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Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified seven biological pillars of aging and a consensus review, “Geroscience: Linking Aging to Chronic Disease,” was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus represent a useful framework with which to study human aging. In this present review, we revisit the seven pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.

Background: Growth Differentiation Factor 15 (GDF-15) is a marker of inflammation and oxidative stress that has been associated with multiple age-related chronic diseases. Since lifestyle is key for preventing these adverse health outcomes, we examined the association between a Mediterranean lifestyle and GDF-15 serum concentrations in Spanish older adults. Methods: We used cross-sectional data from 2502 older adults participating in the Seniors ENRICA-2 cohort. Adherence to the Mediterranean lifestyle was assessed with the 27-item MEDLIFE index, divided into three blocks: 1) “Mediterranean food consumption, 2) Mediterranean dietary habits, 3) Physical activity, rest, social habits, and conviviality”. Analyses of the association between the MEFLIFE index and GDF-15 concentrations were performed using multivariable linear regression models adjusting for the main potential confounders. Results: The MEDLIFE index was inversely associated with GDF-15. Compared with participants in the lowest quartile of the MEDLIFE score, GDF-15 mean percentage differences (95% CI) were − 3.0% (− 8.0, 2.3) for the second quartile, − 8.7% (− 13.0, − 4.1) for the third quartile, and − 10.1% (− 15.0, − 4.9) for the fourth quartile (ptrend, This work was supported by the Institute of Health Carlos III; the Secretary of R+D+I; the European Regional Development Fund/European Social Fund (FIS grants 19/319, 20/00896); the National Plan on Drugs (grant 2020/17); Fundacion ´ Soria Melguizo (MITOFUN project); Ministry of Science, Innovation and Universities (RYC 2018-02069I to MSP); Universidad Autonoma ´ de Madrid (FPI contract to JMR); FACINGLCOVID-CM project, Funding REACT EU Program (Comunidad de Madrid, European Regional Development Fund). Reagents for measuring Growth Differentiation Factor 15 have been provided by Roche Diagnostics International through a Research Agreement with the FUAM (Fundacion ´ de la Universidad Autonoma ´ de Madrid). The funding agencies had no role in study design, data collection and analysis, interpretation of results, manuscript preparation or the decision to submit this manuscript for publication

The immune system is weakened by advancing age, often referred to as immunosenescence, increasing the vulnerability to, and frequently the severity of, infectious diseases in older people. This has become very apparent in the current coronavirus disease 2019 (COVID-19) pandemic for which older people are at higher risk of severe outcomes, even those who are fully vaccinated. Aging affects both the innate and adaptive immune systems and is characterized by an imbalanced inflammatory response. Increasing evidence shows that optimal status of nutrients such as vitamins C, D, and E and selenium and zinc as well as the omega-3 (n-3) fatty acids DHA and EPA can help compensate for these age-related changes. While inadequate intakes of these nutrients are widespread in the general population, this is often more pronounced in older people. Maintaining adequate intakes is a challenge for them due to a range of factors such as physical, physiological, and cognitive changes; altered absorption; and the presence of noncommunicable diseases. While nutritional requirements are ideally covered by a balanced diet, this can be difficult to achieve, particularly for older people. Fortified foods and nutritional complements are effective in achieving adequate micronutrient intakes and should be considered as a safe and cost-effective means for older people to improve their nutritional status and hence support their defense against infections. Complementing the diet with a combination of micronutrients, particularly those playing a key role in the immune system such as vitamins C, D, and E and selenium and zinc as well as DHA and EPA, is recommended for older people. Optimal nutrition to support the immune system in older people will remain essential, particularly in the face of the current COVID-19 pandemic and, thus, developing strategies to ensure adequate nutrition for the growing number of older adults will be an important and cost-effective investment in the future.

Aging promotes a range of degenerative pathologies characterized by progressive losses of tissue and/or cellular function. Fibrosis is the hardening, overgrowth and scarring of various tissues characterized by the accumulation of extracellular matrix components. Aging is an important predisposing factor common for fibrotic heart and respiratory disease. Age-related processes such as senescence, inflammaging, autophagy and mitochondrial dysfunction are interconnected biological processes that diminish the regenerative capacity of the aged heart and lung and have been shown to play a crucial role in cardiac fibrosis and idiopathic pulmonary fibrosis. This review focuses on these four processes of aging in relation to their role in fibrosis. It has long been established that the heart and lung are linked both functionally and anatomically when it comes to health and disease, with an ever-expanding aging population, the incidence of fibrotic disease and therefore the number of fibrosis-related deaths will continue to rise. There are currently no feasible therapies to treat the effects of chronic fibrosis therefore highlighting the importance of exploring the processes of aging and its role in inducing and exacerbating fibrosis of each organ. The focus of this review may help to highlight potential avenues of therapeutic exploration.

Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subjects: Adult (age 18–64 years) and Senior (age ≥ 65 years). OLE and HT were used alone or as a pre-treatment before challenging PBMCs with lipopolysaccharide (LPS). Both polyphenols had no effect on cell viability irrespective of LPS, but 5 µM HT had an LPS-like effect on monocytes, reducing the intermediate subset in Adult subjects. OLE and HT had no effect on LPS-triggered release of TNF-α, IL-6 and IL-8, but 5 µM HT reduced IL-10 secretion by PBMCs from Adult vs. Senior group. In summary, nutritionally relevant concentrations of OLE and HT elicit no anti-inflammatory effect and influence the frequency of immune cell subsets with age-related different outcomes.

Immunosenescence and inflammaging facilitate the insurgence of chronic diseases. The Mediterranean diet is a non-invasive intervention to improve the chronic low-grade inflammatory status associated with aging. Olive oil oleuropein (OLE) and hydroxytyrosol (HT) demonstrated a controversial modulatory action on inflammation in vitro when tested at concentrations exceeding those detectable in human plasma. We studied the potential anti-inflammatory effects of OLE and HT at nutritionally relevant concentrations on peripheral blood mononuclear cells (PBMCs) as regards cell viability, frequency of leukocyte subsets, and cytokine release, performing an age-focused analysis on two groups of subjects: Adult (age 18–64 years) and Senior (age ≥ 65 years). OLE and HT were used alone or as a pre-treatment before challenging PBMCs with lipopolysaccharide (LPS). Both polyphenols had no effect on cell viability irrespective of LPS, but 5 µM HT had an LPS-like effect on monocytes, reducing the intermediate subset in Adult subjects. OLE and HT had no effect on LPS-triggered release of TNF-α, IL-6 and IL-8, but 5 µM HT reduced IL-10 secretion by PBMCs from Adult vs. Senior group. In summary, nutritionally relevant concentrations of OLE and HT elicit no anti-inflammatory effect and influence the frequency of immune cell subsets with age-related different outcomes.

Takotsubo syndrome (TTS), an acute cardiac condition characterized by transient wall motion abnormalities mostly of the left ventricle, results in difficulties in diagnosing patients. We set out to present a detailed blood analysis of TTS patients analyzing novel markers to understand the development of TTS. Significant differences in proinflammatory cytokine expression patterns and sex steroid and glucocorticoid receptor (GR) expression levels were observed in the TTS patient collected. Remarkably, the measured catecholamine serum concentrations determined from TTS patient blood could be shown to be two orders of magnitude lower than the levels determined from experimentally induced TTS in laboratory animals. Consequently, the exposure of endothelial cells and cardiomyocytes in vitro to such catecholamine concentrations did not damage the cellular integrity or function of either endothelial cells forming the blood–brain barrier, endothelial cells derived from myocardium, or cardiomyocytes in vitro. Computational analysis was able to link the identified blood markers, specifically, the proinflammatory cytokines and glucocorticoid receptor GR to microRNA (miR) relevant in the ontogeny of TTS (miR-15) and inflammation (miR-21, miR-146a), respectively. Amongst the well-described risk factors of TTS (older age, female sex), inflammaging-related pathways were identified to add to these relevant risk factors or prediagnostic markers of TTS.

Aging is a gradual, continuous series of natural changes in biological, physiological, immunological, environmental, psychological, behavioral, and social processes. Aging entails changes in the immune system characterized by a decrease in thymic output of naïve lymphocytes, an accumulated chronic antigenic stress notably caused by chronic infections such as cytomegalovirus (CMV), and immune cell senescence with acquisition of an inflammatory senescence-associated secretory phenotype (SASP). For this reason, and due to the SASP originating from other tissues, aging is commonly accompanied by low-grade chronic inflammation, termed “inflammaging”. After decades of accumulating evidence regarding age-related processes and chronic inflammation, the domain now appears mature enough to allow an integrative reinterpretation of old data. Here, we provide an overview of the topics discussed in a recent workshop “Aging and Chronic Inflammation” to which many of the major players in the field contributed. We highlight advances in systematic measurement and interpretation of biological markers of aging, as well as their implications for human health and longevity and the interventions that can be envisaged to maintain or improve immune function in older people.

Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension. Aging triggers a wide range of cellular and molecular aberrations in the body, giving rise to inflammation and associated diseases. In particular, aging is associated with persistent low-grade inflammation even in absence of inflammatory stimuli, a phenomenon commonly referred to as 'inflammaging'. Accumulating evidence has revealed that inflammaging in vascular and cardiac tissues is associated with the emergence of pathological states such as atherosclerosis and hypertension. In this review we survey molecular and pathological mechanisms of inflammaging in vascular and cardiac aging to identify potential targets, natural therapeutic compounds, and other strategies to suppress inflammaging in the heart and vasculature, as well as in associated diseases such as atherosclerosis and hypertension.

Chronological aging is commonly accompanied by chronic low-grade inflammation (or “inflammaging”), a contributor to the development of age-related chronic diseases. Aging increases oxidative stress that accelerates telomere shortening, leading to cell senescence and the generation of senescence-associated secretory phenotype (SASP) that exacerbates inflammation. Dietary antioxidants may help protect telomeres and attenuate inflammation. Thyme essential oil (TEO), reported for its potency against neuroinflammation, was fed to chronologically aged C57BL/6J mice for 24 weeks. The TEO diet showed notable impacts on the hippocampus, indicated by lower expression of the aging-related gene p16INK4A (p = 0.0783) and significantly lower expression of cyclin D kinase Cdk4 and Cdk6 (p < 0.05) compared to the age-matched control mice. The TEO group also showed significantly lower gene expression of the pro-inflammatory cytokine Il6 (p < 0.05) in the hippocampus and lower Il1b expression in the liver and cerebellum (p < 0.05). In vitro experiments conducted on NIH-3T3 cells expressing SASP revealed the dose-dependent anti-inflammatory activity of TEO. Remarkably, TEO diet-fed mice showed higher survival rates and significantly longer blood telomere lengths than the control mice. Monoterpene antioxidants in TEO, particularly thymol and p-cymene, may primarily contribute to the anti-inflammatory and telomere-protecting activities of TEO.

During aging, bone marrow mesenchymal stromal cells (MSCs)—the precursors of osteoblasts—undergo cellular senescence, losing their osteogenic potential and acquiring a pro-inflammatory secretory phenotype. These dysfunctions cause bone loss and lead to osteoporosis. Prevention and intervention at an early stage of bone loss are important, and naturally active compounds could represent a valid help in addition to diet. Here, we tested the hypothesis that the combination of two pro-osteogenic factors, namely orthosilicic acid (OA) and vitamin K2 (VK2), and three other anti-inflammatory compounds, namely curcumin (CUR), polydatin (PD) and quercetin (QCT)—that mirror the nutraceutical BlastiMin Complex® (Mivell, Italy)—would be effective in promoting MSC osteogenesis, even of replicative senescent cells (sMSCs), and inhibiting their pro-inflammatory phenotype in vitro. Results showed that when used at non-cytotoxic doses, (i) the association of OA and VK2 promoted MSC differentiation into osteoblasts, even when cultured without other pro-differentiating factors; and (ii) CUR, PD and QCT exerted an anti-inflammatory effect on sMSCs, and also synergized with OA and VK2 in promoting the expression of the pivotal osteogenic marker ALP in these cells. Overall, these data suggest a potential role of using a combination of all of these natural compounds as a supplement to prevent or control the progression of age-related osteoporosis.

Neurodegenerative diseases are a leading cause of death worldwide with no cures identified. Thus, there is a critical need for preventative measures and treatments as the number of patients is expected to increase. Many neurodegenerative diseases have sex-biased prevalence, indicating a need to examine sex differences when investigating prevention and treatment strategies. Inflammation is a key contributor to many neurodegenerative diseases and is a promising target for prevention since inflammation increases with age, which is known as inflammaging. Here, we analyzed the protein expression levels of cytokines, chemokines, and inflammasome signaling proteins in the cortex of young and aged male and female mice. Our results show an increase in caspase-1, interleukin (IL)-1β, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and ASC specks in females compared to males. Additionally, there was an increase in IL-1α, VEGF-A, CCL3, CXCL1, CCL4, CCL17, and CCL22 in aging females and an increase in IL-8, IL-17a, IL-7, LT-α, and CCL22 in aging males. IL-12/IL-23p40, CCL13, and IL-10 were increased in females compared to males but not with age. These results indicate that there are sex differences in cortical inflammaging and provide potential targets to attenuate inflammation to prevent the development of neurodegenerative disease.

Spaceflight and its associated stressors, such as microgravity, radiation exposure, confinement, circadian derailment and disruptive workloads represent an unprecedented type of exposome that is entirely novel from an evolutionary stand point. Within this perspective, we aimed to review the effects of prolonged spaceflight on immune-neuroendocrine systems, brain and brain-gut axis, cardiovascular system and musculoskeletal apparatus, highlighting in particular the similarities with an accelerated aging process. In particular, spaceflight-induced muscle atrophy/sarcopenia and bone loss, vascular and metabolic changes, hyper and hypo reaction of innate and adaptive immune system appear to be modifications shared with the aging process. Most of these modifications are mediated by molecular events that include oxidative and mitochondrial stress, autophagy, DNA damage repair and telomere length alteration, among others, which directly or indirectly converge on the activation of an inflammatory response. According to the inflammaging theory of aging, such an inflammatory response could be a driver of an acceleration of the normal, physiological rate of aging and it is likely that all the systemic modifications in turn lead to an increase of inflammaging in a sort of vicious cycle. The most updated countermeasures to fight these modifications will be also discussed in the light of their possible application not only for astronauts’ benefit, but also for older adults on the ground. published

The interest in the process of aging, and specifically in how aging affects the working of our immune system, has recently enormously grown among both specialists (immunologists and gerontologists) and representatives of other disciplines of health sciences. An obvious reason for this interest is the current pandemics of COVID-19, known to affect the elderly more than younger people. In this paper current knowledge about mechanisms and complex facets of human immune system aging is presented, stemming from the knowledge about the working of various parts of the immune system, and leading to understanding of immunological mechanisms of chronic, inflammatory, aging-related diseases and of COVID-19.

During female lifetime and pregnancy, inflammation and cellular senescence are implicated in physiological processes, from ovulation and menstruation, to placental homeostasis and delivery. Several lifestyles, nutritional, and environmental insults, as well as long-lasting pregestational inflammatory diseases may lead to detrimental effects in promoting and sustaining a chronic excessive inflammatory response and inflammaging, which finally contribute to the decay of fertility and pregnancy outcome, with a negative effect on placental function, fetal development, and future health risk profile in the offspring. Maladaptation to pregnancy and obstetric disease may in turn increase maternal inflammaging in a feedback loop, speeding up aging processes and outbreak of chronic diseases. Maternal inflammaging may also impact, through transgenerational effects, on future adult health. Hence, efficacious interventions should be implemented by physicians and healthcare professionals involved in prevention activities to reduce the modifiable factors contributing to the inflammaging process in order to improve public health.

The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of "homeostatic frailty" appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly.

Purpose Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy. Materials and Methods Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR). Results Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3+CD4+CD8−, TCD3+CD4−CD8+, B (CD45RA+) and NK (161a+), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte’s ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups. Conclusion Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF’s therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats., Graphical Abstract

Danuta Wrona, Irena Majkutewicz, Grzegorz &Sacute;wi&aogon;tek, Joanna Dunacka, Beata Grembecka, Wojciech Glac Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, Gdansk, 80-308, PolandCorrespondence: Danuta WronaDepartment of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 59 Wita Stwosza Str, Gdansk, 80-308, PolandTel +4858 523 61 21Fax +4858 523 61 21Email wronada3@o2.plPurpose: Intracerebroventricular-(ICV)-streptozotocin-(STZ)-induced neuroinflammation is a model of Alzheimer’s disease (AD) compatible with the inflammation hypothesis of ageing (“inflammaging” state). Previously, we observed age-dependent (young vs aged) dimethyl fumarate (DMF)-induced anti-inflammatory and neuroprotective effects in the brain along with improvement in cognitive functions in rats with the ICV-STZ-induced model of AD. To evaluate whether DMF reduces neuroinflammation based on the peripheral inflammatory response inhibition, we determined peripheral inflammatory mediators in young and aged rats with the ICV-STZ-induced AD pathology following DMF therapy.Materials and Methods: Young (4-month-old) and aged (22-month-old) rats were fed with 0.4% DMF rat chow for 21 consecutive days after ICV-STZ (3 mg/ventricle) injections. After behavioral testing, blood and spleens were collected to determine the numbers of leukocytes (WBC), lymphocytes and their subpopulations, haematological parameters, the concanavalin (Con)-A-induced production and plasma concentration of interferon (IFN)-γ, interleukin (IL)-6, IL-10 and corticosterone (COR).Results: Age-dependent anti-inflammatory effect of the DMF treatment in rats with ICV-STZ injections manifested as decreased peripheral WBC and lymphocyte numbers, including TCD3+CD4+CD8−, TCD3+CD4−CD8+, B (CD45RA+) and NK (161a+), in aged rats. Furthermore, DMF lowered the blood and spleen lymphocyte production of pro-inflammatory IFN-γ and IL-6 in young and aged rats, whereas it enhanced the plasma level of anti-inflammatory IL-10 and lymphocyte’s ability to produce it in aged rats only. In parallel to changes in peripheral WBC numbers in the model of AD, DMF decreased the red blood cell number, haemoglobin concentration, haematocrit and mean platelet volume in aged, but not young, rats. In contrast to controls, DMF did not influence the COR response in STZ groups.Conclusion: Besides preventing neuroinflammation, DMF acts on the pro-/anti-inflammatory balance in the periphery and causes an anti-inflammatory shift in T lymphocytes which could contribute to DMF’s therapeutic effects in the ICV-STZ-induced model of AD, in particular, in aged rats.Keywords: inflammaging, intracerebroventricular-streptozotocin-induced Alzheimer’s disease model, peripheral immunohaematological parameters, neurotherapeutics, inflammation

Biological aging is the main driver of age-associated chronic diseases. In 2014, the United States National Institute of Aging (NIA) sponsored a meeting between several investigators in the field of aging biology, who identified seven biological pillars of aging and a consensus review, “Geroscience: Linking Aging to Chronic Disease,” was published. The pillars of aging demonstrated the conservation of aging pathways in diverse model organisms and thus represent a useful framework with which to study human aging. In this present review, we revisit the seven pillars of aging from the perspective of exercise and discuss how regular physical exercise can modulate these pillars to stave off age-related chronic diseases and maintain functional capacity.

Inflammaging is related to cell senescence and reflects an erratic immune system, which promotes age-associated diseases. Exercise and nutrition, particularly omega-3 fatty acids, are able to affect inflammation. Therefore, we examined the effects of an 8-week exercise and dietary intervention on the inflammatory response in community-dwelling old adults. All participants received weekly vibration and home-based resistance exercise. Furthermore, participants were randomized to either a control, high-protein (1.2–1.5 g/kg), or high-protein, omega-3-enriched (2.2 g/day) diet. Before and after treatment, inflammatory markers in fasting serum and after whole-blood ex vivo lipopolysaccharide (LPS) stimulation were assessed. Gene expression levels of inflammatory markers were quantified in peripheral blood mononuclear cells (PBMC). Sixty-one participants (age: 70.6 ± 4.7 years; 47% men) completed the study. According to generalized linear mixed models, a high-protein, omega-3-enriched diet decreased circulating anti-inflammatory interleukin (IL-) 10 and IL-1 receptor antagonist (IL-1RA). Sex-stratified analyses showed also significantly reduced pro-inflammatory markers in men with a high-protein, omega-3-enriched diet. Gene expression of IL-1RA was significantly reduced after both protein-enriched diets compared with controls. In comparison to a high-protein diet, exercise alone showed lower LPS-induced release of c-c motif chemokine ligand-2 (CCL-2), which tended to be more pronounced in men compared with women. Eight weeks of a high-protein, omega-3-enriched diet combined with exercise decreased circulating anti-inflammatory markers, and pro-inflammatory markers in men. A high-protein diet attenuated anti-inflammatory markers on gene expression level in PBMC. Exercise alone resulted in a lower pro-inflammatory response to LPS-exposure in whole-blood cultures.

Senescence of the immune system is characterized by a state of chronic, subclinical, low-grade inflammation termed ‘inflammaging', with increased levels of proinflammatory cytokines, both at the tissue and systemic levels. Age-related inflammation can be mainly driven by self-molecules with immunostimulant properties, named Damage/death Associated Molecular Patterns (DAMPs), released by dead, dying, injured cells or aged cells. Mitochondria are an important source of DAMPs, including mitochondrial DNA — the small, circular, double-stranded DNA molecule found in multiple copies in the organelle. mtDNA can be sensed by at least three molecules: the Toll-like receptor 9, the NLRP3 inflammasomes, and the cyclic GMP–AMP synthase (cGAS). All these sensors can lead to the release of proinflammatory cytokines when engaged. The release of mtDNA by damaged or necrotic cells has been observed in several pathological conditions, often aggravating the course of the disease. Several lines of evidence indicate that the impairment of mtDNA quality control and of the organelle homeostasis associated with aging determines an increase in the leakage of mtDNA from the organelle to the cytosol, from the cell to the extracellular space, and into plasma. This phenomenon, mirrored by an increase in mtDNA circulating levels in elderly people, can lead to the activation of different innate immune cell types, sustaining the chronic inflammatory status that is characteristic of aging.

In this study, we investigated the impact of the uremic toxin indoxyl sulfate on macrophages and tubular epithelial cells and its role in modulating the response to lipopolysaccharide (LPS). Indoxyl sulfate accumulates in the blood of patients with chronic kidney disease (CKD) and is a predictor of overall and cardiovascular morbidity/mortality. To simulate the uremic condition, primary macrophages and tubular epithelial cells were incubated with indoxyl sulfate at low concentrations as well as concentrations found in uremic patients, both alone and upon LPS challenge. The results showed that indoxyl sulfate alone induced the release of reactive oxygen species and low-grade inflammation in macrophages. Moreover, combined with LPS (proinflammatory conditions), indoxyl sulfate significantly increased TNF-α, CCL2, and IL-10 release but did not significantly affect the polarization of macrophages. Pre-treatment with indoxyl sulfate following LPS challenge induced the expression of aryl hydrocarbon receptor (Ahr) and NADPH oxidase 4 (Nox4) which generate reactive oxygen species (ROS). Further, experiments with tubular epithelial cells revealed that indoxyl sulfate might induce senescence in parenchymal cells and therefore participate in the progression of inflammaging. In conclusion, this study provides evidence that indoxyl sulfate provokes low-grade inflammation, modulates macrophage function, and enhances the inflammatory response associated with LPS. Finally, indoxyl sulfate signaling contributes to the senescence of tubular epithelial cells during injury.

Triggered by microbial ligands, inflammation serves as a "double-edged sword" to fight infections on the one hand, but on the other hand causing tissue damage due to oxidative stress if it is dysregulated. For example, chronic inflammation can contribute to inflammaging, which is now widely regarded as one of the causes of ageing. In my interdisciplinary dissertation, my colleagues and I investigated three interrelated aspects of inflammation, using an evolutionary framework and various free-living birds as models: (1) ecological and evolutionary determinants of gut microbiota (GM) composition and diversity, a driver of wild bird immunity, (2) diversity in immune genes affecting inflammatory responses in wild birds and (3) inflammation-related physiological senescence in a free-living passerine bird, the great tit (Parus major). Firstly, using 16S rRNA gene metabarcoding, we revealed high intra- and interspecific variation in passerine gut microbiota (GM) dominated by the major phyla Proteobacteria, Firmicutes, Actinobacteria and Bacteroidetes. Although in mammals GM depends strongly on host phylogeny and diet, in birds we found only moderate effects of phylogeny and very limited effects of host geography and ecology on GM composition. While microbiota diverged between the upper and lower...

Stand der Forschung: Kardiovaskuläre Erkrankungen sind weltweit die führende Todesursache, wobei insbesondere altersbedingte vaskuläre Veränderungen in den Fokus rücken. Die Arteriosklerose ist eine wichtige Entität systemischer Gefäßveränderungen und gekennzeichnet durch eine Kalzifizierung der tunica media („medial arterial calcification“, MAC). Ein bedeutender Risikofaktor für die MAC ist die chronische Nierenkrankheit. Verschiedene Mediatoren und Inhibitoren beeinflussen die MAC Pathogenese. Hierbei rücken evolutionär konservierte Mechanismen der Mustererkennung, u.a. die Aktivierung des „NOD-, LRR- and pyrin domain-containing protein“ 3 (Nlrp3) Inflammasom und das einhergehende „Inflammaging“ in den Fokus der Untersuchungen. Fragestellung: Das Ziel dieser kumulativen Arbeit ist Etablierung von geeigneten Modellen und die Charakterisierung zentraler Signalwege in glatten Gefäßmuskelzellen („vascular smooth muscle cell“, VSMC) innerhalb des urämischen „Inflammaging“. Ergebnisse: Um die multifaktorielle MAC Genese und insbesondere die Interaktion der Signalwege untersuchen zu können, wurde in der ersten Arbeit ein Einzelzell-basiertes Modell zum Nachweis verschiedener Seneszenz- und Kalzifizierungsmarker etabliert. Durch die Etablierung des neuen ex vivo Modells der isoliert-perfundierten Arterie im Rahmen der zweiten Arbeit kann die MAC Pathogenese unter Perfusionsbedingungen analysiert werden. Die Bedeutung reaktiver Sauerstoffspezies (ROS) im Signalweg der MAC konnte in der dritten und vierten Arbeit sowohl in vitro als auch in vivo gezeigt werden. ROS aktivieren das Nlrp3 Inflammasom als intrazellulären Mustererkennungsrezeptor. Über die Sekretion von Interleukin 1β werden pro-inflammatorische und osteogene Signalwege in VSMC induziert, die mit einer Phänotyptransformation einhergehen und so die MAC Pathogenese beeinflussen. Diskussion & Ausblick: Zellulärer Stress der VSMC resultiert im „Inflammaging“ und osteogenem Phänotyp, die letztendlich in Mechanismen der Kalzifizierung münden. In Abhängigkeit von der Art des Stressors nehmen die VSMC zusätzlich einen seneszenten Phänotyp an, der „Inflammaging“ und Kalzifizierung verstärkt. Das Nlrp3 Inflammasom nimmt eine zentrale Rolle im intrazellulären Signalweg der Pathogenese ein. Diese Defektheilung geht mit erheblichen strukturellen und rheologischen Veränderungen im Gefäß einher, stabilisieren aber die Gefäßintegrität. Die Urämie ist ein prädestiniertes Krankheitsbild für die Ausbildung eines chronisch-urämischen „Inflammaging“ und einer vaskulären Progerie. Die Modulation des chronisch-urämischen „Inflammaging“ kann ein therapeutisches Ziel für die urämische Progerie sein. Neben der Suche nach neuen Wirkstoffkandidaten können etablierte Wirkstoffe therapeutische Optionen bieten, um die hohe kardiovaskuläre Morbidität und Mortalität von niereninsuffizienten Patienten reduzieren zu können.

As humans age, their immune system undergoes modifications, including a low-grade inflammatory status called inflammaging. These changes are associated with a loss of physical and immune resilience, amplifying the risk of being malnourished and frail. Under the COVID-19 scenario, inflammaging increases the susceptibility to poor prognostics. We aimed to bring the current concepts of inflammaging and its relationship with frailty and COVID-19 prognostic; highlight the importance of evaluating the nutritional risk together with frailty aiming to monitor older adults in COVID-19 scenario; explore some compounds with potential to modulate inflammaging in perspective to manage the COVID-19 infection. Substances such as probiotics and senolytics can help reduce the high inflammatory status. Also, the periodic evaluation of nutrition risk and frailty will allow interventions, assuring the appropriate care.

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most prevalent neurodegenerative diseases, affecting millions of people globally and causing significant disability and mortality. Animal models are the final step in completing preclinical studies and the most appropriate approach for gaining a thorough understanding of disease pathophysiology. Modeling of idiopathic AD and PD in rodents requires stereotactic injections of disease‑triggering substances. The placebo surgery group is an integral component of the design of these experiments in order to diminish study bias as a result of animal stress and non‑specific surgical impact. Inflammation is the most commonly reported non‑specific post‑surgery phenomenon, which can manifest in different ways in animals of different ages used in these experiments. Objective — to compare the long‑term pro‑inflammatory effects of placebo surgery, commonly employed for PD and AD modeling, in rats of different ages. Materials and methods. Adult male Wistar rats aged 4 and 14 months were used in the study. The placebo surgery consisted of a stereotactic unilateral intracerebral infusion of buffer solution. Before the placebo surgery, animals were anaesthetized using ketamine or xylazine administered intraperitoneally. Intact animals of both ages were used as a control. The evaluation of pro‑inflammatory effects of placebo surgery was conducted using biomarkers of local and systemic inflammation: metabolic polarization of phagocytes (microglia, peripheral blood cells), C‑reactive protein (CRP) plasma level, and systemic inflammation indexes calculated from the hemogram study. Results. In young lesioned animals, a pronounced pro‑inflammatory functional shift of microglia and signs of the resolution of systemic inflammation (an anti‑inflammatory skew of circulating phagocyte metabolism as compared to age‑matched intact controls) were observed in the long term after the placebo neurosurgery. In old intact animals, hematological and immunological markers of low‑grade systemic inflammation were observed. In lesioned old rats, residual neuroinflammation along with pronounced systemic inflammatory responses (leukocytosis, substantially increased SIRI and SII values, pro‑inflammatory metabolic shift of peripheral blood phagocytes as compared to age‑matched intact controls) were registered. Conclusions. The effects of placebo neurosurgical manipulations in rats depend on age. Meta‑inflammation inherent to aged rats is aggravated by non‑specific post‑surgery inflammation, leading to pronounced, persistent systemic inflammatory responses., Хвороба Альцгеймера (ХА) та хвороба Паркінсона (ХП) є найпоширенішими нейродегенеративними захворюваннями. Вони вражають мільйони людей у всьому світі та спричиняють значну інвалідизацію і смертність. Останнім кроком для завершення доклінічних досліджень і найбільш адекватним підходом для глибокого розуміння патофізіології цих захворювань є використання тваринних моделей. Моделювання ідіопатичних ХА та ХП вимагає ін’єкції речовин, які викликають захворювання, з використанням стереотаксичної хірургії. Групу плацебо хірургії, як невід’ємний компонент дизайну цих експериментів, використовують як контроль неспецифічних побічних ефектів, викликаних хірургічними маніпуляціями. Запалення, як найчастіший неспецифічний післяопераційний феномен, може по-різному проявлятися у тварин різного віку, що використовуються в цих експериментах. Мета дослідження полягала у порівнянні довгострокових прозапальних ефектів плацебо-хірургічного втручання, яке зазвичай використовується для моделювання ХА та ХП, у щурів різного віку. Матеріали та методи. У дослідженні використовували дорослих самців щурів Wistar віком 4 та 14 місяців. Операція плацебо полягала у стереотаксичній унілатеральній внутрішньомозковій інфузії буферного розчину. Перед плацебо-операцією тварин анестезували внутрішньочеревно кетаміном/ксилазином. За контроль використовували інтактних тварин такого ж віку. Оцінку прозапальних ефектів плацебо-хірургії проводили за допомогою біомаркерів місцевого та системного запалення: метаболічної поляризації фагоцитів (мікроглії, периферичної крові), за рівнем С-реактивного білка (СРБ) у плазмі крові, а також індексів системного запалення, розрахованих за результатами дослідження гемограми. Результати. У молодих оперованих тварин у віддалені терміни після плацебо нейрохірургічної маніпуляції спостерігали виразні прозапальні функціональні зміни мікроглії та відсутність ознак системного запалення (протизапальний метаболічний зсув циркулюючих фагоцитів). У старих інтактних тварин були наявні гематологічні та імунологічні ознаки системного запалення низького ступеня (мета-запалення). В оперованих старих щурів реєстрували залишкове нейрозапалення у поєднанні з виразними системними запальними реакціями (лейкоцитоз, суттєво підвищені показники індексу системної запальної відповіді (SIRI) та індексу системного імунного запалення (SII), прозапальний метаболічний зсув фагоцитів периферичної крові). Висновки. Наслідки проведення плацебо нейрохірургічних маніпуляцій у щурів залежать від віку. Мета-запалення, характерне для старих щурів, посилюється неспецифічним післяопераційним запаленням, що призводить до виразного стійкого персистентного системного запального процесу.

Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.

Background The SARS-CoV-2 pandemic continues to spread sporadically in the Unites States and worldwide. The severity and mortality excessively affected the frail elderly with co-existing medical diseases. There is growing evidence that cross-talk between the gut microbiome, Vitamin D and RAS/ACE2 system is essential for a balanced functioning of the elderly immune system and in regulating inflammation. In this review, we hypothesize that the state of gut microbiome, prior to infection determines the outcome associated with COVID-19 sepsis and may also be a critical factor in success to vaccination. Methods Articles from PubMed/Medline searches were reviewed using a combination of terms "SARS-CoV-2, COVID-19, Inflammaging, Immune-senescence, Gut microbiome, Vitamin D, RAS/ACE2, Vaccination". Conclusion Evidence indicates a complex association between gut microbiota, ACE-2 expression and Vitamin D in COVID-19 severity. Status of gut microbiome is highly predictive of the blood molecular signatures and inflammatory markers and host responses to infection. Vitamin D has immunomodulatory function in innate and adaptive immune responses to viral infection. Anti-inflammatory functions of Vit D include regulation of gut microbiome and maintaining microbial diversity. It promotes growth of gut-friendly commensal strains of Bifida and Fermicutus species. In addition, Vitamin D is a negative regulator for expression of renin and interacts with the RAS/ ACE/ACE-2 signaling axis. Collectively, this triad may be the critical, link in determination of outcomes in SARS-CoV-2 infection. The presented data are empirical and informative. Further research using advanced systems biology techniques and artificial intelligence-assisted integration could assist with correlation of the gut microbiome with sepsis and vaccine responses. Modulating these factors may impact in guiding the success of vaccines and clinical outcomes in COVID-19 infections.

The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.

BACKGROUND: Age-related chronic low-grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia-defining parameters, quality of life (QoL), and physical activity in middle-aged and older men. METHODS: Men aged 40-79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003-2005) and again after a median follow-up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high-sensitive C-reactive protein (hs-CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF-36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole-body dual X-ray absorptiometry) and strength. In this subgroup, cross-sectional associations between baseline inflammatory markers and sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking. RESULTS: At baseline, hs-CRP and WBC were negatively associated with PASE score (hs-CRP: β = -7.920, P

Obesity and aging promote chronic low-grade systemic inflammation. The aim of the study was to analyze the effects of long-term physical exercise and/or omega-3 fatty acid Docosahexaenoic acid (DHA) supplementation on genes or proteins related to muscle metabolism, inflammation, muscle damage/regeneration and myokine expression in aged and obese mice. Two-month-old C57BL/6J female mice received a control or a high-fat diet for 4 months. Then, the diet-induced obese (DIO) mice were distributed into four groups: DIO, DIO + DHA, DIO + EX (treadmill training) and DIO + DHA + EX up to 18 months. Mice fed a control diet were sacrificed at 2, 6 and 18 months. Aging increased the mRNA expression of Tnf-α and decreased the expression of genes related to glucose uptake (Glut1, Glut4), muscle atrophy (Murf1, Atrogin-1, Cas-9) and myokines (Metrnl, Il-6). In aged DIO mice, exercise restored several of these changes. It increased the expression of genes related to glucose uptake (Glut1, Glut4), fatty acid oxidation (Cpt1b, Acox), myokine expression (Fndc5, Il-6) and protein turnover, decreased Tnf-α expression and increased p-AKT/AKT ratio. No additional effects were observed when combining exercise and DHA. These data suggest the effectiveness of long-term training to prevent the deleterious effects of aging and obesity on muscle dysfunction.

Background Monocytes are a heterogenous population of immune cells whose subsets and functions become substantially dysregulated with advanced age. Although much of our current understanding of the age-related changes in monocytes is derived from fasting blood samples, most people are predominately in the postprandial state during waking hours. As hormonal, metabolic, and immunological changes in response to the consumption of a meal are manifested in postprandial blood, it’s unclear how age-dependent changes in peripheral monocytes at fasting are impacted by a dietary challenge. Objective We investigated the impact of age and meal consumption on circulating monocyte frequencies and subsets defined as classical (CD14 + CD16-), intermediate (CD14 + CD16 +), or non-classical (CD14dim CD16 +) in a cohort of 349 healthy adult volunteers grouped into categories based on their age: young adults (18–33 y, n = 123), middle adults (34–49 y, n = 115), and older adults (50–66 y, n = 111). Results Following 12-h fast total monocyte counts inversely correlated with subject age. Older adults had significantly fewer circulating monocytes along with elevated levels of TGs, cholesterol, glucose, IL-6, IL-8, TNF, neopterin, and CCL2 compared with young adults. Circulating monocyte pools in older adults consisted of smaller proportions of classical but larger proportions of intermediate and non-classical monocytes. Proportions of classical monocytes were inversely correlated with plasma TNF, IL-8, and neopterin while intermediate monocytes were positively correlated with plasma IL-6, TNF, and neopterin. Three hours after consuming a fat-containing meal postprandial monocyte counts increased in all age groups. Despite age-dependent differences in monocyte subsets at fasting, consumption of a meal induced similar changes in the proportions of classical and non-classical monocytes across age groups. Within the circulating postprandial monocyte pool, percentages of classical monocytes decreased while non-classical monocytes increased. However no change in precursory intermediate monocytes were detected. Our study confirms that ageing is associated with changes in monocyte frequencies and subsets and shows that consuming a fat-containing meal induces temporal changes in monocyte frequency and subsets independently of subject age. Clinical trial Registered on ClincialTrials.gov (Identifier: NCT02367287)

Advanced maternal age is a risk factor for female infertility, and placental dysfunction is considered one of the causes of pregnancy complications. We investigated the effects of advanced maternal aging on pregnancy outcomes and placental senescence. Female pregnant mice were separated into three groups: young (2-3 months old), middle (8-9 months old), and aged (11-13 months old). Although the body weights of young and middle dams gradually increased during pregnancy, the body weight of aged dams only increased slightly. The placental weight and resorption rate were significantly higher, and live fetal weights were reduced in a maternal age-dependent manner. Although mRNA expression of senescence regulatory factors (p16 and p21) increased in the spleen of aged dams, mRNA expression of p16 did not change and that of p21 was reduced in the placenta of aged dams. Using a cytokine array of proteins extracted from placental tissues, the expression of various types of senescence-associated secretory phenotype (SASP) factors was decreased in aged dams compared with young and middle dams. The aged maternal placenta showed reduced immune cell accumulation compared with the young placenta. Our present results suggest that models using pregnant mice older than 8 months are more suitable for verifying older human pregnancies. These findings suggest that general cellular senescence programs may not be included in the placenta and that placental functions, including SASP production and immune cell accumulation, gradually decrease in a maternal age-dependent manner, resulting in a higher rate of pregnancy complications.

Aging has been identified as one of the most relevant risk factors for poor outcomes in COVID-19 infection. Since now, different mechanisms responsible for worse outcomes in the elderly have been proposed, which include the remodeling of immune system, the higher prevalence of malnutrition and sarcopenia, the increased burden of multimorbidity, and, to a lesser extent, the direct effects of age on the respiratory system and hormonal profile. It seems that the interplay between all these causes, rather than the individual pathophysiological mechanism, explains the increased severity of the disease with age.

International audience; Impairment of gut function is one of the explanatory mechanisms of health status decline in elderly population. These impairments involve a decline in gut digestive physiology, metabolism and immune status, and associated to that, changes in composition and function of the microbiota it harbors. Continuous deteriorations are generally associated with the development of systemic dysregulations and ultimately pathologies that can worsen the initial health status of individuals. All these alterations observed at the gut level can then constitute a wide range of potential targets for development of nutritional strategies that can impact gut tissue or associated microbiota pattern. This can be key, in a preventive manner, to limit gut functionality decline, or in a curative way to help maintaining optimum nutrients bioavailability in a context on increased requirements, as frequently observed in pathological situations. The aim of this review is to give an overview on the alterations that can occur in the gut during aging and lead to the development of altered function in other tissues and organs, ultimately leading to the development of pathologies. Subsequently is discussed how nutritional strategies that target gut tissue and gut microbiota can help to avoid or delay the occurrence of aging-related pathologies.

Aging is a universal biological process characterized by a progressive deterioration in functional capacity and an increased risk of morbidity and mortality over time. In the lungs, there are considerable changes in lung structure and function with advancing age; however, research on the transcriptomic profile implicated in this process is scanty. In this study, we addressed the lung transcriptome changes during aging, through a global gene expression analysis of normal lungs of mice aged 4- and 18-months old. Functional pathway enrichment analysis by Ingenuity Pathway Analysis (IPA) revealed that the most enriched signaling pathways in aged mice lungs are involved in the regulation of cell apoptosis, senescence, development, oxidative stress, and inflammation. We also found 25 miRNAs significantly different in the lungs of old mice compared with their younger littermates, eight of them upregulated and 17 downregulated. Using the miRNet database we identified TNFα, mTOR, TGFβ, WNT, FoxO, Apoptosis, Cell cycle, and p53 signaling pathways as the potential targets of several of the dysregulated miRNAs supporting that old lungs have increased susceptibility for apoptosis, inflammation, and fibrosis. These findings reveal differential expression profiles of genes and miRNAs affecting cell survival and the inflammatory response during lung aging.

According to the theory of inflammaging, aging of the body and the development of age-related diseases are a consequence of a chronic progressive generalized inflammatory process that develops and persists throughout life under the influence of negative factors of an infectious and non-infectious nature. Inflammaging has a number of features that distinguish it from acute inflammation: a chronic nature of inflammation, a low level of inflammation, blurry clinical state (in the early stages of clinical manifestations there may not be any at all). The key pathogenetic role in inflammation plays age-associated changes in the innate immune system, which are referred to in the English literature as “immunosenescence” and oxidative stress. The main source of reactive oxygen species and free radicals in the cells are mitochondria. With age, the concentration of intracellular glutathione, one of the main factors of the antioxidant protection of the cell, decreases and a pathological condition arises in which the rate of production of free radicals and reactive oxygen species significantly exceeds the antioxidant capabilities, which leads to the formation of oxidative stress and disruption of the structure and function of cells. Oxidative stress, inflammation and neuroinflammation are closely related to cognitive impairment, pathological state that is often observed in a group of elderly and senile patients. Further study of the pathogenesis of Inflammaging and the role of oxidative stress in it will potentially lead to development of methods to slow down aging and treat age-related cognitive impairments.

Backgroundsarcopenia is a highly prevalent condition in elderly individuals which is characterized by loss of muscle mass and functions; recent results showed that it is also associated with inflammation. Rehabilitation protocols for sarcopenia are designed to improve physical conditions, but very scarce data are available on their effects on inflammation We verified whether in sarcopenic patients the inflammation is reduced by rehabilitation and investigated the biological correlates of such effect.MethodsTwenty-one sarcopenic patients undergoing a specifically-designed rehabilitation program were enrolled in the study. Physical, cognitive and nutritional parameters, as well as the concentration of C-Reactive Protein (CRP), pro-and anti-inflammatory cytokines and cytokine production-modulating miRNAs were measured at the beginning (T0) and at end (30-days; T1) of the rehabilitation.ResultsRehabilitation resulted in a significant improvement of physical and cognitive conditions; this was accompanied by a significant reduction of CRP (p = 0.04) as well as of IL-18 (p = 0.008) and IL-37 (p = 0.009) concentration. Notably, the concentration of miR-335-3p (p = 0.007) and miR-657, the two known post-transcriptional regulators of IL-37 production, was increased by the rehabilitation protocol.ConclusionsResults herein confirm that successful rehabilitation for sarcopenia results in a reduction of the inflammatory milieu, raise the possibility that IL-37 may be a key target to monitor the rehabilitation-associated improvement in sarcopenia, and suggest that this cytokine could be a therapeutic target in sarcopenic patients.

Background Chronological age (CA) is a predictor of adverse coronavirus disease 2019 (COVID-19) outcomes; however, CA alone does not capture individual responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. Method In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (intensive care unit admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. Results We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel >0 had higher risk of death and critical illness compared to those with lower values (log-rank p < .001). Using unsupervised clustering, we identified 4 adaptive responses to SARS-CoV-2 infection: (i) inflammaging associated with CA, (ii) metabolic dysfunction associated with cardiometabolic comorbidities, (iii) unfavorable hematological response, and (iv) response associated with favorable outcomes. Conclusions Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.

A challenging and promising new branch of aging-related research fields is the identification of natural compounds able to modulate the senescence-associated secretory phenotype (SASP), which characterizes senescent cells and can contribute to fuel the inflammaging. We investigated both the anti-SASP and anti-inflammatory activities of a nutritional supplement, namely Fenoxidol™, composed of turmeric extract bioCurcumin (bCUR), Polydatin (the natural glycosylated precursor of Resveratrol-RSV), and liposomal β-caryophyllene (BCP), in two human cellular models, such as the primary endothelial cell line, HUVECs and the monocytic cell line, THP-1. Replicative and Doxorubicin-induced senescent HUVECs, both chosen as cellular models of SASP, and lipopolysaccharides (LPS)-stimulated THP-1, selected as a model of the inflammatory response, were treated with the three single natural compounds or with a combination of them (MIX). In both senescent HUVEC models, MIX treatment significantly reduced IL-1β and IL-6 expression levels and p16ink4a protein, and also increased SIRT1 protein level, as well as downregulated miR-146a and miR-21 expression, two of the so-called inflamma-miRNAs, more effectively than the single compounds. In THP-1 cells stimulated with LPS, the MIX showed a significant effect in decreasing IL-1β, IL-6, TNF-α, and miR-146a expression levels and Caspase-1 activation, in association with an up-regulation of SIRT1 protein, compared to the single compounds. Overall, our results suggest that the three analysed compounds can have a combined effect in restraining SASP in senescent HUVECs as well as the inflammatory response in LPS-stimulated THP-1 cells. Supplementary Information The online version contains supplementary material available at 10.1007/s10522-021-09915-0.

Surgeons are increasingly faced with an ageing and frail patient population. There is a significant absence of biomarkers capable of risk stratifying patients undergoing emergency laparotomy. Inflammaging describes a state of chronic inflammation associated with ageing and frailty that may predict worse outcomes after surgery. This retrospective observational study evaluated pre-morbid inflammatory markers in the prognostication of older adult patients undergoing emergency laparotomy. Patients aged ≥65 years undergoing surgery between 1 April 2017 and 1 April 2022 were identified. Pre-admission and acute C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), total white cell count (WCC), neutrophil count (NC) and lymphocyte count (LC) datapoints were captured. Pre-operative risk stratification scores and post-operative outcomes were recorded using the National Emergency Laparotomy Audit (NELA) database. A cohort of 196 patients was included: 57.7% were female, median age 74.5 years. High risk (NELA risk of mortality ≥ 5%) and frail (clinical frailty scale ≥ 4) patients experienced a significantly longer hospital and critical care stay (p < 0.05). Pre-admission ESR ≥ 16 and LC ≥ 4.1 were significantly associated with a longer critical care stay (p < 0.05); no statistical significance was observed with CRP, WCC and NC in predicting adverse outcomes. We found that an elevated pre-morbid ESR and LC identifies a potential inflammaging cohort that demonstrates worse outcomes following emergency laparotomy. The prognostication of older adult surgical patients remains a challenge and represents an area of research deserving of future attention.

Aging is related to a low-grade and sterile inflammation called inflammaging, recognized as the main risk factor for age-related disease (ARD) development. Inflammaging is fostered by the repeated activation of immune cells, as well as by the accumulation of senescent cells. Recently, a number of natural compounds have gained attention to be tested as anti-aging therapies, based on their anti-inflammatory activity and/or ability to reduce the pro-inflammatory secretome of senescent cells (senomorphyc activity). Here, we investigated the anti-inflammatory and senomorphic properties of an Asian-native Zingiber officinale Roscoe extract (ZOE), commonly consumed as a food spice and herbal medicine. We employed two models of primary endothelial cells (HUVECs), such as the replicative-senescence and LPS-induced response, to investigate the anti-inflammatory/senomorphic effect of ZOE, and one cellular model of neuroinflammation, i.e., immortalized murine microglial cells (BV2). First, we found that the ZOE treatment induced the inhibition of NF-kB activation in BV2 cells. Among the constituents of ZOE, we showed that the terpenoid-enriched fraction (ZTE) was the component able to counteract the phosphorylation of NF-kB(p65), while 6-gingerol (GIN) and 6-shogaol (SHO) did not produce any significant effect. Further, we observed that the treatment with 10 µg/mL of ZOE exerted anti-inflammatory activity on LPS-stimulated young (y)HUVEC and senomorphyc activity on replicative senescent (s)HUVEC, significantly reducing the expression levels of IL-1β, TNF -α, IL-8, MCP-1, and ICAM-1. Moreover, the ZTE treatment was able to significantly reduce the IL-8 levels secreted in the medium of both LPS-stimulated yHUVEC and sHUVEC. Overall, our data suggest a potential protective role of ZOE on neuroinflammation and endothelial inflammation/activation, thus suggesting its potential relevance in delaying/postponing ARD development and progression, characterized by endothelial dysfunction.

COVID-19 is a highly contagious respiratory disease caused by the novel coronavirus SARS-CoV-2. Since October 2020 the second wave of the pandemic has been observed around the world, as pathogen specific herd immunity has not been built yet. Moreover, the current, more contagious pathogen carrying the D614G mutation has become the globally dominant form of SARS-CoV-2. In this article we present the current state of knowledge on the impact of ACE2 and the reninangiotensin system (RAS) and the innate immune system on different outcomes of COVID-19. Especially, we point out the dual role of the immune system and ACE2 in pathogenesis of the disease. Namely, at the initial stage of the infection anti-viral activity of innate immunity is responsible for inhibition of SARS-CoV-2 replication. On the other hand, a dysregulated immune response may cause the detrimental hyperinflammation (“cytokine storm”) responsible for the severe course of the disease. Concomitantly, we analyse the roles of ACE2 in both facilitation of infection and abrogation of its effects, as the major cellular entry receptor for SARS-CoV-2 and an important enzyme responsible for tissue protection, respectively. Finally, we discuss the dominant impact of aging on the fatal outcome of COVID-19.

The prevalence of osteoarthritis (OA) increases in proportion to age, so in the population of people over 65 years of age. The pathogenesis of OA is based on inflammation of the cartilage tissue of the joint, which leads to damage to the cartilage, activation of signaling pathways and increased levels of cytokines. Aim.To study the literature data on bone and cartilage remodeling with the development of resorptive processes and discuss possible algorithms and recommendations for the management of patients with OA on the background of chondroprotective therapy. Materials and methods.A comprehensive analysis of data presented in open sources, published and available on such resources as PubMed, EMBASE, Cochrane, and Library. Results.According to the available recommendations and the opinion of experts, among the methods of OA therapy, drugs containing pharmaceutical chondroitin sulfate are currently being discussed, which in a number of studies has demonstrated high antiresorptive effectiveness. Conclusion.The use of drugs based on pharmaceutical chondroitin sulfate (Chondroguard) contributes not only to the reduction of pain in OA, but also has a positive effect on the processes of inflammation, including those associated with age-related changes in the body.

Alexander P Horkowitz,1,2 Ashley V Schwartz,3 Carlos A Alvarez,1,2 Edgar B Herrera,1 Marilyn L Thoman,1 Dale A Chatfield,4 Kent G Osborn,5 Ralph Feuer,2 Uduak Z George,3 Joy A Phillips1 1Donald P. Shiley Biosciences Center, San Diego State University, San Diego, California, USA; 2Department of Biology, San Diego State University, San Diego, California, USA; 3Department of Mathematics and Statistics, San Diego State University, San Diego, California, USA; 4Department of Chemistry, San Diego State University, San Diego, California, USA; 5Office of Animal Research, University of California San Diego, San Diego, California, USACorrespondence: Joy A PhillipsDonald P Shiley BioSciences Center, San Diego State University, 5500 Campanile Dr MC4650, San Diego, CA 92182-4650, USATel +1 619 488 2169Fax +1 619 0594 8184Email jphillips@sdsu.eduIntroduction: This study was designed to explore the role of acetylcholine (ACh) in pulmonary viral infection and recovery. Inflammatory control is critical to recovery from respiratory viral infection. ACh secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation.Methods: ACh and lymphocyte cholinergic status in the lungs were measured over the course of influenza infection and recovery. The role of ACh was examined by inhibiting ACh synthesis in vivo. Pulmonary inflammation was monitored by Iba1 immunofluorescence, using a novel automated algorithm. Tissue repair was monitored histologically.Results: Pulmonary ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the BAL and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers and were retained in the resident memory regions of the lung up to 2 months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. Inflammation was monitored by ionized calcium-binding adapter molecule 1 (Iba1) immunofluorescence, using a novel automated algorithm. When ACh production was inhibited, mice exhibited increased tissue inflammation and delayed recovery. Histologic examination revealed abnormal tissue repair when ACh was limited.Conclusion: These findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.Keywords: influenza, acetylcholine, acetylcholinesterase, inflammation, pulmonary repair, ChAT, cholinergic lymphocytes, CD4 resident memory, Iba1, Aif-1, automated algorithm, MATLAB, inflammaging, cholinergic anti-inflammatory pathway

Aging is a complex process that can be characterized by functional and cognitive decline in an individual. Aging can be assessed based on the functional capacity of vital organs and their intricate interactions with one another. Thus, the nature of aging can be described by focusing on a specific organ and an individual itself. However, to fully understand the complexity of aging, one must investigate not only a single tissue or biological process but also its complex interplay and interdependencies with other biological processes. Here, using RNA-seq, we monitored changes in the transcriptome during aging in four tissues (including brain, blood, skin and liver) in mice at 9 months, 15 months, and 24 months, with a final evaluation at the very old age of 30 months. We identified several genes and processes that were differentially regulated during aging in both tissue-dependent and tissue-independent manners. Most importantly, we found that the electron transport chain (ETC) of mitochondria was similarly affected at the transcriptome level in the four tissues during the aging process. We also identified the liver as the tissue showing the largest variety of differentially expressed genes (DEGs) over time. Lcn2 (Lipocalin-2) was found to be similarly regulated among all tissues, and its effect on longevity and survival was validated using its orthologue in Caenorhabditis elegans. Our study demonstrated that the molecular processes of aging are relatively subtle in their progress, and the aging process of every tissue depends on the tissue’s specialized function and environment. Hence, individual gene or process alone cannot be described as the key of aging in the whole organism.

Alexander P Horkowitz,1,2 Ashley V Schwartz,3 Carlos A Alvarez,1,2 Edgar B Herrera,1 Marilyn L Thoman,1 Dale A Chatfield,4 Kent G Osborn,5 Ralph Feuer,2 Uduak Z George,3 Joy A Phillips1 1Donald P. Shiley Biosciences Center, San Diego State University, San Diego, California, USA; 2Department of Biology, San Diego State University, San Diego, California, USA; 3Department of Mathematics and Statistics, San Diego State University, San Diego, California, USA; 4Department of Chemistry, San Diego State University, San Diego, California, USA; 5Office of Animal Research, University of California San Diego, San Diego, California, USACorrespondence: Joy A PhillipsDonald P Shiley BioSciences Center, San Diego State University, 5500 Campanile Dr MC4650, San Diego, CA 92182-4650, USATel +1 619 488 2169Fax +1 619 0594 8184Email jphillips@sdsu.eduIntroduction: This study was designed to explore the role of acetylcholine (ACh) in pulmonary viral infection and recovery. Inflammatory control is critical to recovery from respiratory viral infection. ACh secreted from non-neuronal sources, including lymphocytes, plays an important, albeit underappreciated, role in regulating immune-mediated inflammation.Methods: ACh and lymphocyte cholinergic status in the lungs were measured over the course of influenza infection and recovery. The role of ACh was examined by inhibiting ACh synthesis in vivo. Pulmonary inflammation was monitored by Iba1 immunofluorescence, using a novel automated algorithm. Tissue repair was monitored histologically.Results: Pulmonary ACh remained constant through the early stage of infection and increased during the peak of the acquired immune response. As the concentration of ACh increased, cholinergic lymphocytes appeared in the BAL and lungs. Cholinergic capacity was found primarily in CD4 T cells, but also in B cells and CD8 T cells. The cholinergic CD4+ T cells bound to influenza-specific tetramers and were retained in the resident memory regions of the lung up to 2 months after infection. Histologically, cholinergic lymphocytes were found in direct physical contact with activated macrophages throughout the lung. Inflammation was monitored by ionized calcium-binding adapter molecule 1 (Iba1) immunofluorescence, using a novel automated algorithm. When ACh production was inhibited, mice exhibited increased tissue inflammation and delayed recovery. Histologic examination revealed abnormal tissue repair when ACh was limited.Conclusion: These findings point to a previously unrecognized role for ACh in the transition from active immunity to recovery and pulmonary repair following respiratory viral infection.Keywords: influenza, acetylcholine, acetylcholinesterase, inflammation, pulmonary repair, ChAT, cholinergic lymphocytes, CD4 resident memory, Iba1, Aif-1, automated algorithm, MATLAB, inflammaging, cholinergic anti-inflammatory pathway

Childhood acute lymphoblastic leukemia (ALL) survivors are at higher risk of developing many late effects later in life. They experience multiple health problems that have significant public health implications, such as frailty, premature onset of lifestyle diseases, and second tumors. There is some evidence that chronic inflammation causes accelerated aging in childhood cancer survivors; however, the available data are very limited. The aim of the study was to evaluate the broad panel of cytokines among asymptomatic ALL survivors after anticancer treatment. The study included 56 subjects with a mean age of 16.11 ± 3.98 years. The commercially available Bio-Plex Pro Human Cytokine Screening 48-Plex Panel Assay and Bio-Plex TGF-β Assay were used for simultaneous determination of 48 cytokines and 3 isoforms of TGF-β. Among 51 tested cytokines, the levels of 33 were statistically significantly higher in ALL survivors than in the control group (p < 0.05). Increased levels of pro-inflammatory cytokines, including the IL-1 family (IL-1 β, IL-1Ra; p < 0.0001), IL-6 (p < 0.001), IL-17 (p < 0.001), IL-18 (p < 0.05), TNFα (p < 0.01), IFNα2 (p < 0.05), and IFNγ (p < 0.01), were found elevated in the entire study group, compared with the controls. Subjects treated previously according to the high-risk protocol had higher IL-18 levels than low- and intermediate-risk groups (p < 0.05). Elevated levels of IL-1ra, IL-6, IL-12 (p70), IL-17, LIF, M-CSF, CSF, and VEGF were found in ALL survivors treated before the age of 5, compared with subjects treated over 5 years of age (p < 0.05). Moreover, individuals who received radiotherapy presented elevated levels of both IL-18 (p < 0.05) and MIG (p < 0.05). In conclusion, we found that young asymptomatic survivors after ALL treatment demonstrated a biological profile of complex low-grade chronic inflammation.

Cerebral small vessel disease (CSVD) is one of the most important causes of vascular dementia. Immunosenescence and inflammatory response, with the involvement of the cerebrovascular system, constitute the basis of this disease. Immunosenescence identifies a condition of deterioration of the immune organs and consequent dysregulation of the immune response caused by cellular senescence, which exposes older adults to a greater vulnerability. A low-grade chronic inflammation status also accompanies it without overt infections, an “inflammaging” condition. The correlation between immunosenescence and inflammaging is fundamental in understanding the pathogenesis of age-related CSVD (ArCSVD). The production of inflammatory mediators caused by inflammaging promotes cellular senescence and the decrease of the adaptive immune response. Vice versa, the depletion of the adaptive immune mechanisms favours the stimulation of the innate immune system and the production of inflammatory mediators leading to inflammaging. Furthermore, endothelial dysfunction, chronic inflammation promoted by senescent innate immune cells, oxidative stress and impairment of microglia functions constitute, therefore, the framework within which small vessel disease develops: it is a concatenation of molecular events that promotes the decline of the central nervous system and cognitive functions slowly and progressively. Because the causative molecular mechanisms have not yet been fully elucidated, the road of scientific research is stretched in this direction, seeking to discover other aberrant processes and ensure therapeutic tools able to enhance the life expectancy of people affected by ArCSVD. Although the concept of CSVD is broader, this manuscript focuses on describing the neurobiological basis and immune system alterations behind cerebral aging. Furthermore, the purpose of our work is to detect patients with CSVD at an early stage, through the evaluation of precocious MRI changes and serum markers of inflammation, to treat untimely risk factors that influence the burden and the worsening of the cerebral disease.