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As we age, our immune system’s ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals.

Nrf2 is a master transcriptional regulator of a number of genes involved in the adaptive response to oxidative stress. Among the genes upregulated by Nrf2, heme oxygenase-1 (HO-1) has received significant attention, given that the products of HO-1-induced heme catabolism have well established antioxidant and anti-inflammatory properties. This is evidenced in numerous models of inflammatory and autoimmune disease whereby induction of HO-1 expression or administration of tolerable amounts of HO-1 reaction products can ameliorate disease symptoms. Unsurprisingly, Nrf2 and HO-1 are now considered viable drug targets for a number of conditions. In recent years, the term ‘inflammaging’ has been used to describe the low-grade chronic inflammation observed in aging/aged cells. Increased oxidative stress is also a key factor associated with aging and there is convincing evidence that Nrf2, not only declines with age, but that Nrf2 and HO-1 can reduce cellular senescence and the senescence-associated secretory phenotype (SASP) which is now considered an underlying driver of age-related inflammatory disease. In this review, we describe the role of oxidative stress in ‘inflammaging’ and highlight the potential anti-aging properties of the Nrf2-HO-1 system. We also highlight established and newly emerging Nrf2 activators and their therapeutic application in age-related disease.

IntroductionAutism spectrum disorder (ASD) is a heterogeneous group of neurodevelopmental Q8 conditions characterized by deficits in social interaction/communication and restrictive/repetitive behaviors. Recent studies highlight the role of immune system dysfunction and inflammation in ASD pathophysiology. Indeed, elevated levels of pro-inflammatory cytokines were described in the brain and peripheral blood of ASD individuals. Despite this, how this pro-inflammatory profile evolves with aging and whether it may be associated with behavioral deficits is unknown. In this work, we explored the impact of aging on motor behavior and inflammation using Shank3b mutant mice, a model for syndromic ASD. MethodsUsing RT-qPCR and flow cytometry, we examined the expression of key pro-inflammatory molecules in the cerebellum, bone marrow, spleen, and peripheral blood, comparing adult and old Shank3b+/+, Shank3b+/-, and Shank3b-/- mice.Results and discussionOur findings revealed genotype- and age-related differences in inflammation and motor behavior, with Shank3b-/- mice exhibiting accelerated aging and motor impairments. Correlations between pro-inflammatory molecules and behavioral deficits suggest that a link may be present between systemic inflammation and ASD-related behaviors, underscoring the potential role of age-related inflammation (“inflammaging”) in exacerbating ASD symptoms.

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.

Elliot Dinetz,1 Claudia Zeballos-Palacios,2 Claudia A Martinez3 1Department of Integrative and Family Medicine, University of Miami Miller School of Medicine Miami, Miami, FL, USA; 2Department of Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN, USA; 3Department of Medicine, Cardiovascular Division, University of Miami Miller School of Medicine, Miami, FL, USACorrespondence: Elliot Dinetz, Tel +786.490.5915, Email dr@elliotdinetz.comAbstract: 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.Keywords: vascular aging, cardiovascular aging, inflammaging, systems biology medicine, microbiome, toxic metals, bioidentical hormone replacement

Abstract 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-1β, 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.

Objectives: The study was conducted to explore associations between markers of mitochondrial quality control (MQC) from vastus lateralis muscle biopsies, serum inflammatory markers, and measures of muscle power assessed by two different tools in a sample of older adults. Design: Secondary analysis of data collected in the PeppeR develOpMental ProjecT (PROMPT) at the University of Florida (Gainesville, FL, USA). Methods: Forty-three older adults (n = 20 women) were included in the study. Muscle volume of the calf and thigh was quantified by three-dimensional magnetic resonance imaging. Lower-limb muscle power was estimated using 5-time sit-to-stand (5STS) muscle power equations and isokinetic test. Protein markers of MQC were measured in muscle samples by Western immoblotting (n = 12–23), while type I and II fiber cross-sectional area (CSA) and their proportion were quantified using immunohistochemistry (n = 12). Cytochrome C oxidase enzyme activity was measured spectrophotometrically. Finally, inflammatory markers were quantified in the serum using a multiplex immunoassay (n = 39). Results: Mean age of participants was 78.1 ± 5.5 years, and the average body mass index was 26.2 ± 4.5 kg/m2. Markers of mitochondrial biogenesis (i.e., PGC-1α), mitochondrial import proteins (i.e., cHsp70 and mtHsp70), and type I fiber CSA were significantly associated with muscle power estimated via both 5STS muscle power equations and isokinetic test (p < 0.05). Specific associations were also found according to the muscle power assessment method. 5STS muscle power measures were negatively correlated with ClvCasp3, P-AMPK, T-AMPK, P-p38, GM-CSF, INF-γ, IL1b, IL6, IL8, and TNF-α, whereas positive associations were found with BAX (p < 0.05). In contrast, isokinetic measures were significantly and positively correlated with RIP140, Hsp60, and type II muscle fiber CSA (p < 0.05). Conclusions: Markers of mitochondrial biogenesis (PGC-1α), mitochondrial import proteins (cHsp70 and mtHsp70), and type I muscle fiber CSA were significantly linked to lower-limb muscle power in older adults. These results suggest that muscle power is influenced by mitochondrial signaling. We also found that the relationship between mitochondrial mediators, inflammatory markers, and muscle power varied according to the assessment tool used.

Sarcopenia is associated with structural, ultrastructural, and molecular abnormalities of skeletal muscle. Mitochondrial dysfunction is a pivotal factor involved in muscle aging and sarcopenia. Mitochondrial bioenergetics are significantly reduced in muscles of older adults which is associated with whole-body aerobic capacity, muscle strength, and physical performance. Transcriptional profiling of muscle samples from older adults also revealed inverse correlations between gene expression patterns of autophagy and mitophagy and muscle volume and physical performance. This is in line with the proposition that mitochondrial quality control (MQC) processes are key to organellar and tissue health. MQC encompasses mitochondrial biogenesis, dynamics, and mitophagy. The latter has recently been included among the hallmarks of aging and alterations in MQC have been associated with chronic sterile inflammation as well as muscle atrophy and dysfunction. Several biomarkers spanning MQC, inflammation, metabolism, intercellular communication, and gut microbiota have been linked to sarcopenia. Findings from these initial studies hold promise to inform geroscience-based research in the field of sarcopenia by offering a plausible biological framework for developing gerotherapeutics and monitoring their effects.

ABSTRACTIncreased life expectancy, attributed to improved access to healthcare and drug development, has led to an increase in multimorbidity, a key contributor to polypharmacy. Polypharmacy is characterised by its association with a variety of adverse events in the older persons. The mechanisms involved in the development of age-related chronic diseases are largely unknown; however, altered redox homeostasis due to ageing is one of the main theories. In this context, the present review explores the development and interaction between different age-related diseases, mainly linked by oxidative stress. In addition, drug interactions in the treatment of various diseases are described, emphasising that the holistic management of older people and their pathologies should prevail over the individual treatment of each condition.

IntroductionThe incidence of obesity, a condition characterized by systemic chronic inflammation, has reached pandemic proportions and is a poor prognostic factor in many pathologic states. However, its role on immune parameters has been diverse and at times contradictory. We have previously demonstrated that obesity can result in what has been called the "obesity paradox" which results in increased T cell exhaustion, but also greater efficacy of immune checkpoint blockade in cancer treatment.MethodsThe role of obesity, particularly in the context of aging, has not been robustly explored using preclinical models. We therefore evaluated how age impacts the immune environment on T cell development and function using diet-induced obese (DIO) mice.ResultsWe observed that DIO mice initially displayed greater thymopoiesis but then developed greater thymic involution over time compared to their lean counterparts. Both aging and obesity resulted in increased T cell memory conversion combined with increased expression of T cell exhaustion markers and Treg expansion. This increased T cell immunosuppression with age then resulted in a loss of anti-tumor efficacy by immune checkpoint inhibitors (ICIs) in older DIO mice compared to the younger DIO counterparts.DiscussionThese results suggest that both aging and obesity contribute to T cell dysfunction resulting in increased thymic involution. This combined with increased T cell exhaustion and immunosuppressive parameters affects immunotherapy efficacy reducing the advantage of obesity in cancer immunotherapy responses.

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset of benign prostatic hyperplasia, prostatitis, and prostate cancer. In this study, we used 14 aged male Sprague Dawley rats, which were allocated into two groups, at the age of 18 months old. One group was fed ad libitum (a normal diet (ND)), and the other group followed a caloric restriction diet with a 60% decrease in intake. The rats were sacrificed at the age of 24 months. By immunohistochemical (IHC) and Western blot (WB) analyses, we studied the variations between the two groups in immune inflammation and fibrosis-related markers in aged prostate tissues. Morphological examinations showed lower levels of prostatic hyperplasia and fibrosis in the CR rats vs. the ND rats. The IHC results revealed that the prostates of the CR rats exhibited a lower immune proinflammatory infiltrate level and a reduced expression of the NLRP3 inflammasome pathway, together with significantly reduced expressions of mesenchymal markers and the profibrotic factor TGFβ1. Finally, by WB analysis, we observed a reduced expression of ERα, which is notoriously implicated in prostate stromal proliferation, and increased expressions of SOD1 and Hsp70, both exerting protective effects against oxidative stress. Overall, these data suggest that CR brings potential benefits to prostatic tissues as it reduces the physiological immune–inflammatory processes and the tissue remodeling caused by aging. [ABSTRACT FROM AUTHOR]

Inflammation contributes to the onset and exacerbation of numerous age-related diseases, often manifesting as a chronic condition during aging. Given that cellular senescence fosters local and systemic inflammation, senotherapeutic interventions could potentially aid in managing or even reducing inflammation. Here, we investigated the immunomodulatory effects of the senotherapeutic Peptide 14 (Pep 14) in human peripheral blood mononuclear cells (PBMCs), monocytes, and macrophages. We found that, despite failing to significantly influence T cell activation and proliferation, the peptide promoted a Th2/Treg gene expression and cytokine signature in PBMCs, characterized by increased expression of the transcription factors GATA3 and FOXP3, as well as the cytokines IL-4 and IL-10. These observations were partially confirmed through ELISA, in which we observed increased IL-10 release by resting and PHA-stimulated PBMCs. In monocytes from the U-937 cell line, Pep 14 induced apoptosis in lipopolysaccharide (LPS)-stimulated cells and upregulated IL-10 expression. Furthermore, Pep 14 prevented LPS-induced activation and promoted an M2-like polarization in U-937-derived macrophages, evidenced by decreased expression of M1 markers and increased expression of M2 markers. We also showed that the conditioned media from Pep 14-treated macrophages enhanced fibroblast migration, indicative of a functional M2 phenotype. Taken together, our findings suggest that Pep 14 modulates immune cell function towards an anti-inflammatory and regenerative phenotype, highlighting its potential as a therapeutic intervention to alleviate immunosenescence-associated dysregulation. [ABSTRACT FROM AUTHOR]

Introduction: Growth Differentiation Factor 15 (GDF15) is a mitokine expressed in response to various stresses whose circulating levels increase with age and are associated with numerous pathological conditions, including muscle wasting and sarcopenia. However, the use of circulating GDF15 (c-GDF15) as a biomarker of sarcopenia is still debated. Moreover, the role of GDF15 intracellular precursor, pro-GDF15, in human skeletal muscle (SM-GDF15) is not totally understood. In order to clarify these points, the association of both forms of GDF15 with parameters of muscle strength, body composition, metabolism and inflammation was investigated. Methods: the levels of c-GDF15 and SM-GDF15 were evaluated in plasma and muscle biopsies, respectively, of healthy subjects (HS) and patients with lower limb mobility impairment (LLMI), either young (<40 years-old) or old (>70 years-old). Other parameters included in the analysis were Isometric Quadriceps Strength (IQS), BMI, lean and fat mass percentage, Vastus lateralis thickness, as well as circulating levels of Adiponectin, Leptin, Resistin, IGF-1, Insulin, IL6, IL15 and c-PLIN2. Principal Component Analysis (PCA), Canonical Discriminant Analysis (CDA) and Receiving Operating Characteristics (ROC) analysis were performed. Results: c-GDF15 but not SM-GDF15 levels resulted associated with decreased IQS and IGF-1 levels in both HS and LLMI, while only in LLMI associated with increased levels of Resistin. Moreover, in LLMI both c-GDF15 and SM-GDF15 levels were associated with IL-6 levels, but interestingly SM-GDF15 is lower in LLMI with respect to HS. Furthermore, a discrimination of the four groups of subjects based on these parameters was possible with PCA and CDA. In particular HS, LLMI over 70 years or under 40 years of age were discriminated based on SMGDF15, c-GDF15 and Insulin levels, respectively. Conclusion: our data support the idea that c-GDF15 level could be used as a biomarker of decreased muscle mass and strength. Moreover, it is suggested that c-GDF15 has a different diagnostic significance with respect to SM-GDF15, which is likely linked to a healthy and active state. [ABSTRACT FROM AUTHOR]

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-1β, 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. [ABSTRACT FROM AUTHOR]

Inflammaging, a coexistence of inflammation and aging, is a persistent, systemic, low-grade inflammation seen in the geriatric population. Various natural compounds have been greatly explored for their potential role in preventing and treating inflammaging. Withania somnifera has been used for thousands of years in traditional medicine as a nutraceutical for its numerous health benefits including regenerative and adaptogenic effects. Recent preclinical and clinical studies on the role of Withania somnifera and its active compounds in treating aging, inflammation, and oxidative stress have shown promise for its use in healthy aging. We discuss the chemistry of Withania somnifera, the etiology of inflammaging and the protective role(s) of Withania somnifera in inflammaging in key organ systems including brain, lung, kidney, and liver as well as the mechanistic underpinning of these effects. Furthermore, we elucidate the beneficial effects of Withania somnifera in oxidative stress/DNA damage, immunomodulation, COVID-19, and the microbiome. We also delineate a putative protein–protein interaction network of key biomarkers modulated by Withania somnifera in inflammaging. In addition, we review the safety/potential toxicity of Withania somnifera as well as global clinical trials on Withania somnifera. Taken together, this is a synthetic review on the beneficial effects of Withania somnifera in inflammaging and highlights the potential of Withania somnifera in improving the health-related quality of life (HRQoL) in the aging population worldwide. [ABSTRACT FROM AUTHOR]

Objective: Inflammaging and immunosenescence are characteristics of senescent immune system alterations. This review provides insights into inflammaging and immunosenescence in periodontitis and focuses on the innerlink of inflammaging and immunosenescence in alveolar bone turnover from a perspective of cell–cell interaction. Methods: This review is conducted by a narrative approach to discuss the effect of inflammaging and immunosenescence in aging‐related alveolar bone loss. A comprehensive literature research in PubMed and Google was applied to identify reports in English. Results: Inflammaging is concerned with abnormal M1 polarization and increasing circulating inflammatory cytokines, while immunosenescence involves reduced infection and vaccine responses, depressed antimicrobial function, and infiltration of aged B cells and memory T cells. TLR‐mediated inflammaging and altered adaptive immunity significantly affect alveolar bone turnover and aggravate aging‐related alveolar bone loss. Besides, energy consumption also plays a vital role in aged immune and skeletal system of periodontitis. Conclusions: Senescent immune system exerts a significant function in aging‐related alveolar bone loss. Inflammaging and immunosenescence interact functionally and mechanistically, which affects alveolar bone turnover. Therefore, further clinical treatment strategies targeting alveolar bone loss could be based on the specific molecular mechanism connecting inflammaging, immunosenescence, and alveolar bone turnover. [ABSTRACT FROM AUTHOR]

The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune‐driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence‐related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging. [ABSTRACT FROM AUTHOR]

In atrial fibrillation (AF), multifactorial pathologic atrial alterations are manifested by structural and electrophysiological changes known as atrial remodeling. AF frequently develops in the context of underlying cardiac abnormalities. A critical mechanistic role played by atrial stretch is played by abnormal substrates in a number of conditions that predispose to AF, including obesity, heart failure, hypertension, and sleep apnea. The significant role of overweight and obesity in the development of AF is known; however, the differential effect of overweight, obesity, cardiovascular comorbidities, lifestyle, and other modifiable risk factors on the occurrence and recurrence of AF remains to be determined. Reverse remodeling of the atrial substrate and subsequent reduction in the AF burden by conversion into a typical sinus rhythm has been associated with weight loss through lifestyle changes or surgery. This makes it an essential pillar in the management of AF in obese patients. According to recently published research, microRNAs (miRs) may function as post-transcriptional regulators of genes involved in atrial remodeling, potentially contributing to the pathophysiology of AF. The focus of this review is on their modulation by both weight loss and catheter ablation interventions to counteract atrial remodeling in AF. Our analysis outlines the experimental and clinical evidence supporting the synergistic effects of weight loss and catheter ablation (CA) in reversing atrial electrical and structural remodeling in AF onset and in recurrent post-ablation AF by attenuating pro-thrombotic, pro-inflammatory, pro-fibrotic, arrhythmogenic, and male-sex-associated hypertrophic remodeling pathways. Furthermore, we discuss the promising role of miRs with prognostic potential as predictive biomarkers in guiding approaches to AF recurrence prevention. [ABSTRACT FROM AUTHOR]

Adipose-derived stem cells (ADSCs) have been proven to promote healing in diabetic wounds, which are one of the most serious chronic refractory wounds. However, reactive oxygen species (ROS) induced by high glucose (HG) lead to oxidative stress and aging in ADSCs, which limits the therapeutic effect of ADSCs. In this study, we investigated the role of GKT137831, a NOX1/4 inhibitor that can reduce ROS production, in protecting ADSCs from hyperglycemia and in diabetic wound healing. In vitro, ROS levels and NOX4 expression were increased after HG treatment of ADSCs, while the oxidative stress marker malondialdehyde was increased; mitochondrial membrane potential was decreased; inflammatory aging–related indicators such as p16, p21, matrix metalloproteinase-1 (MMP1), MMP3, interleukin-6, and β-galactosidase were increased; and migration was weakened. In vivo, we constructed a diabetic mouse wound model and found that the combination of ADSCs and GKT137831 synergistically promoted the 21-day wound healing rate, increased the expression of collagen and hydroxyproline, increased the number of blood vessels and the expression of CD31, and reduced the expression of interleukin-6, MMP1, MMP3, and p21. These results suggest that GKT137831 could protect ADSCs from oxidative stress and aging induced by HG and enhance the therapeutic effect of ADSCs on diabetic wounds. [ABSTRACT FROM AUTHOR]

Adaptive immunity plays a profound role in atherosclerosis pathogenesis by regulating antigen-specific responses, inflammatory signaling and antibody production. However, as we age, our immune system undergoes a gradual functional decline, a phenomenon termed "immunosenescence". This decline is characterized by a reduction in proliferative naïve B- and T cells, decreased Band T cell receptor repertoire and a pro-inflammatory senescence associated secretory profile. Furthermore, aging affects germinal center responses and deteriorates secondary lymphoid organ function and structure, leading to impaired T-B cell dynamics and increased autoantibody production. In this review, we will dissect the impact of aging on adaptive immunity and the role played by age-associated B- and T cells in atherosclerosis pathogenesis, emphasizing the need for interventions that target age-related immune dysfunction to reduce cardiovascular disease risk. [ABSTRACT FROM AUTHOR]

The notion that viruses played a crucial role in the evolution of life is not a new concept. However, more recent insights suggest that this perception might be even more expansive, highlighting the ongoing impact of viruses on host evolution. Endogenous retroviruses (ERVs) are considered genomic remnants of ancient viral infections acquired throughout vertebrate evolution. Their exogenous counterparts once infected the host's germline cells, eventually leading to the permanent endogenization of their respective proviruses. The success of ERV colonization is evident so that it constitutes 8% of the human genome. Emerging genomic studies indicate that endogenous retroviruses are not merely remnants of past infections but rather play a corollary role, despite not fully understood, in host genetic regulation. This review presents some evidence supporting the crucial role of endogenous retroviruses in regulating host genetics. We explore the involvement of human ERVs (HERVs) in key physiological processes, from their precise and orchestrated activities during cellular differentiation and pluripotency to their contributions to aging and cellular senescence. Additionally, we discuss the costs associated with hosting a substantial amount of preserved viral genetic material. [ABSTRACT FROM AUTHOR]

Chronic inflammation is increasingly considered as the most important component of vascular aging, contributing to the progression of age‐related cardiovascular diseases. To delay the process of vascular aging, anti‐inflammation may be an effective measure. The anti‐inflammatory factor annexin A1 (ANXA1) is shown to participate in several age‐related diseases; however, its function during vascular aging remains unclear. Here, an ANXA1 knockout (ANXA1−/−) and an endothelial cell‐specific ANXA1 deletion mouse (ANXA1△EC) model are used to investigate the role of ANXA1 in vascular aging. ANXA1 depletion exacerbates vascular remodeling and dysfunction while upregulates age‐ and inflammation‐related protein expression. Conversely, Ac2‐26 (a mimetic peptide of ANXA1) supplementation reverses this phenomenon. Furthermore, long‐term tumor necrosis factor‐alpha (TNF‐α) induction of human umbilical vein endothelial cells (HUVECs) increases cell senescence. Finally, the senescence‐associated secretory phenotype and senescence‐related protein expression, rates of senescence‐β‐galactosidase positivity, cell cycle arrest, cell migration, and tube formation ability are observed in both ANXA1‐knockdown HUVECs and overexpressed ANXA1‐TNF‐α induced senescent HUVECs. They also explore the impact of formyl peptide receptor 2 (a receptor of ANXA1) in an ANXA1 overexpression inflammatory model. These data provide compelling evidence that age‐related inflammation in arteries contributes to senescent endothelial cells that promote vascular aging. [ABSTRACT FROM AUTHOR]

Aging is a complex process characterized by a myriad of physiological changes, including alterations in the immune system termed immunosenescence. It exerts profound effects on both the bone marrow and the central nervous system, with significant implications for immunosenescence in neurological contexts. Our mini-review explores the complex relationship between bone marrow aging and its impact on immunosenescence, specifically within the context of neurological diseases. The bone marrow serves as a crucial hub for hematopoiesis and immune cell production, yet with age, it undergoes significant alterations, including alterations in hematopoietic stem cell function, niche composition, and inflammatory signaling. These age-related shifts in the bone marrow microenvironment contribute to dysregulation of immune cell homeostasis and function, impacting neuroinflammatory processes and neuronal health. In our review, we aim to explore the complex cellular and molecular mechanisms that link bone marrow aging to immunosenescence, inflammaging, and neuroinflammation, with a specific focus on their relevance to the pathophysiology of age-related neurological disorders. By exploring this interplay, we strive to provide a comprehensive understanding of how bone marrow aging impacts immune function and contributes to the progression of neurological diseases in aging individuals. Ultimately, this knowledge can hold substantial promise for the development of innovative therapeutic interventions aimed at preserving immune function and mitigating the progression of neurological disorders in the elderly population. [ABSTRACT FROM AUTHOR]

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10. [ABSTRACT FROM AUTHOR]

Frailty syndrome refers to the nonspecific state of increased body vulnerability and decreased antistress and recovery abilities after stress during aging. Sarcopenia is the major component of frailty and is characterized by the gradual loss of muscle mass, strength, and function with age. Inflammaging is the gradual increase in inflammatory status during aging, and it disrupts immune tolerance, causes physiological changes in tissues, organs, and normal cells, and is related to frailty and sarcopenia. The gut microbiota is an extremely complex and diverse microbial community that coevolves with the host. The composition and structure of the gut microbiota and the metabolism of tryptophan (Trp) significantly change in older adults with frailty and sarcopenia. The gut microbiota participates in regulating the Trp metabolic pathways of kynurenine (Kyn), 5-hydroxytryptamine (5-HT), and indole in the gastrointestinal tract. The Trp metabolites derived from the gut microbiota may synergistically promote the occurrence of age-related frailty and sarcopenia by promoting inflammation in the intestines, nervous system, and muscles. The role and mechanisms of the gut microbiota, Trp metabolism, and inflammaging in age-related frailty and sarcopenia may be a worthwhile research direction to help promote healthy aging. [ABSTRACT FROM AUTHOR]

Introduction: As the population over the age of 65 increases, rates of neurodegenerative disorders and dementias will rise - necessitating further research into the cellular and molecular mechanisms that contribute to brain aging. With the critical importance of astrocytes to neuronal health and functioning, we hypothesized that alterations in astrocyte expression of aging-associated markers p16INK4a (p16) and sirtuin 1 (SIRT1) with age would correlate with increased rates of neurodegeneration, as measured by FluoroJade C (FJC) staining. Methods: To test this hypothesis, 19 rhesus macaques at the Tulane National Primate Research Center were selected based on the following criteria: archival FFPE CNS tissue available to use, no noted neuropathology, and an age range of 5-30 years. Tissues were cut at 5 µm and stained for GFAP, p16, SIRT1, and FJC, followed by whole-slide imaging and HALO® image analysis for percentage of marker-positive cells and relative intensity of each stain. Results: We found the percentage of p16+ cells increases with age in total cells and astrocytes of the frontal (p = 0.0021, p = 0.0012 respectively) and temporal (p = 0.0226, p = 0.0203 respectively) lobes, as well as the relative intensity of p16 staining (frontal lobe: p = 0.0060; temporal lobe: p = 0.0269). For SIRT1, we found no correlation with age except for an increase in the relative intensity of SIRT1 in the temporal lobe (p = 0.0033). There was an increase in neurodegeneration, as measured by the percentage of FJC+ cells in the frontal lobe with age (p = 0.0057), as well as in the relative intensity of FJC staining in the frontal (p = 0.0030) and parietal (p = 0.0481) lobes. Importantly, increased p16 and SIRT1 expression in astrocytes correlated with increasing neurodegeneration in the frontal lobe (p = 0.0009, p = 0.0095 respectively). Discussion: Together, these data suggest that age-associated alterations in astrocytes contribute to neurodegeneration and provide a target for mechanistic studies in the future. [ABSTRACT FROM AUTHOR]

Immunosenescence refers to age-related alterations in immune system function affecting both the humoral and cellular arm of immunity. Understanding immunosenescence and its impact on the vaccination of older adults is essential since primary vaccine responses in older individuals can fail to generate complete protection, especially vaccines targeting infections with increased incidence among the elderly, such as the respiratory syncytial virus. Here, we review clinical trials of both candidate and approved vaccines against respiratory syncytial virus (RSV) that include adults aged ≥50 years, with an emphasis on the evaluation of immunogenicity parameters. Currently, there are 10 vaccine candidates and 2 vaccines approved for the prevention of RSV in the older adult population. The number of registered clinical trials for this age group amounts to 42. Our preliminary evaluation of published results and interim analyses of RSV vaccine clinical trials indicates efficacy in older adult participants, demonstrating immunity levels that closely resemble those of younger adult participants. [ABSTRACT FROM AUTHOR]

Immune system aging is becoming a field of increasing public health interest because of prolonged life expectancy, which is not paralleled by an increase in health expectancy. As age progresses, innate and adaptive immune systems undergo changes, which are defined, respectively, as inflammaging and immune senescence. A wealth of available data demonstrates that these two conditions are closely linked, leading to a greater vulnerability of elderly subjects to viral, bacterial, and opportunistic infections as well as lower post-vaccination protection. To face this novel scenario, an in-depth assessment of the immune players involved in this changing epidemiology is demanded regarding the individual and concerted involvement of immune cells and mediators within endogenous and exogenous factors and co-morbidities. This review provides an overall updated description of the changes affecting the aging immune system, which may be of help in understanding the underlying mechanisms associated with the main age-associated infectious diseases. [ABSTRACT FROM AUTHOR]

The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300–350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle. [ABSTRACT FROM AUTHOR]

Introduction: Aging studies in humans and mice have played a key role in understanding the intestinal microbiome and an increased abundance of “inflammaging” Gram-negative (Gn) bacteria. The mechanisms underlying this inflammatory profile in the aging microbiome are unknown. We tested the hypothesis that an aging-related decrease in colonic crypt epithelial cell anti)microbial peptide (AMP) gene expression could promote colonic microbiome inflammatory Gn dysbiosis and inflammaging. Methods: As a model of aging, C57BL/6J mice fecal (colonic) microbiota (16S) and isolated colonic crypt epithelial cell gene expression (RNA-seq) were assessed at 2 months (mth) (human: 18 years old; yo), 15 mth (human: 50 yo), and 25 mth (human: 84 yo). Informatics examined aging-related microbial compositions, differential colonic crypt epithelial cell gene expressions, and correlations between colonic bacteria and colonic crypt epithelial cell gene expressions. Results: Fecal microbiota exhibited significantly increased relative abundances of pro-inflammatory Gn bacteria with aging. Colonic crypt epithelial cell gene expression analysis showed significant age-related downregulation of key AMP genes that repress the growth of Gn bacteria. The aging-related decrease in AMP gene expressions is significantly correlated with an increased abundance in Gn bacteria (dysbiosis), loss of colonic barrier gene expression, and senescence- and inflammation-related gene expression. Conclusion: This study supports the proposed model that aging-related loss of colonic crypt epithelial cell AMP gene expression promotes increased relative abundances of Gn inflammaging-associated bacteria and gene expression markers of colonic inflammaging. These data may support new targets for aging-related therapies based on intestinal genes and microbiomes. [ABSTRACT FROM AUTHOR]

Aim: Physical exercise triggers the secretion of small extracellular vesicles (sEVs) into the circulation in humans, enabling signalling crosstalk between tissues. Exercise‐derived EVs and their cargo have been proposed to mediate adaptations to exercise; however, our understanding of how exercise‐derived EV protein cargo is modulated by factors such as aerobic fitness and age of an individual is currently unknown. Here, we examined the circulating sEV proteome following aerobic exercise in healthy males of different ages and aerobic fitness to understand exercise‐induced EV response during the aging process. Methods: Twenty‐eight healthy men completed a bout of 20‐min cycling exercise at 70% estimated VO2peak. Small EVs were isolated from blood samples collected before and immediately after exercise, and then quantified using particle analysis and Western blotting. Small EV proteome was examined using quantitative proteomic analysis. Results: We identified a significant increase in 13 proteins in small plasma EVs following moderate‐to‐vigorous intensity exercise. We observed distinct changes in sEV proteome after exercise in young, mature, unfit, and fit individuals, highlighting the impact of aerobic fitness and age on sEV protein secretion. Functional enrichment and pathway analysis identified that the majority of the significantly altered sEV proteins are associated with the innate immune system, including proteins known to be damage‐associated molecular patterns (DAMPs). Conclusion: Together, our findings suggest that exercise‐evoked acute stress can positively challenge the innate immune system through the release of signalling molecules such as DAMPs in sEVs, proposing a novel EV‐based mechanism for moderate‐to‐vigorous intensity exercise in immune surveillance pathways. [ABSTRACT FROM AUTHOR]

Besides cellular changes in the dermis aging takes place in the extracelluar matrix (ECM). Lack of homoeostasis leads to dysregulation and loss of collagen, elastin, and hyaluronic acid as main structures of the ECM. Adding hyaluronic acid and amino acids as important factors to reconstruct the collagen system is a very promising method to reestablish homoeostasis in the ECM. The importance of the exact concentration of the ingredients must be underlined. [ABSTRACT FROM AUTHOR]

One of the current challenges of biomedicine is to elucidate the multicomponent and multilevel mechanism of integrated neuroimmunoendocrine regulation of physiological functions. Respiratory diseases are leading in the structure of general morbidity among the population and remain one of the most relevant problems of modern healthcare. Numerous risk factors can contribute to the development of such pulmonary pathologies as pneumonia, lung cancer, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, pulmonary fibrosis and others, whose incidence tends to increase annually. In this regard, signaling molecules, which are involved in neuroimmunoendocrine respiratory regulation and can be considered as both prognostic biomarkers and potential therapeutic targets, are coming into focus of modern translational biomedicine. This review addresses the role of one of the key actors in the neuroimmunoendocrine regulation of homeostasis, a ubiquitous transcription factor NF-κB, in the regulation of respiratory function in health and during the pathogenesis of lung diseases. There is ample evidence that many pulmonary pathologies, resulting from ongoing inflammatory processes, are associated with NF-κB activation. A comprehensive investigation of the mechanisms underlying NF-κB activation and its relationship with other signaling pathways will contribute to solving the main task of translational biomedicine, the development of innovative approaches to prevention and personalized targeted therapies for human socially significant pathologies, including respiratory diseases. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in various physiological processes within mammalian cells, including energy metabolism, redox homeostasis, and genetic regulation. In the majority of mammalian cellular contexts, NAD+ biosynthesis primarily relies on vitamin B3, including nicotinamide (NAM) and nicotinic acid (NA). The concept of NAD+ augmentation therapy has recently emerged as a promising strategy to mitigate aging-associated phenomena, termed rejuvenation. Despite the involvement of diverse enzymatic cascades in NAD+ biosynthesis, certain cellular environments exhibit deficiencies in specific enzymes, suggesting cell type-dependent variability in optimal NAD+ precursor selection. However, the optimization of NAD+ precursors for topical formulations has received scant attention thus far. In the present investigation, we sought to delineate the most efficacious precursor for augmenting NAD+ levels in human skin keratinocytes. Remarkably, NA supplementation led to a significant 1.3-fold elevation in intracellular NAD+ levels, even in the presence of nicotinamide phosphoribosyltransferase inhibition by FK866. Additionally, NA mononucleotide demonstrated a 1.5-fold increase (but not significant) in NAD+ levels following 100 μM application. Conversely, NAM and its derivatives failed to elicit a NAD+ response in keratinocytes. Notably, NA supplementation elicited up-regulation of mitochondrial superoxide dismutase (SOD2) and sirtuin 3 (SIRT3), indicative of its beneficial impact on mitochondrial function. Furthermore, NA mitigated rotenone-induced mitochondrial reactive oxygen species (ROS) accumulation. Collectively, these findings advocate for the potential utility of NA in topical applications aimed at skin rejuvenation. [ABSTRACT FROM AUTHOR]

Sporadic inclusion body myositis (sIBM) is the most common muscle disease of older people and is clinically characterized by slowly progressive asymmetrical muscle weakness, predominantly affecting the quadriceps, deep finger flexors, and foot extensors. At present, there are no enduring treatments for this relentless disease that eventually leads to severe disability and wheelchair dependency. Although sIBM is considered a rare muscle disorder, its prevalence is certainly higher as the disease is often undiagnosed or misdiagnosed. The histopathological phenotype of sIBM muscle biopsy includes muscle fiber degeneration and endomysial lymphocytic infiltrates that mainly consist of cytotoxic CD8+ T cells surrounding nonnecrotic muscle fibers expressing MHCI. Muscle fiber degeneration is characterized by vacuolization and the accumulation of congophilic misfolded multi-protein aggregates, mainly in their non-vacuolated cytoplasm. Many players have been identified in sIBM pathogenesis, including environmental factors, autoimmunity, abnormalities of protein transcription and processing, the accumulation of several toxic proteins, the impairment of autophagy and the ubiquitin–proteasome system, oxidative and nitrative stress, endoplasmic reticulum stress, myonuclear degeneration, and mitochondrial dysfunction. Aging has also been proposed as a contributor to the disease. However, the interplay between these processes and the primary event that leads to the coexistence of autoimmune and degenerative changes is still under debate. Here, we outline our current understanding of disease pathogenesis, focusing on degenerative mechanisms, and discuss the possible involvement of aging. [ABSTRACT FROM AUTHOR]

Cockayne syndrome (CS) is a rare autosomal recessive disorder that affects the DNA repair process. It is a progeroid syndrome predisposing patients to accelerated aging and to increased susceptibility to respiratory infections. Here, we studied the immune status of CS patients to determine potential biomarkers associated with pathological aging. CS patients, as well as elderly and young, healthy donors, were enrolled in this study. Complete blood counts for patients and donors were assessed, immune cell subsets were analyzed using flow cytometry, and candidate cytokines were analyzed via multi-analyte ELISArray kits. In CS patients, we noticed a high percentage of lymphocytes, an increased rate of intermediate and non-classical monocytes, and a high level of pro-inflammatory cytokine IL-8. In addition, we identified an increased rate of particular subtypes of T Lymphocyte CD8+ CD28− CD27−, which are senescent T cells. Thus, an inflammatory state was found in CS patients that is similar to that observed in the elderly donors and is associated with an immunosenescence status in both groups. This could explain the CS patients' increased susceptibility to infections, which is partly due to an aging-associated inflammation process. [ABSTRACT FROM AUTHOR]

Background Persistent inflammation related to aging ("inflammaging") is exacerbated by chronic infections and contributes to frailty in older adults. We hypothesized associations between Toxoplasma gondii (T. gondii), a common parasite causing an oligosymptomatic unremitting infection, and frailty, and secondarily between T. gondii and previously reported markers of immune activation in frailty. Methods We analyzed available demographic, social, and clinical data in Spanish and Portuguese older adults [ N = 601; age: mean (SD) 77.3 (8.0); 61% women]. Plasma T. gondii immunoglobulin G (IgG) serointensity was measured with an enzyme-linked immunosorbent assay. The Fried criteria were used to define frailty status. Validated translations of Mini-Mental State Examination, Geriatric Depression Scale, and the Charlson Comorbidity Index were used to evaluate confounders. Previously analyzed biomarkers that were significantly associated with frailty in both prior reports and the current study, and also related to T. gondii serointensity, were further accounted for in multivariable logistic models with frailty as outcome. Results In T. gondii -seropositives, there was a significant positive association between T. gondii IgG serointensity and frailty, accounting for age (p =.0002), and resisting adjustment for multiple successive confounders. Among biomarkers linked with frailty, kynurenine/tryptophan and soluble tumor necrosis factor receptor II were positively associated with T. gondii serointensity in seropositives (p <.05). Associations with other biomarkers were not significant. Conclusions This first reported association between T. gondii and frailty is limited by a cross-sectional design and warrants replication. While certain biomarkers of inflammaging were associated with both T. gondii IgG serointensity and frailty, they did not fully mediate the T. gondii –frailty association. [ABSTRACT FROM AUTHOR]

Background: Immunosenescence is a multifactorial stress response to different intrinsic and extrinsic insults that cause immune deterioration and is accompanied by genomic or epigenomic perturbations. It is now widely recognized that genes and proteins contributing in the process of immunosenescence are regulated by various noncoding (nc) RNAs, including microRNAs (miRNAs), long ncRNAs, and circular RNAs. Aims: This review article aimed to evaluate the regulatore RNAs roles in the process of immunosenescence. Methods: We analyzed publications that were focusing on the different roles of regulatory RNAs on the several aspects of immunosenescence. Results: In the immunosenescence setting, ncRNAs have been found to play regulatory roles at both transcriptional and post‐transcriptional levels. These factors cooperate to regulate the initiation of gene expression programs and sustaining the senescence phenotype and proinflammatory responses. Conclusion: Immunosenescence is a complex process with pivotal alterations in immune function occurring with age. The extensive network that drive immunosenescence‐related features are are mainly directed by a variety of regulatory RNAs such as miRNAs, lncRNAs, and circRNAs. Latest findings about regulation of senescence by ncRNAs in the innate and adaptive immune cells as well as their role in the immunosenescence pathways, provide a better understanding of regulatory RNAs function in the process of immunosenescence. Highlights: The immunosenescence process is strictly controlled by genetic and epigenetic factorsInnate and adaptive immune responses are affected by immunosenescenceThe proteostasis is a major hallmark of aging and cellular senescenceThe regulatory RNAs are involved in the aging of immune system [ABSTRACT FROM AUTHOR]

SARS-CoV-2 virulence is known to increase with lowering of environmental temperature and solar ultraviolet radiation; therefore, we have focused our real-world nationwide study concerning with COVID-19 trend and dynamics on the coldest seasons of the year in Italy, the Western country hardest hit at the onset of the pandemic, comparing the autumn–winter of 2020 (before mass vaccination but when the emergency machinery was fully operative in terms of tracing and swabs) with the autumn–winter of 2021 (after mass vaccination), and analyzing the mortality burden by age groups and life stages in the years 2019 (pre-COVID-19), 2020 (before mass vaccination), and 2021 (after mass vaccination). Methods: During the state of national health emergency, the Civil Defense Department released the aggregate data coming from the Higher Institute of Health, the Ministry of Health, the Italian Regions, and the Independent Provinces, to inform the population about the pandemic situation, daily. Among these data, there were the number of contagions, performed swabs, hospitalizations in Intensive Care Units (ICU), non-ICU patients, and deaths. By means of a team effort, we have collected and elaborated all these data, comparing the COVID-19 pandemic in Italy during the autumn–winter of 2020 with the autumn–winter of 2021. Moreover, we have extracted from the database of the National Institute of Statistics the total number of annual deaths in Italy during the years 2019, 2020, and 2021, comparing them to each other in order to evaluate the mortality burden attributable to COVID-19. Results: From the autumn–winter of 2020 to the autumn–winter of 2021, the contagions increased by ≈285%, against a ≈290% increase in the performed swabs; therefore, the mean positivity rate passed from 8.74% before mass vaccination to 8.59% after mass vaccination. The unprecedent vaccination campaign allowed a ≈251% abatement in COVID-19 deaths, and a reduction of ≈224% and ≈228% in daily ICU and non-ICU hospitalizations due to COVID-19, respectively. Regarding COVID-19 deaths, in 2020, there was a mortality excess of ≈14.3% quantifiable in 105,900 more deaths compared to 2019, the pre-COVID-19 year; 103,183 out of 105,900 deaths occurred in older adults (≥60 years), which is equivalent to ≈97.4%, while in adults over 50, the segment of population just below older adults, in 2020, there were 2807 more deaths than in 2019. Surprisingly, from the analysis of our data, it is emerged that in people under the age of 40 in the years 2019, 2020, and 2021, there were 7103, 6808, and 7165 deaths, respectively. This means that in subjects under 40 during 2020, there were 295 fewer deaths than in 2019, while during 2021, there were 357 more deaths than in 2020, equivalent to ≈5.2% more. Conclusions: COVID-19 is a potential life-threatening disease mainly in older adults, as they are the most vulnerable due to inherent immunosenescence and inflammaging. Extensive vaccination in this segment of population with up-to-date vaccines is the means to reduce deaths, hospitalizations, and ICU pressure in the public interest. In the event of future threats, a new mass vaccination campaign should not be implemented without taking into account the individual age; it should primarily be aimed at people over 60 and at patients of any age with immune deficits, and secondly at people over 50. COVID-19 vaccination shows a favorable benefit–risk ratio in older adults, while the balance steps down under the age of 40; this younger segment of the population should be therefore exempt from any mandatory vaccination. [ABSTRACT FROM AUTHOR]

Immunosenescence refers to the age-related progressive decline of immune function contributing to the increased susceptibility to infectious diseases in older people. Neurocryptococcosis, an infectious disease of central nervous system (CNS) caused by Cryptococcus neoformans (C. Neoformans) and C. gattii, has been observed with increased frequency in aged people, as result of the reactivation of a latent infection or community acquisition. These opportunistic microorganisms belonging to kingdom of fungi are capable of surviving and replicating within macrophages. Typically, cryptococcus is expelled by vomocytosis, a non-lytic expulsive mechanism also promoted by interferon (IFN)-I, or by cell lysis. However, whereas in a first phase cryptococcal vomocytosis leads to a latent asymptomatic infection confined to the lung, an enhancement in vomocytosis, promoted by IFN-I overproduction, can be deleterious, leading the fungus to reach the blood stream and invade the CNS. Cryptococcus may not be easy to diagnose in older individuals and, if not timely treated, could be potentially lethal. Therefore, this review aims to elucidate the putative causes of the increased incidence of cryptococcal CNS infection in older people discussing in depth the mechanisms of immunosenscence potentially able to predispose to neurocryptococcosis, laying the foundations for future research. A deepest understanding of this relationship could provide new ways to improve the prevention and recognition of neurocryptococcosis in aged frail people, in order to quickly manage pharmacological interventions and to adopt further preventive measures able to reduce the main risk factors.

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-1β, 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.

Immunosenescence is a phenomenon caused by changes in the immune system, and part of these changes involves an increase in circulating immunological biomarkers, a process known as “Inflammaging.” Inflammaging can be associated with many diseases related to older people. As the older population continues to grow, understanding changes in the immune system becomes essential. While prior studies assessing these alterations have been conducted in countries with Caucasian populations, this investigation marks a pioneering effort. The object of the study is to describe for the first time that the distribution of cytokines, chemokines, and growth factors serum levels, assessed by Luminex platform, has been examined in a Brazilian population-based study of older adult females and males by age. Blood samples from 2111 participants (≥50 years old) were analyzed at the baseline (2015/2016) of the ELSI-Brazil study. The exploratory variables considered in the study were age, sex, educational level, residence area, geographic region, alcohol and smoking consumption, physical activity, and self-reported medical diagnoses of hypertension, diabetes, asthma, arthritis, and cancer. The association between serum biomarker levels and age was assessed by a quantile regression model adjusted in the total population and stratified by sex. The significance level considered in the analysis was 0.05. The mean age of the participants was 62.9 years, with a slight majority of female (52.7 %). Differences were found between the sexes in the median circulating levels of the CCL11, CXCL10, and FGF biomarkers. Eight biomarkers showed significant associations with age, including the pro-inflammatory CXCL10, TNF-α, IL-6, IL-17, and IL-2; and type 2/regulatory CCL11 and IL-4, showing positive associations, and anti-inflammatory IL-1Ra showing a negative association. The results suggest similar associations between the sexes, revealing an inflammatory profile characterized by types 1 and 2. Remarkably, these findings reinforce the concept of the Inflammaging process in Brazilian population. These findings add novel insights to about the immunosenescence aspects in middle-income countries and help define biomarkers capable of monitoring inflammation in older adults.

Immune checkpoint inhibitors (ICIs) are employed in immunotherapeutic applications for patients with weakened immune systems and can improve the ability of T cells to kill cancer cells. Although ICIs can potentially treat different types of cancers in various groups of patients, their effectiveness may differ among older individuals. The reason ICIs are less effective in older adults is not yet clearly understood, but age-related changes in the immune system, such as immunosenescence and inflammation, may play a role. Therefore, this review focuses on recent advances in understanding the effects of immunosenescence and inflammation on the efficacy of ICIs.