduction in serum CRP but without reaching statistical significance. However, LpHEAL9 significantly decreased fecal calprotectin levels compared to placebo. LpHEAL9+Berries did not show any effect on inflammation. Both probiotic groups showed a trend in improving cognitive function albeit not reaching statistical significance. Our findings suggest that the probiotic strain L. plantarum HEAL9 has a modest impact on LGI in a healthy older population (ClinicalTrials.gov ID: NCT02342496).

Characteristics of T cell premature senescence in maintenance hemodialysis patients.

BACKGROUND: Uremia-associated immunodeficiency, mainly characterized by T cell dysfunction, exists in patients on maintenance hemodialysis (MHD) and promotes systemic inflammation. However, T cell senescence, one of the causes of T cell dysfunction, has not been clearly revealed yet. In this cross-sectional research, we aimed to study the manifestation of T cell premature senescence in MHD patients and further investigate the associated clinical factors. METHODS: 76 MHD patients including 33 patients with cardiovascular diseases (CVD) and 28 patients with arteriovenous fistula (AVF) event history were enrolled in this study. Complementarity determining region 3 (CDR3) of T cell receptor (TCR) was analyzed by immune repertoire sequencing (IR-Seq). CD28- T cell subsets and expression of senescence marker p16 and p21 genes were detected by multicolor flow cytometry and RT-qPCR, respectively. RESULTS: MHD patients had significantly decreased TCR diversity (P < 0.001), increased CDR3 clone proliferation (P = 0.001) and a left-skewed CDR3 length distribution. The proportion of CD4 + CD28- T cells increased in MHD patients (P = 0.014) and showed a negative correlation with TCR diversity (P = 0.001). p16 but not p21 expression in T cells was up-regulated in MHD patients (P = 0.039). Patients with CVD exhibited increased expression of p16 and p21 genes (P = 0.010 and 0.004, respectively), and patients with AVF events showed further TCR diversity and evenness reduction (P = 0.002 and 0.017, respectively) compared to patients without the comorbidities. Moreover, age, average convection volume, total cholesterol, high-density lipoprotein cholesterol and transferrin saturation were associated with TCR diversity or CD4 + CD28- T cell proportion (P < 0.05). CONCLUSIONS: MHD patients undergo T cell premature senescence characterized by significant TCR diversity reduction and repertoire skew, as well as accumulation of the CD4 + CD28- subset and up-regulation of p16 gene. Patients with CVD or AVF events show higher level of immunosenescence. Furthermore, T cell senescence in MHD patients is associated with blood cholesterol and uremic toxin retention, suggesting potential intervention strategies in the future.

Identification of crucial inflammaging related risk factors in multiple sclerosis.

Background: Multiple sclerosis (MS) is an immune-mediated disease characterized by inflammatory demyelinating lesions in the central nervous system. Studies have shown that the inflammation is vital to both the onset and progression of MS, where aging plays a key role in it. However, the potential mechanisms on how aging-related inflammation (inflammaging) promotes MS have not been fully understood. Therefore, there is an urgent need to integrate the underlying mechanisms between inflammaging and MS, where meaningful prediction models are needed. Methods: First, both aging and disease models were developed using machine learning methods, respectively. Then, an integrated inflammaging model was used to identify relative risk factors, by identifying essential "aging-inflammation-disease" triples. Finally, a series of bioinformatics analyses (including network analysis, enrichment analysis, sensitivity analysis, and pan-cancer analysis) were further used to explore the potential mechanisms between inflammaging and MS. Results: A series of risk factors were identified, such as the protein homeostasis, cellular homeostasis, neurodevelopment and energy metabolism. The inflammaging indices were further validated in different cancer types. Therefore, various risk factors were integrated, and even both the theories of inflammaging and immunosenescence were further confirmed. Conclusion: In conclusion, our study systematically investigated the potential relationships between inflammaging and MS through a series of computational approaches, and could present a novel thought for other aging-related diseases.

Cell-free DNA methylation patterns in aging and their association with inflamm-aging.

Aim: Liquid biopsies analyzing cell-free DNA (cfDNA) methylation in plasma offer a noninvasive diagnostic for diseases, with the potential of aging biomarkers underexplored. Methods: Utilizing enzymatic methyl-seq (EM-seq), this study assessed cfDNA methylation patterns in aging with blood from 35 healthy individuals. Results: It found aging signatures, including higher cfDNA levels and variations in fragment sizes, plus approximately 2000 age-related differentially methylated CpG sites. A biological age predictive model based on 48 CpG sites showed a strong correlation with chronological age, verified by two datasets. Age-specific epigenetic shifts linked to inflammation were revealed through differentially methylated regions profiling and Olink proteomics. Conclusion: These findings suggest cfDNA methylation as a potential aging biomarker and might exacerbate immunoinflammatory reactivity in older individuals.

Our bodies undergo many changes as we age, some of which might affect our health. To better understand these changes, scientists study something called 'cell-free DNA' (cfDNA) in our blood. This cfDNA can give us clues about our health and the risk of diseases like cancer or heart conditions.In our research, we analyzed cfDNA from the blood of 35 people to identify patterns associated with aging. We discovered that approximately 2000 specific spots in our DNA change in a way that's linked to aging. These changes might help us figure out someone's biological age ­ essentially, how old their body seems based on various health factors, which can differ from their actual age.We also found that these DNA changes could indicate how aging might make the body's defense system ­ which fights off diseases ­ react more intensely. Understanding this could be crucial for managing health as we get older.Our study suggests that cfDNA could be a useful marker for aging, offering a new approach to understanding and possibly managing the health effects associated with growing older.

Exploring the Pathophysiology of Long COVID: The Central Role of Low-Grade Inflammation and Multisystem Involvement.

Long COVID (LC), also referred to as Post COVID-19 Condition, Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), and other terms, represents a complex multisystem disease persisting after the acute phase of COVID-19. Characterized by a myriad of symptoms across different organ systems, LC presents significant diagnostic and management challenges. Central to the disorder is the role of low-grade inflammation, a non-classical inflammatory response that contributes to the chronicity and diversity of symptoms observed. This review explores the pathophysiological underpinnings of LC, emphasizing the importance of low-grade inflammation as a core component. By delineating the pathogenetic relationships and clinical manifestations of LC, this article highlights the necessity for an integrated approach that employs both personalized medicine and standardized protocols aimed at mitigating long-term consequences. The insights gained not only enhance our understanding of LC but also inform the development of therapeutic strategies that could be applicable to other chronic conditions with similar pathophysiological features.

Relationship between Hypoxia and Hypercapnia Tolerance and Life Expectancy.

The review discusses the potential relationship between hypoxia resistance and longevity, the influence of carbon dioxide on the mechanisms of aging of the mammalian organism, and intermittent hypercapnic-hypoxic effects on the signaling pathways of aging mechanisms. In the article, we focused on the potential mechanisms of the gero-protective efficacy of carbon dioxide when combined with hypoxia. The review summarizes the possible influence of intermittent hypoxia and hypercapnia on aging processes in the nervous system. We considered the perspective variants of the application of hypercapnic-hypoxic influences for achieving active longevity and the prospects for the possibilities of developing hypercapnic-hypoxic training methods.

Molecular Signatures of Senescence in Periodontitis: Clinical Insights.

Most of the elderly population is afflicted by periodontal diseases, creating a health burden worldwide. Cellular senescence is one of the hallmarks of aging and associated with several chronic comorbidities. Senescent cells produce a variety of deleterious secretions, collectively termed the senescence-associated secretory phenotype (SASP). This disrupts neighboring cells, leading to further senescence propagation and inciting chronic inflammation, known as "inflammaging." Detrimental repercussions within the tissue microenvironment can trigger senescence at a younger age, accelerate biological aging, and drive the initiation or progression of diseases. Here, we investigated the biological signatures of senescence in healthy and diseased gingival tissues by assessing the levels of key senescence markers (p16, lipofuscin, and ß-galactosidase) and inflammatory mediators (interleukin [IL]-1ß, IL-6, IL-8, matrix metalloproteinase [MMP]-1, MMP-3, and tumor necrosis factor-α). Our results showed significantly increased senescence features including p16, lipofuscin, and ß-galactosidase in both epithelial and connective tissues of periodontitis patients compared with healthy sites in all age groups, indicating that an inflammatory microenvironment can trigger senescence-like alterations in younger diseased gingival tissues as well. Subsequent analyses using double staining with specific cell markers noted the enrichment of ß-galactosidase in fibroblasts and macrophages. Concurrently, inflammatory mediators consistent with SASP were increased in the gingival biopsies obtained from periodontitis lesions. Together, our findings provide the first clinical report revealing susceptibility to elevated senescence and inflammatory milieu consistent with senescence secretome in gingival tissues, thus introducing senescence as one of the drivers of pathological events in the oral mucosa and a novel strategy for targeted interventions.

Immune cell phenotypes and mortality in the Framingham Heart Study.

BACKGROUND: Global life expectancy is rising, with the 60 + age group projected to hit 2 billion by 2050. Aging impacts the immune system. A notable marker of immune system aging is the presence of Aging-Related Immune Cell Phenotypes (ARIPs). Despite their importance, links between immune cell phenotypes including ARIPs and mortality are underexplored. We prospectively investigated 16 different immune cell phenotypes using flow cytometry and IL-6 in relation to survival outcome among dementia-free Framingham Heart Study (FHS) offspring cohort participants who attended the seventh exam (1998-2001). RESULTS: Among 996 participants (mean age 62 years, range 40 to 88 years, 52% female), the 19-year survival rate was 65%. Adjusting for age, sex, and cytomegalovirus (CMV) serostatus, higher CD4/CD8 and Tc17/CD8 + Treg ratios were significantly associated with lower all-cause mortality (HR: 0.86 [0.76-0.96], 0.84 [0.74-0.94], respectively), while higher CD8 regulatory cell levels (CD8 + CD25 + FoxP3 +) were associated with increased all-cause mortality risk (HR = 1.17, [1.03-1.32]). Elevated IL-6 levels correlated with higher all-cause, cardiovascular, and non-cardiovascular mortality (HR = 1.43 [1.26-1.62], 1.70 [1.31-2.21], and 1.36 [1.18-1.57], respectively). However, after adjusting for cardiovascular risk factors and prevalent cancer alongside age, sex, and CMV, immune cell phenotypes were no longer associated with mortality in our cohort. Nonetheless, IL-6 remained significantly associated with all-cause and cardiovascular mortality (HRs: 1.3 [1.13-1.49], 1.5 [1.12-1.99], respectively). CONCLUSIONS: In 19-year follow-up, higher Tc17/CD8 + Treg and CD4/CD8 ratios were associated with lower all-cause mortality, while the CD8 + CD25 + FoxP3 + (CD8 + Treg) phenotype showed increased risk. Elevated IL-6 levels consistently correlated with amplified mortality risks. These findings highlight the links between immune phenotypes and mortality, suggesting implications for future research and clinical considerations.

Fluid biomarkers unveil signatures of pathological aging.

Aging is a multifaceted and highly varied process in the brain. Identifying aging biomarkers is one means of distinguishing pathological from physiological aging. The aim of this narrative review is to focus on two new developments in the field of fluid biomarkers and draw attention to this excellent tool for the early detection of potential brain pathologies that delay, alter, or enable physiological aging to become pathological. Pathological aging can lower the threshold for the development of specific diseases such as late-onset epilepsy. Fluid biomarkers can reveal pathological levels at an early stage and thus indicate disease processes in the brain that begin before symptoms develop; they thus differ from physiological aging.

Changes in plasma metabolite concentrations and enzyme activities in aging riding horses.

In older horses, basal metabolic rate decreases, and plasma metabolite and hormone concentrations related to energy metabolism change. The occurrence of age-related diseases, which increases in old animals, may enhance inflammatory reactivity (inflammaging). Finding the appropriate treatment for inflammaging at an early stage may prevent various age-related diseases. Changes in metabolite and hormone concentrations and enzyme activities involved in energy metabolism in the plasma of clinically healthy riding horses of various ages were measured to identify biomarkers of inflammaging (persistent low-grade inflammation that occurs with aging). All horses were clinically healthy, and their body condition scores (BCSs) were 4 or 5 (9-point scale). Plasma triglyceride (TG), total cholesterol (T-Cho), blood urea nitrogen (BUN), insulin concentrations, malondialdehyde (MDA), and serum amyloid A (SAA) concentrations generally increased with age. Adiponectin concentrations, plasma superoxide dismutase (SOD), and leukocyte AMP-activated protein kinase (AMPK) activities decreased, while plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT), and glutathione peroxidase (GPx) remained unchanged as horses aged. Although riding horses that partake in continuous exercise seems to be less likely to develop inflammaging, horses over 17 years of age tend to show proinflammatory signs with disordered lipid metabolism. In riding horses, SAA, in combination with other markers, may be a useful biomarker for inflammaging and dysregulated lipid metabolism in aging horses.

Longitudinal urinary neopterin is associated with hearing threshold change over time in independent older adults.

Low-grade chronic inflammation is associated with many age-related conditions. Non-invasive methods to monitor low-grade chronic inflammation may improve the management of older people at risk of poorer outcomes. This longitudinal cohort study has determined baseline inflammation using neopterin volatility in monthly urine samples of 45 independent older adults (aged 65-75 years). Measurement of neopterin, an inflammatory metabolite, enabled stratification of individuals into risk categories based on how often in a 12-month period their neopterin level was raised. Hearing was measured (pure-tone audiometry) at baseline, 1 year and 3 years of the study. Results show that those in the highest risk category (neopterin raised greater than 50% of the time) saw greater deterioration, particularly in high-frequency, hearing. A one-way Welch's ANOVA showed a significant difference between the risk categories for change in high-frequency hearing (W (3, 19.6) = 9.164, p = 0.0005). Despite the study size and duration individuals in the highest risk category were more than twice as likely to have an additional age-related morbidity than those in the lowest risk category. We conclude that volatility of neopterin in urine may enable stratification of those at greatest risk of progression of hearing loss.

Increased levels of GM-CSF and CXCL10 and low CD8+ memory stem T Cell count are markers of immunosenescence and severe COVID-19 in older people.

BACKGROUND: Ageing leads to altered immune responses, resulting in higher susceptibility to certain infections in the elderly. Immune ageing is a heterogeneous process also associated with inflammaging, a low-grade chronic inflammation. Altered cytotoxic T cell responses and cytokine storm have previously been described in severe COVID-19 cases, however the parameters responsible for such immune response failures are not well known. The aim of our study was to characterize CD8+ T cells and cytokines associated with ageing, in a cohort of patients aged over 70 years stratified by COVID-19 severity. RESULTS: One hundred and four patients were included in the study. We found that, in older people, COVID-19 severity was associated with (i) higher level of GM-CSF, CXCL10 (IP-10), VEGF, IL-1ß, CCL2 (MCP-1) and the neutrophil to lymphocyte ratio (NLR), (ii) increased terminally differentiated CD8+T cells, and (ii) decreased early precursors CD8+ T stem cell-like memory cells (TSCM) and CD27+CD28+. The cytokines mentioned above were found at higher concentrations in the COVID-19+ older cohort compared to a younger cohort in which they were not associated with disease severity. CONCLUSIONS: Our results highlight the particular importance of the myeloid lineage in COVID-19 severity among older people. As GM-CSF and CXCL10 were not associated with COVID-19 severity in younger patients, they may represent disease severity specific markers of ageing and should be considered in older people care.

High-fat diet and aging-associated memory impairments persist in the absence of microglia in female rats.

Aging is associated with a priming of microglia such that they are hypersensitive to further immune challenges. As such high-fat diet during aging can have detrimental effects on cognition that is not seen in the young. However, conflicting findings also suggest that obesity may protect against cognitive decline during aging. Given this uncertainty we aimed here to examine the role of microglia in high-fat, high-sucrose diet (HFSD)-induced changes in cognitive performance in the aging brain. We hypothesised that 8 weeks of HFSD-feeding would alter microglia and the inflammatory milieu in aging and worsen aging-related cognitive deficits in a microglia-dependent manner. We found that both aging and HFSD reduced hippocampal neuron numbers and open field exploration; they also impaired recognition memory. However, the aging-related deficits occurred in the absence of a pro-inflammatory response and the deficits in memory performance persisted after depletion of microglia in the Cx3cr1-Dtr knock-in rat. Our data suggest that mechanisms additional to the acute microglial contribution play a role in aging- and HFSD-associated memory dysfunction.

The companion dog as a model for inflammaging: a cross-sectional pilot study.

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging.

Addressing the Missing Links in Cardiovascular Aging.

The aim of this manuscript is to provide a review of available options to enhance cardiovascular health and prevent cardiovascular disease (CVD) in the aging population using a systems-biology approach. These include the role of the gut microbiome, the early identification and removal of environmental toxins, and finally age related sex hormones and supplement replacement which all influence aging. Implementing such a comprehensive approach has the potential to facilitate earlier risk assessment, disease prevention, and even improve mortality. Further study in these areas will continue to advance our understanding and refine therapeutic interventions for a healthier cardiovascular aging process.

Inflammaging score as a potential prognostic tool for cancer: A population-based cohort study.

This study aimed to develop a clinically applicable inflammaging score by combining the inflammatory status and age of patients. Kaplan-Meier analysis was used to compare survival differences among patients with different grades of inflammation scores. Cox proportional hazard regression analysis was used to explore the relationship between the inflammaging score and survival. As the age of patients increased, their levels of systemic inflammation gradually increased. A unique inverse relationship was found between the level of inflammation and cancer prognosis during the ageing process. Mediation analysis indicated that systemic inflammation mediates 10.1%-17.8% of the association between ageing and poor prognosis. With an increase in the inflammaging score from grades I to V, the survival rate showed a gradient decline. The inflammation score could effectively stratify the prognosis of patients with lung, bronchial, gastrointestinal, and other types of cancers. Compared with grade I, the hazard ratios for grades II-V were 1.239, 1.604, 1.724, and 2.348, respectively. In the external validation cohort, the inflammaging score remained an independent factor affecting the prognosis of patients with cancer. The inflammaging score, which combines ageing and inflammation, is a robust prognostic assessment tool for cancer patients.

A Perfect Storm: The Convergence of Aging, Human Immunodeficiency Virus Infection, and Inflammasome Dysregulation.

The emergence of combination antiretroviral therapy (cART) has greatly transformed the life expectancy of people living with HIV (PWH). Today, over 76% of the individuals with HIV have access to this life-saving therapy. However, this progress has come with a new challenge: an increase in age-related non-AIDS conditions among patients with HIV. These conditions manifest earlier in PWH than in uninfected individuals, accelerating the aging process. Like PWH, the uninfected aging population experiences immunosenescence marked by an increased proinflammatory environment. This phenomenon is linked to chronic inflammation, driven in part by cellular structures called inflammasomes. Inflammatory signaling pathways activated by HIV-1 infection play a key role in inflammasome formation, suggesting a crucial link between HIV and a chronic inflammatory state. This review outlines the inflammatory processes triggered by HIV-1 infection and aging, with a focus on the inflammasomes. This review also explores current research regarding inflammasomes and potential strategies for targeting inflammasomes to mitigate inflammation. Further research on inflammasome signaling presents a unique opportunity to develop targeted interventions and innovative therapeutic modalities for combating HIV and aging-associated inflammatory processes.