Is inflammaging an auto[innate]immunity subclinical syndrome?

The low-grade, chronic, systemic inflammatory state that characterizes the aging process (inflammaging) results from late evolutive-based expression of the innate immune system. Inflammaging is characterized by the complex set of five conditions which can be described as 1. low-grade, 2. controlled, 3. asymptomatic, 4. chronic, 5. systemic, inflammatory state, and fits with the antagonistic pleiotropy theory on the evolution of aging postulating that senescence is the late deleterious effect of genes (pro-inflammatory versus anti-inflammatory)that are beneficial in early life. Evolutionary programming of the innate immune system may act via selection on these genetic traits. Here I propose that the already acquired knowledge in this field may pave the way to a new chapter in the pathophysiology of autoimmunity: the auto-innate-immunity syndromes. Indeed, differently from the well known chapter of conventional autoimmune diseases and syndromes where the main actor is the adaptive immunity, inflammaging may constitute the subclinical paradigm of a new chapter of autoimmunity, namely that arising from an autoimmune inflammatory response of the innate-immune-system, an old actor of immunity and yet a new actor of autoimmunity, also acting as a major determinant of elderly frailty and age-associated diseases.     

Is inflammaging an auto[innate]immunity subclinical syndrome?

The low-grade, chronic, systemic inflammatory state that characterizes the aging process (inflammaging) results from late evolutive-based expression of the innate immune system. Inflammaging is characterized by the complex set of five conditions which can be described as 1. low-grade, 2. controlled, 3. asymptomatic, 4. chronic, 5. systemic, inflammatory state, and fits with the antagonistic pleiotropy theory on the evolution of aging postulating that senescence is the late deleterious effect of genes (pro-inflammatory versus anti-inflammatory)that are beneficial in early life. Evolutionary programming of the innate immune system may act via selection on these genetic traits. Here I propose that the already acquired knowledge in this field may pave the way to a new chapter in the pathophysiology of autoimmunity: the auto-innate-immunity syndromes. Indeed, differently from the well known chapter of conventional autoimmune diseases and syndromes where the main actor is the adaptive immunity, inflammaging may constitute the subclinical paradigm of a new chapter of autoimmunity, namely that arising from an autoimmune inflammatory response of the innate-immune-system, an old actor of immunity and yet a new actor of autoimmunity, also acting as a major determinant of elderly frailty and age-associated diseases.     

免疫基因多态性与衰老和增龄相关疾病关系

衰老是进行性的、多细胞普遍存在的、不可逆的功能减退状态。免疫衰老主要表现为造血干细胞再生和淋巴系分化能力下降、机体对感染和疫苗的反应减弱、对炎症反应的放大和自身的免疫反应增加, 与衰老和增龄相关疾病密切相关。免疫基因变异, 影响机体免疫反应, 可加速或延缓衰老和增龄相关疾病。获得性免疫基因, 如对自身免疫性疾病起保护性作用的HLA II 抗原基因DRB1*11和DRB*16相关的单倍型在长寿老人频率增加。抗炎因子IL-10-1082G等位基因频率和TGFβ1单倍型cnd10T/C、cnd25G/G、-988C/C、-800G/A频率的下降, 促炎因子TNFα低表达相关的扩展的TNF-A基因型-1031C/C、-863C/A、-857C/C、IL-6-174 CC基因型, 和IFN-γ+874 T等位基因频率减少与免疫炎症反应易感性, 衰老相关疾病的发病率和死亡率正相关。固有免疫基因, 如高频表达抗炎的+896 G KIR4等位基因、CCR5Δ32突变、-765 C Cox-2等位基因、-1708 G和21 C 5-Lox等位基因多见于长寿老人。KIR 单倍型 KIR2DS5、A1B10减少, MBL2表达缺乏的单倍型LYPB、LYQC 和HYPD增加的老年人常伴有较高血清CMV抗体滴度。高频出现的CRP ATG单倍型和CFH 402 His 等位基因预示老年人高死亡率风险。文章对固有和获得性免疫基因多态性、单倍体与衰老及衰老相关疾病关系进展进行综述。加强分析扩展的单倍型、表观遗传学和造血干细胞衰老的遗传学研究将有助于更好地理解衰老和长寿的免疫遗传学基础。     

Exosomal vesicles enhance immunosuppression in chronic inflammation: Impact in cellular senescence and the aging process

Exosomes represent an evolutionarily conserved signaling pathway which can act as an alarming mechanism in responses to diverse stresses, e.g. chronic inflammation activates the budding of exosomal vesicles in both immune and non-immune cells. Exosomes can contain both pro- and anti-inflammatory cargos but in chronic inflammation, exosomes mostly carry immunosuppressive cargos, e.g. enzymes and miRNAs. The aging process is associated with chronic low-grade inflammation and the accumulation of pro-inflammatory senescent cells into tissues. There is clear evidence that aging increases the number of exosomes in both the circulation and tissues. Especially, the secretion of immunosuppressive exosomes robustly increases from senescent cells. There are observations that the exosomes from senescent cells are involved in the expansion of senescence into neighbouring cells. Interestingly, the age-related exosomes contain immune suppressive cargos which enhance the immunosuppression within recipient immune cells, i.e. tissue-resident and recruited immune cells including M2 macrophages, myeloid-derived suppressor cells (MDSC), and regulatory T cells (Treg). It seems that increased immunosuppression with aging impairs the clearance of senescent cells and their accumulation within tissues augments the aging process.     

Adipose tissue aging: mechanisms and therapeutic implications

Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. These changes cause physiological declines and age-related disease in the elderly population. Here, we review the age-related changes in adipose tissue at multiple levels and highlight the underlying mechanisms regulating the aging process. We also discuss the pathogenic pathways of age-related fat dysfunctions and their systemic negative consequences, such as dyslipidemia, chronic general inflammation, insulin resistance, and type 2 diabetes (T2D). Age-related changes in adipose tissue involve redistribution of deposits and composition, in parallel with the functional decline of adipocyte progenitors and accumulation of senescent cells. Multiple pathogenic pathways induce defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance, leading to adipose tissue dysfunction. Changes in gene expression and extracellular signaling molecules regulate the aging process of adipose tissue through various pathways. In addition, adipose tissue aging impacts other organs that are infiltrated by lipids, which leads to systemic inflammation, metabolic system disruption, and aging process acceleration. Moreover, studies have indicated that adipose aging is an early onset event in aging and a potential target to extend lifespan. Together, we suggest that adipose tissue plays a key role in the aging process and is a therapeutic target for the treatment of age-related disease, which deserves further study to advance relevant knowledge.Subject terms: Senescence, Endocrine system and metabolic diseases     

Increased inflammatory response in aged mice is associated with age-related zinc deficiency and zinc transporter dysregulation

Aging is a complex process associated with physiological changes in numerous organ systems. In particular, aging of the immune system is characterized by progressive dysregulation of immune responses, resulting in increased susceptibility to infectious diseases, impaired vaccination efficacy and systemic low-grade chronic inflammation. Increasing evidence suggest that intracellular zinc homeostasis, regulated by zinc transporter expression, is critically involved in the signaling and activation of immune cells. We hypothesize that epigenetic alterations and nutritional deficits associated with aging may lead to zinc transporter dysregulation, resulting in decreases in cellular zinc levels and enhanced inflammation with age. The goal of this study was to examine the contribution of age-related zinc deficiency and zinc transporter dysregulation on the inflammatory response in immune cells. The effects of zinc deficiency and age on the induction of inflammatory responses were determined using an in vitro cell culture system and an aged mouse model. We showed that zinc deficiency, particularly the reduction in intracellular zinc in immune cells, was associated with increased inflammation with age. Furthermore, reduced Zip 6 expression enhanced proinflammatory response, and age-specific Zip 6 dysregulation correlated with an increase in Zip 6 promoter methylation. Furthermore, restoring zinc status via dietary supplementation reduced aged-associated inflammation. Our data suggested that age-related epigenetic dysregulation in zinc transporter expression may influence cellular zinc levels and contribute to increased susceptibility to inflammation with age.     

Oxidative stress, inflamm-aging and immunosenescence

Immunosenescence is characterized by a decreased ability of the immune system to respond to foreign antigens, as well as a decreased ability to maintain tolerance to self-antigens. This results in an increased susceptibility to infection and cancer and reduced responses to vaccination [1-5]. The mechanisms underlying immunosenescence comprise a series of cellular and molecular events involving alteration of several biochemical pathways and different cellular populations, and for the most part our understanding of these molecular mechanisms is still fragmentary. In this review we will focus on the process of senescence associated with oxidative stress, in particular how protein oxidation alters the functionality of immune cells and how oxidative stress contributes to a chronic inflammatory process often referred as inflamm-aging.     

Stress responses and innate immunity: aging as a contributory factor

Evolutionary pressure has selected individuals with traits that allow them to survive to reproduction, without consideration of the consequences for the post-child rearing years and old age. In the 21st century, society is populated increasingly by the elderly and with the falling birth rate and improved health care this trend is set to continue for the foreseeable future. To minimize the potential burden on health services one would hope that 'growing old gracefully' should also mean 'growing old healthily'. However, for too many the aging process is accompanied by increasing physical and mental frailty producing an elevated risk of physical and psychological stress in old age. Stress is a potent modulator of immune function, which in youth can be compensated for by the presence of an optimal immune response. In the elderly the immune response is blunted as a result of the decline in several components of the immune system (immune senescence) and a shifting to a chronic pro-inflammatory status (the so-called 'inflamm-aging' effect). We discuss here what is known of the effects of both stress and aging upon the innate immune system, focusing in particular upon the age-related alterations in the hypopituitary-adrenal axis. We propose a double hit model for age and stress in which the age-related increase in the cortisol/sulphated dehydroepiandrosterone ratio synergizes with elevated cortisol during stress to reduce immunity in the elderly significantly.     

Functional analysis of the Drosophila immune response during aging

One of the most dramatic changes associated with aging involves immunity. In aging mammals, immune function declines and chronic inflammation develops. The biological significance of this phenomenon and its relationship with aging is a priority for aging research. Drosophila is an invaluable tool in understanding the effects of aging on the immune response. Similar to the state of chronic inflammation in mammals, Drosophila exhibits a drastic up-regulation of immunity-related genes with age. However, it remains unclear whether immune function declines with age as seen in mammals. We evaluated the impact of aging on Drosophila immune function by examining across age the ability to eliminate and survive different doses of bacterial invaders. Our findings show that aging reduces the capacity to survive a bacterial infection. In contrast, we found no evidence that aging affects the ability to eliminate bacteria indicating that the mechanisms underlying immune senescence are not involved in eliminating bacteria or preventing their proliferation.     

Immunological aspects of age-related diseases

The proportion of elderly people rises in the developed countries. The increased susceptibility of the elderly to infectious diseases is caused by immune dysfunction, especially T cell functional decline. Age-related hematopoietic stem cells deviate from lymphoid lineage to myeloid lineage. Thymus shrinks early in life, which is followed by the decline of na?ve T cells. T-cell receptor repertoire diversity declines by aging, which is caused by cytomegalovirus-driven T cell clonal expansion. Functional decline of B cell induces antibody affinity declines by aging. Many effector functions including phagocytosis of myeloid cells are down regulated by aging. The studies of aging of myeloid cells have some controversial results. Although M1 macrophages have been shown to be replaced by antiinflammatory(M2) macrophages by advanced age, many human studies showed that pro-inflammatory cytokines are elevated in older human. To solve this discrepancy here we divide age-related pathological changes into two categories. One is an aging of immune cell itself. Second is involvement of immune cells to age-related pathological changes. Cellular senescence and damaged cells in aged tissue recruit pro-inflammatory M1 macrophages, which produce pro-inflammatory cytokines and proceed to agerelated diseases. Underlying biochemical and metabolic studies will open nutritional treatment.     

Immunosenescence in aging: between immune cells depletion and cytokines up-regulation

Background

The immunosenescence is a relatively recent chapter, correlated with the linear extension of the average life began in the nineteenth century and still in progress. The most important feature of immunosenescence is the accumulation in the “immunological space” of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens (inhalant allergens, food, etc.). This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by poor contact with viral infections and parasitic diseases. Furthermore the immunosenescence is characterized by a particular “remodelling” of the immune system, induced by oxidative stress. Apoptosis plays a central role in old age, a period in which the ability of apoptosis can change. The remodelling of apoptosis, together with the Inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in the innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells and dendritic cells, acting up to the establishment of a adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes. The markers of “Inflammaging” in adaptive immunity in centenarians are characterized by a decrease in T cells “naive.” The reduction of CD8 virgins may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of T cell-virgin (CD95?), which are replaced with the clonal expansion of CD28-T cells.

Conclusions

The increase of pro-inflammatory cytokines is associated with dementia, Parkinson’s disease, atherosclerosis, diabetes type 2, sarcopenia and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.

     

Dysfunctional telomeres through mitostress‐induced cGAS/STING activation to aggravate immune senescence and viral pneumonia

Disproportionately high incidence and mortality of respiratory infection such as influenza A virus (IAV) and SARS‐CoV‐2 have been evidenced in the elderly, but the role and the mechanism of age‐associated immune deregulation in disease exacerbation are not well defined. Using a late generation of mice deficient in telomerase RNA (Terc^−/−), we herein demonstrated that aged mice were exquisitely susceptible to respiratory viral infection, with excessive inflammation and increased mortality. Furthermore, we identified the cGAS/STING pathway, which was essentially induced by the leaked mitochondrial DNA, as a biologically relevant mechanism contributing to exaggerated inflammation in Terc^−/− mice following viral infection. Innate immune cells, mainly, macrophages with shortened telomeres, exhibited hallmarks of cellular senescence, mitochondrial distress, and aberrant activation of STING and NLRP3 inflammasome pathways, which predisposed mice to severe viral pneumonia during commonly mild infections. Application of STING inhibitor and, more importantly, senolytic agent, reduced the burden of stressed macrophages, improved mitochondrial integrity, and suppressed STING activation, thereby conferring the protection for Terc^−/− mice against respiratory infection. Together, the findings expand our understanding of innate immune senescence and reveal the potential of the senolytics as a promising treatment to alleviate the symptom of viral pneumonia, particularly for the older population.     

调节慢性炎症防治衰老相关疾病的研究进展

衰老是应激、损伤、感染、免疫反应衰退以及代谢障碍等综合作用积累的结果。细胞在衰老的过程中会分泌大量的炎性因子。相关研究表明,老年人的皮肤及粘膜对细菌、病毒感染、外伤等等方面的抵抗和防御能力明显低于青年人,炎性因子不断增多,加速细胞衰老。由此可见,控制慢性炎症可能是干预衰老的有效途径。生物活性透明质酸可能通过诱导防卫素分泌和与CD44/TLR4受体结合,抑制细菌生长和炎症进展,从而发挥抗衰老作用。本文对有关慢性炎症和衰老之间的关系的研究进行综述,探讨生物活性透明质酸对慢性炎症的调节作用及其抗衰老机制。     

Modulación antioxidante y antiinflamatoria del ejercicio físico durante el envejecimiento

Aging is characterised by a gradual loss of the functional reserve. This, along with the fostering of sedentary habits and the increase in risk factors, causes a deterioration of antioxidant defences and an increase of the circulatory levels of inflammatory and oxidative markers, boosting a low-rate chronic inflammation, defined as inflamm-aging. This phenomenon is present in the aetiopathology of chronic diseases, as well as in cognitive deterioration cases associated with aging. The objective of this review is to describe the modulation of antioxidant and anti-inflammatory effects of physical exercise of moderate intensity and volume in the elderly. Evidence of its effectiveness as a non-pharmacological resource is presented, which decreases some deleterious effects of aging. This is mainly due to its neuroprotective action, the increase in circulating anti-inflammatory markers, and the improvement of antioxidant defence derived from its practice.     

Monocyte epigenetics and innate immunity to malaria: yet another level of complexity?

Children under the age of 5 years living in areas of moderate to high malaria transmission are highly susceptible to clinical malaria with fever that prompts treatment of blood stage infection with anti-malarial drugs. In contrast, older school age children frequently experience subclinical malaria, i.e. chronic Plasmodium falciparum parasitemia without fever or other clinical symptoms. The role of innate immune cells in regulating inflammation at a level that is sufficient to control the parasite biomass, while at the same time maintaining a disease-tolerant clinical phenotype, i.e., subclinical malaria, is not well understood. Recent studies suggest that host epigenetic mechanisms underlie the innate immune homeostasis associated with subclinical malaria. This Current Opinion article presents evidence supporting the notion that modifications of the host monocyte/macrophage epigenome regulate innate immune functions pertinent to subclinical malaria.     

Immunosenescence in wild animals: meta‐analysis and outlook

Immunosenescence, the decline in immune defense with age, is an important mortality source in elderly humans but little is known of immunosenescence in wild animals. We systematically reviewed and meta‐analysed evidence for age‐related changes in immunity in captive and free‐living populations of wild species (321 effect sizes in 62 studies across 44 species of mammals, birds and reptiles). As in humans, senescence was more evident in adaptive (acquired) than innate immune functions. Declines were evident for cell function (antibody response), the relative abundance of naïve immune cells and an in vivo measure of overall immune responsiveness (local response to phytohaemagglutinin injection). Inflammatory markers increased with age, similar to chronic inflammation associated with human immunosenescence. Comparisons across taxa and captive vs free‐living animals were difficult due to lack of overlap in parameters and species measured. Most studies are cross‐sectional, which yields biased estimates of age‐effects when immune function co‐varies with survival. We therefore suggest longitudinal sampling approaches, and highlight techniques from human cohort studies that can be incorporated into ecological research. We also identify avenues to address predictions from evolutionary theory and the contribution of immunosenescence to age‐related increases in disease susceptibility and mortality.     

Chronic WNT/β-catenin signaling induces cellular senescence in lung epithelial cells

The rapid expansion of the elderly population has led to the recent epidemic of age-related diseases, including increased incidence and mortality of chronic lung diseases, such as Idiopathic Pulmonary Fibrosis (IPF). Cellular senescence is a major hallmark of aging and has a higher occurrence in IPF. The lung epithelium represents a major site of tissue injury, cellular senescence and aberrant activity of developmental pathways such as the WNT/β-catenin pathway in IPF. The potential impact of WNT/β-catenin signaling on alveolar epithelial senescence in general as well as in IPF, however, remains elusive. Here, we characterized alveolar epithelial cells of aged mice and assessed the contribution of chronic WNT/β-catenin signaling on alveolar epithelial type (AT) II cell senescence. Whole lungs from old (16–24 months) versus young (3 months) mice had relatively less epithelial (EpCAM⁺) but more inflammatory (CD45⁺) cells, as assessed by flow cytometry. Compared to young ATII cells, old ATII cells showed decreased expression of the ATII cell marker Surfactant Protein C along with increased expression of the ATI cell marker Hopx, accompanied by increased WNT/β-catenin activity. Notably, when placed in an organoid assay, old ATII cells exhibited decreased progenitor cell potential. Chronic canonical WNT/β-catenin activation for up to 7 days in primary ATII cells as well as alveolar epithelial cell lines induced a robust cellular senescence, whereas the non-canonical ligand WNT5A was not able to induce cellular senescence. Moreover, chronic WNT3A treatment of precision-cut lung slices (PCLS) further confirmed ATII cell senescence. Simultaneously, chronic but not acute WNT/β-catenin activation induced a profibrotic state with increased expression of the impaired ATII cell marker Keratin 8. These results suggest that chronic WNT/β-catenin activity in the IPF lung contributes to increased ATII cell senescence and reprogramming. In the fibrotic environment, WNT/β-catenin signaling thus might lead to further progenitor cell dysfunction and impaired lung repair.     

Infection susceptibility and immune senescence with advancing age replicated in accelerated aging LmnaDhe mice

Aging confers increased susceptibility to common pathogens including influenza A virus. Despite shared vulnerability to infection with advancing age in humans and rodents, the relatively long time required for immune senescence to take hold practically restricts the use of naturally aged mice to investigate aging‐induced immunological shifts. Here, we show accelerated aging Lmna^Dhe mice with spontaneous mutation in the nuclear scaffolding protein, lamin A, replicate infection susceptibility, and substantial immune cell shifts that occur with advancing age. Naturally aged (≥20 month) and 2‐ to 3‐month‐old Lmna^Dhe mice share near identically increased influenza A susceptibility compared with age‐matched Lmna^WT control mice. Increased mortality and higher viral burden after influenza infection in Lmna^Dhe mice parallel reduced accumulation of lung alveolar macrophage cells, systemic expansion of immune suppressive Foxp3⁺ regulatory T cells, and skewed immune dominance among viral‐specific CD8⁺ T cells similar to the immunological phenotype of naturally aged mice. Thus, aging‐induced infection susceptibility and immune senescence are replicated in accelerated aging Lmna^Dhe mice.