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Chronic inflammation and the hallmarks of aging.
Baechle, JJ, Chen, N, Makhijani, P, Winer, S, Furman, D, Winer, DA
Molecular metabolism. 2023;:101755
Abstract
BACKGROUND Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, the low-grade chronic inflammation during aging, without overt infection, is defined as "inflammaging," which is associated with increased morbidity and mortality in the aging population. Emerging evidence suggests a bidirectional and cyclical relationship between chronic inflammation and the development of age-related conditions, such as cardiovascular diseases, neurodegeneration, cancer, and frailty. How the crosstalk between chronic inflammation and other hallmarks of aging underlies biological mechanisms of aging and age-related disease is thus of particular interest to the current geroscience research. SCOPE OF REVIEW This review integrates the cellular and molecular mechanisms of age-associated chronic inflammation with the other eleven hallmarks of aging. Extra discussion is dedicated to the hallmark of "altered nutrient sensing," given the scope of Molecular Metabolism. The deregulation of hallmark processes during aging disrupts the delicate balance between pro-inflammatory and anti-inflammatory signaling, leading to a persistent inflammatory state. The resultant chronic inflammation, in turn, further aggravates the dysfunction of each hallmark, thereby driving the progression of aging and age-related diseases. MAIN CONCLUSIONS The crosstalk between chronic inflammation and other hallmarks of aging results in a vicious cycle that exacerbates the decline in cellular functions and promotes aging. Understanding this complex interplay will provide new insights into the mechanisms of aging and the development of potential anti-aging interventions. Given their interconnectedness and ability to accentuate the primary elements of aging, drivers of chronic inflammation may be an ideal target with high translational potential to address the pathological conditions associated with aging.
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Regulation of the immune system by the insulin receptor in health and disease.
Makhijani, P, Basso, PJ, Chan, YT, Chen, N, Baechle, J, Khan, S, Furman, D, Tsai, S, Winer, DA
Frontiers in endocrinology. 2023;:1128622
Abstract
The signaling pathways downstream of the insulin receptor (InsR) are some of the most evolutionarily conserved pathways that regulate organism longevity and metabolism. InsR signaling is well characterized in metabolic tissues, such as liver, muscle, and fat, actively orchestrating cellular processes, including growth, survival, and nutrient metabolism. However, cells of the immune system also express the InsR and downstream signaling machinery, and there is increasing appreciation for the involvement of InsR signaling in shaping the immune response. Here, we summarize current understanding of InsR signaling pathways in different immune cell subsets and their impact on cellular metabolism, differentiation, and effector versus regulatory function. We also discuss mechanistic links between altered InsR signaling and immune dysfunction in various disease settings and conditions, with a focus on age related conditions, such as type 2 diabetes, cancer and infection vulnerability.
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Oats Lower Age-Related Systemic Chronic Inflammation (iAge) in Adults at Risk for Cardiovascular Disease.
Dioum, EHM, Schneider, KL, Vigerust, DJ, Cox, BD, Chu, Y, Zachwieja, JJ, Furman, D
Nutrients. 2022;14(21)
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The immune system and more specifically a form of inflammation is thought to be involved in the development of heart disease. Therefore, reducing inflammation may serve to lower an individual’s risk for heart disease. In a previous study, it was shown that the consumption of an oat-based product improved the risk of heart disease development in individuals with high cholesterol. This randomised control study of 191 healthy male and females aimed to analyse the participants from that study and see if the consumption of an oat-based product affected their level of inflammation also. The results showed that inflammation in individuals who consumed the oat-based product was improved but only in individuals who had elevated inflammation at the start of the trial. This was largely attributed to a decrease in a protein associated with ageing. It was concluded that oats when recommended as part of a personalised diet plan, may decrease inflammation, and prevent heart disease in those who are at an elevated risk. This study could be used by healthcare professionals to understand that the use of oats as part of a personalised diet plan can help to reduce the risk of heart disease.
Abstract
Despite being largely preventable, cardiovascular disease (CVD) is still the leading cause of death globally. Recent studies suggest that the immune system, particularly a form of systemic chronic inflammation (SCI), is involved in the mechanisms leading to CVD; thus, targeting SCI may help prevent or delay the onset of CVD. In a recent placebo-controlled randomized clinical trial, an oat product providing 3 g of β-Glucan improved cholesterol low-density lipoprotein (LDL) levels and lowered cardiovascular risk in adults with borderline high cholesterol. Here, we conducted a secondary measurement of the serum samples to test whether the oat product has the potential to reduce SCI and improve other clinical outcomes related to healthy aging. We investigated the effects of the oat product on a novel metric for SCI called Inflammatory Age® (iAge®), derived from the Stanford 1000 Immunomes Project. The iAge® predicts multimorbidity, frailty, immune decline, premature cardiovascular aging, and all-cause mortality on a personalized level. A beneficial effect of the oat product was observed in subjects with elevated levels of iAge® at baseline (>49.6 iAge® years) as early as two weeks post-treatment. The rice control group did not show any significant change in iAge®. Interestingly, the effects of the oat product on iAge® were largely driven by a decrease in the Eotaxin-1 protein, an aging-related chemokine, independent of a person’s gender, body mass index, or chronological age. Thus, we describe a novel anti-SCI role for oats that could have a major impact on functional, preventative, and personalized medicine.
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Obesity and Leptin Resistance in the Regulation of the Type I Interferon Early Response and the Increased Risk for Severe COVID-19.
Muskiet, FAJ, Carrera-Bastos, P, Pruimboom, L, Lucia, A, Furman, D
Nutrients. 2022;(7)
Abstract
Obesity, and obesity-associated conditions such as hypertension, chronic kidney disease, type 2 diabetes, and cardiovascular disease, are important risk factors for severe Coronavirus disease-2019 (COVID-19). The common denominator is metaflammation, a portmanteau of metabolism and inflammation, which is characterized by chronically elevated levels of leptin and pro-inflammatory cytokines. These induce the "Suppressor Of Cytokine Signaling 1 and 3" (SOCS1/3), which deactivates the leptin receptor and also other SOCS1/3 sensitive cytokine receptors in immune cells, impairing the type I and III interferon early responses. By also upregulating SOCS1/3, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV)-2 adds a significant boost to this. The ensuing consequence is a delayed but over-reactive immune response, characterized by high-grade inflammation (e.g., cytokine storm), endothelial damage, and hypercoagulation, thus leading to severe COVID-19. Superimposing an acute disturbance, such as a SARS-CoV-2 infection, on metaflammation severely tests resilience. In the long run, metaflammation causes the "typical western" conditions associated with metabolic syndrome. Severe COVID-19 and other serious infectious diseases can be added to the list of its short-term consequences. Therefore, preventive measures should include not only vaccination and the well-established actions intended to avoid infection, but also dietary and lifestyle interventions aimed at improving body composition and preventing or reversing metaflammation.
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A clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring.
Alpert, A, Pickman, Y, Leipold, M, Rosenberg-Hasson, Y, Ji, X, Gaujoux, R, Rabani, H, Starosvetsky, E, Kveler, K, Schaffert, S, et al
Nature medicine. 2019;25(3):487-495
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The human immune system changes with age, ultimately leading to a clinically evident, profound deterioration resulting in high morbidity and mortality rates attributed to infectious and chronic diseases. The aim of this study was to assess at high resolution the dynamics of older adults’ immune systems. The study uses multiple ‘omics’ technologies in a cohort of 135 adults (63 young adults and 72 older adults) of different ages who were sampled longitudinally over the course of 9 years to comprehensively capture population- and individual-level changes in the immune system over time. Results indicate that immune-cell frequencies changed at substantially different rates; some cell subsets show no directionality of change yet differ between young and old individuals, whereas other cell subsets continued changing (either increasing or decreasing) throughout the course of the study. Authors postulate that an individual’s immune age is a function of life history, namely environmental exposure coupled with genetic background. Thus, immune modulators may one day be identified that affect the position of an individual’s immune system along the immunological landscape.
Abstract
Immune responses generally decline with age. However, the dynamics of this process at the individual level have not been characterized, hindering quantification of an individual's immune age. Here, we use multiple 'omics' technologies to capture population- and individual-level changes in the human immune system of 135 healthy adult individuals of different ages sampled longitudinally over a nine-year period. We observed high inter-individual variability in the rates of change of cellular frequencies that was dictated by their baseline values, allowing identification of steady-state levels toward which a cell subset converged and the ordered convergence of multiple cell subsets toward an older adult homeostasis. These data form a high-dimensional trajectory of immune aging (IMM-AGE) that describes a person's immune status better than chronological age. We show that the IMM-AGE score predicted all-cause mortality beyond well-established risk factors in the Framingham Heart Study, establishing its potential use in clinics for identification of patients at risk.
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Chronic inflammation in the etiology of disease across the life span.
Furman, D, Campisi, J, Verdin, E, Carrera-Bastos, P, Targ, S, Franceschi, C, Ferrucci, L, Gilroy, DW, Fasano, A, Miller, GW, et al
Nature medicine. 2019;(12):1822-1832
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Abstract
Although intermittent increases in inflammation are critical for survival during physical injury and infection, recent research has revealed that certain social, environmental and lifestyle factors can promote systemic chronic inflammation (SCI) that can, in turn, lead to several diseases that collectively represent the leading causes of disability and mortality worldwide, such as cardiovascular disease, cancer, diabetes mellitus, chronic kidney disease, non-alcoholic fatty liver disease and autoimmune and neurodegenerative disorders. In the present Perspective we describe the multi-level mechanisms underlying SCI and several risk factors that promote this health-damaging phenotype, including infections, physical inactivity, poor diet, environmental and industrial toxicants and psychological stress. Furthermore, we suggest potential strategies for advancing the early diagnosis, prevention and treatment of SCI.
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Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination.
Furman, D, Hejblum, BP, Simon, N, Jojic, V, Dekker, CL, Thiébaut, R, Tibshirani, RJ, Davis, MM
Proceedings of the National Academy of Sciences of the United States of America. 2014;111(2):869-74
Abstract
Females have generally more robust immune responses than males for reasons that are not well-understood. Here we used a systems analysis to investigate these differences by analyzing the neutralizing antibody response to a trivalent inactivated seasonal influenza vaccine (TIV) and a large number of immune system components, including serum cytokines and chemokines, blood cell subset frequencies, genome-wide gene expression, and cellular responses to diverse in vitro stimuli, in 53 females and 34 males of different ages. We found elevated antibody responses to TIV and expression of inflammatory cytokines in the serum of females compared with males regardless of age. This inflammatory profile correlated with the levels of phosphorylated STAT3 proteins in monocytes but not with the serological response to the vaccine. In contrast, using a machine learning approach, we identified a cluster of genes involved in lipid biosynthesis and previously shown to be up-regulated by testosterone that correlated with poor virus-neutralizing activity in men. Moreover, men with elevated serum testosterone levels and associated gene signatures exhibited the lowest antibody responses to TIV. These results demonstrate a strong association between androgens and genes involved in lipid metabolism, suggesting that these could be important drivers of the differences in immune responses between males and females.