•Telomere shortening accompanies mammalian aging in vivo.•Environmental factors could modulate the activity of telomerase during pregnancy.•Telomeric repeats prevent the activation of the ...pro-inflammatory misplaced nucleic acid sensing pathway.•Organisms with longer telomeres could exploit the anti-inflammatory effects of telomere sequences over an extended time span.
Telomere shortening accompanies mammalian aging in vivo, and the burden of senescent cells with short telomeres and a senescence-associated secretory phenotype (SASP) increases with aging. The release into the cytoplasm and the extracellular vesicle-mediated intercellular exchange of telomeric TTAGGG repeats could exert an anti-inflammatory activity by preventing the activation of the misplaced nucleic acid-sensing pathway. Many pharmacological and genetic strategies have been developed to prevent telomere shortening or to achieve telomere elongation. Recently, it was demonstrated that telomere elongation can be obtained – without genetic manipulation – by culturing mice embryonic stem cells into appropriate media. Based on this observation, we hypothesize that environmental factors could affect the initial length of telomeres by modulating the activity of telomerase during the early stages of pregnancy. Therefore, organisms with longer telomeres could exploit the anti-inflammatory activity of telomeric sequences over an extended time span, eventually delaying the development and progression of age-related diseases.
•Tocilizumab (TCZ) is currently being tested in COVID‐19‐induced cytokine storm.•COVID-19 patients responding to TCZ have higher post-treatment levels of circulating miR-146a.•Low levels of miR-146a ...are associated with death in COVID-19 patients not responding to TCZ.•MicroRNAs can represent biomarkers of response to anti-inflammatory interventions in COVID-19.
Current COVID-19 pandemic poses an unprecedented threat to global health and healthcare systems. The most amount of the death toll is accounted by old people affected by age-related diseases that develop a hyper-inflammatory syndrome. In this regard, we hypothesized that COVID-19 severity may be linked to inflammaging. Here, we examined 30 serum samples from patients enrolled in the clinical trial NCT04315480 assessing the clinical response to a single-dose intravenous infusion of the anti-IL-6 receptor drug Tocilizumab (TCZ) in COVID-19 patients with multifocal interstitial pneumonia.
In these serum samples, as well as in 29 age- and gender-matched healthy control subjects, we assessed a set of microRNAs that regulate inflammaging, i.e. miR-146a-5p, miR-21-5p, and miR-126-3p, which were quantified by RT-PCR and Droplet Digital PCR.
We showed that COVID-19 patients who did not respond to TCZ have lower serum levels of miR-146a-5p after the treatment (p = 0.007). Among non-responders, those with the lowest serum levels of miR-146a-5p experienced the most adverse outcome (p = 0.008). Our data show that a blood-based biomarker, such as miR-146a-5p, can provide clues about the molecular link between inflammaging and COVID-19 clinical course, thus allowing to better understand the use of biologic drug armory against this worldwide health threat.
Type 2 diabetes mellitus (T2DM) is a complex multifactorial disease causing the development of a large range of cardiovascular (CV) complications. Lifestyle changes and pharmacological therapies only ...partially halt T2DM progression, and existing drugs are unable to completely suppress the increased CV risk of T2DM patients. Extracellular vesicles (EV)s are membrane-coated nanoparticles released by virtually all living cells and are emerging as novel mediators of T2DM and its CV complications. As a matter of fact, several preclinical models suggest a key involvement of EVs in the initiation and/or progression of insulin resistance, β-cell dysfunction, diabetic dyslipidaemia, atherosclerosis, and other T2DM complications. In addition, preliminary findings also suggest that EV-associated molecular cargo, and in particular the miRNA repertoire, may provide with useful diagnostic and/or prognostic information for the management of T2DM. Here, we review the latest findings showing that EV biology is altered during the entire trajectory of T2DM,
from diagnosis to development of CV complications. We also critically highlight the potential of this emerging research field, by describing both preclinical and clinical observations, and the limitations that must be overcome to translate the preclinical findings into the development of EV-based nano-diagnostic and/or nano-therapeutic tools. Finally, we summarize how two lifestyle changes known to prevent or limit T2DM,
diet and exercise, affect EV number and composition, with a focus on the possible role of EVs contained in food in shaping metabolic responses, a promising approach still in its infancy.
•Inflammaging is a key contributor to Alzheimer’s disease (AD) pathophysiology.•Most of the cellular and molecular mechanisms of aging are involved in the AD-related vascular dysfunction.•Early ...cardiovascular interventions modulate the trajectory of age-related cognitive decline.•Understanding the connection between dementia, frailty, and cardiovascular disease is crucial in the prevention of AD.
Aging plays an important role in the etiology of the most common age-related diseases (ARDs), including Alzheimer’s disease (AD). The increasing number of AD patients and the lack of disease-modifying drugs warranted intensive research to tackle the pathophysiological mechanisms underpinning AD development. Vascular aging/dysfunction is a common feature of almost all ARDs, including cardiovascular (CV) diseases, diabetes and AD. To this regard, interventions aimed at modifying CV outcomes are under extensive investigation for their pleiotropic role in ameliorating and slowing down cognitive impairment in middle-life and elderly individuals. Evidence from observational and clinical studies confirm the notion that the earlier the interventions are conducted, the most favorable are the effects on cognitive function. Therefore, epidemiological research should focus on the early detection of deviations from a healthy cognitive aging trajectory, through the stratification of adult individuals according to the rate of aging.
Here, we review the interplay between vascular and cognitive dysfunctions associated with aging, to disentangle the complex mechanisms underpinning the development and progression of neurodegenerative disorders, with a specific focus on AD.
Sex/gender-related differences in inflammaging Olivieri, Fabiola; Marchegiani, Francesca; Matacchione, Giulia ...
Mechanisms of ageing and development,
April 2023, 2023-04-00, 20230401, Letnik:
211
Journal Article
Recenzirano
Odprti dostop
Geroscience puts mechanisms of aging as a driver of the most common age-related diseases and dysfunctions. Under this perspective, addressing the basic mechanisms of aging will produce a better ...understanding than addressing each disease pathophysiology individually. Worldwide, despite greater functional impairment, life expectancy is higher in women than in men. Gender differences in the prevalence of multimorbidity lead mandatory to the understanding of the mechanisms underlying gender-related differences in multimorbidity patterns and disability-free life expectancy. Extensive literature suggested that inflammaging is at the crossroad of aging and age-related diseases. In this review, we highlight the main evidence on sex/gender differences in the mechanisms that foster inflammaging, i.e. the age-dependent triggering of innate immunity, modifications of adaptive immunity, and accrual of senescent cells, underpinning some biomarkers of inflammaging that show sex-related differences. In the framework of the “gender medicine perspective”, we will also discuss how sex/gender differences in inflammaging can affect sex differences in COVID-19 severe outcomes.
●Inflammaging is at the crossroad of aging and age-related diseases.●Sex-related differences exist in the age-dependent accrual of senescent cells and remodeling of innate and adaptive immunity.●The most extensively investigated biomarkers of inflammaging show sex-related differences.●Sex-related differences in immunological responses and inflammaging rate could affect COVID-19 outcomes.
Metformin is the first-choice therapy to lower glycaemia and manage type 2 diabetes. Continuously emerging epidemiological data and experimental models are showing additional protective effects of ...metformin against a number of age-related diseases (ARDs), e.g., cardiovascular diseases and cancer. This evidence has prompted the design of a specific trial, i.e., the Targeting Aging with Metformin (TAME) trial, to test metformin as an anti-ageing molecule. However, a unifying or prevailing mechanism of action of metformin is still debated. Here, we summarize the epidemiological data linking metformin to ARD prevention. Then, we dissect the deeply studied mechanisms of action explaining its antihyperglycemic effect and the putative mechanisms supporting its anti-ageing properties, focusing on studies using clinically pertinent doses. We hypothesize that the molecular observations obtained in different models with metformin could be indirectly mediated by its effect on gut flora. Novel evidence suggests that metformin reshapes the human microbiota, promoting the growth of beneficial bacterial species and counteracting the expansion of detrimental bacterial species. In turn, this action would influence the balance between pro- and anti-inflammatory circulating factors, thereby promoting glycaemic control and healthy ageing. This framework may reconcile diverse observations, providing information for designing further studies to elucidate the complex interplay between metformin and the metabiome harboured in mammalian body compartments, thereby paving the way for innovative, bacterial-based therapeutics to manage type 2 diabetes and foster a longer healthspan.
•Circulating microRNA-146a levels show a significant age-related decline.•MiR-146a shows gender-related correlations with specific biochemical variables.•MiR-146a is overexpressed in type 2 diabetes ...patients treated with metformin.•MiR-146a levels follow inverted U-shaped trajectories in healthy/unhealthy aging.•MiR-146a could represent a functional biomarker of healthy/unhealthy aging.
To evaluate the combined effect of age and glycemic state on circulating levels of the inflamma-miR‐146a levels, 188 healthy subjects (CTR) aged 20–104 years and 144 type-2 diabetic patients (T2DM), aged 40‐80 years, were analyzed. In CTR subjects, miR-146a levels showed a significant age-related decline. When a gender-stratified analysis was ran, the miR‐146a age-related trajectory was confirmed only in men and a negative correlation with PAI-1, uric acid, and creatinine was also observed. In women, miR-146a circulating levels showed negative correlations with azotemia, uric acid, waist/hip ratio and ferritin. A significant miR-146a decline with aging was also observed in T2DM patients. Significant positive correlations were found between miR-146a in diabetic patients and total cholesterol, LDL-C, ApoA1, ApoB, and platelets, and negative correlations with serum iron and ferritin. Notably, miR-146a was significantly overexpressed in T2DM patients treated with metformin. MiR-146a levels were significantly lower in diabetic patients than in age-matched CTR and negatively correlated to both fasting glucose and HbA1c in males. Finally, age-related trajectories for circulating miR-146a levels showed an inverted U-shaped relationship; however, in T2DM patients the trajectory was significantly shifted towards lower levels. Our findings support the hypothesis that miR-146a could be a functional biomarker of healthy/unhealthy aging.
The COVID-19 pandemic caused by SARS-CoV-2 infection has been of unprecedented clinical and socio-economic worldwide relevance. The case fatality rate for COVID-19 grows exponentially with age and ...the presence of comorbidities. In the older patients, COVID-19 manifests predominantly as a systemic disease associated with immunological, inflammatory, and procoagulant responses. Timely diagnosis and risk stratification are crucial steps to define appropriate therapies and reduce mortality, especially in the older patients. Chronically and systemically activated innate immune responses and impaired antiviral responses have been recognized as the results of a progressive remodeling of the immune system during aging, which can be described by the words ‘immunosenescence’ and ‘inflammaging’. These age-related features of the immune system were highlighted in patients affected by COVID-19 with the poorest clinical outcomes, suggesting that the mechanisms underpinning immunosenescence and inflammaging could be relevant for COVID-19 pathogenesis and progression. Increasing evidence suggests that senescent myeloid and endothelial cells are characterized by the acquisition of a senescence-associated pro-inflammatory phenotype (SASP), which is considered as the main culprit of both immunosenescence and inflammaging. Here, we reviewed this evidence and highlighted several circulating biomarkers of inflammaging that could provide additional prognostic information to stratify COVID-19 patients based on the risk of severe outcomes.
•Immunosenescence and inflammaging are emerging risk factors for the development of COVID-19 severe outcomes.•Markers of NETosis – the program for formation of neutrophil extracellular traps – are increased in COVID-19.•COVID-19 thrombotic complications result from activation of immunothrombosis and dysfunction of the coagulation system.•Inflammaging and immunosenescence biomarkers should be implemented into clinical practice for predicting COVID-19 prognosis.
Alzheimer's disease (AD) is a rapidly growing global concern due to a consistent rise of the prevalence of dementia which is mainly caused by the aging population worldwide. An early diagnosis of AD ...remains important as interventions are plausibly more effective when started at the earliest stages. Recent developments in clinical research have focused on the use of blood-based biomarkers for improve diagnosis/prognosis of neurodegenerative diseases, particularly AD. Unlike invasive cerebrospinal fluid tests, circulating biomarkers are less invasive and will become increasingly cheaper and simple to use in larger number of patients with mild symptoms or at risk of dementia. In addition to AD-specific markers, there is growing interest in biomarkers of inflammaging/neuro-inflammaging, an age-related chronic low-grade inflammatory condition increasingly recognized as one of the main risk factor for almost all age-related diseases, including AD. Several inflammatory markers have been associated with cognitive performance and AD development and progression. The presence of senescent cells, a key driver of inflammaging, has also been linked to AD pathogenesis, and senolytic therapy is emerging as a potential treatment strategy. Here, we describe blood-based biomarkers clinically relevant for AD diagnosis/prognosis and biomarkers of inflammaging associated with AD. Through a systematic review approach, we propose that a combination of circulating neurodegeneration and inflammatory biomarkers may contribute to improving early diagnosis and prognosis, as well as providing valuable insights into the trajectory of cognitive decline and dementia in the aging population.
•Inflammaging is a key contributor to Alzheimer’s disease (AD) pathophysiology.•Circulating brain-specific markers are emerging as tools to track neurodegeneration.•Combinations of circulating brain-specific and inflammatory biomarkers for the diagnosis of AD warrant further investigation.
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