Idiopathic pulmonary fibrosis (IPF) is a paradigmatic aging-related lung disorder. In this retrospective cohort study, we evaluated 101 treatment-naïve patients at diagnosis (T0) and a subgroup (n = 31) after one year of antifibrotic therapy (T1). Analyses included leukocyte telomere length (LTL), DNA methylation age [DNAmAge assessed by Horvath, Levine (PhenoAge), Skin & Blood, Hannum, BLUP, Elastic Net (EN), and a 5-CpG panel], age acceleration (AgeAcc), and genetic susceptibility. At T1, LTL was independently predicted by baseline LTL (p = 0.0004) and treatment duration (p = 0.0056). Longitudinally, ΔLTL increased in nintedanib- versus pirfenidone-treated patients (p = 0.0402) and with treatment duration (p = 0.0233). DNAmAge modestly increased with chronological aging across all clocks, while AgeAcc remained stable, decreasing at follow-up (p = 0.0435) and higher in males (p = 0.0204). Genetic analyses on 17 IPF-associated SNPs confirmed enrichment of established risk variants, including MUC5B and DPP9, and identified an association between higher genetic burden and lower forced vital capacity (p = 0.0136). Extending this approach, genome-wide imputation enabled polygenic risk score (PRS) analysis, revealing significant case-control differences and discrimination (AUC up to 0.79), supporting a measurable polygenic contribution to disease susceptibility. These findings highlight the added value of integrating telomeric, epigenetic, and genome-wide genetic burden-captured through PRS-for improved risk stratification in IPF.

As human life expectancy continues to rise, ageing and age-related diseases have become critical societal challenges, driving extensive research across genetics, molecular biology, biochemistry, and behavioral sciences. In this context, domestic dogs (Canis lupus familiaris) offer a unique model for ageing research due to their shared environmental exposures with humans, diverse genetic profiles, and relatively short lifespans. This review aims to identify potential biomarkers of ageing in dogs, facilitating a deeper understanding of age-related mechanisms and supporting the evaluation of interventions designed to promote healthy ageing. We present a research of peer-reviewed literature on age-related variations of various parameters across multiple biological systems, including epigenetic, telomere, immune, metabolic, and cognitive markers in dogs. Our findings highlight several robust biomarkers, such as DNA methylation-based epigenetic clocks, telomere attrition, CD4+/CD8+ T-cell ratio, hematological markers (e.g., globulin levels), and cognitive function scores. These biomarkers demonstrate strong parallels with human ageing processes, particularly concerning genomic and epigenetic alterations. However, challenges remain, including breed-specific variability, body size differences, and inconsistent evidence regarding inflammageing markers, such as pro-inflammatory cytokines. Despite these limitations, indicators of chronic inflammation (e.g., anemia of chronic disease and elevated globulins) are evident in older dogs. Future research directions include the standardization of biomarker protocols for dogs, the development of longitudinal studies to track dynamic age-related changes, and further exploration of emerging biomarkers, such as those related to microbiome composition and oxidative stress.

DNA methylation represents a crucial epigenetic mechanism orchestrating gene expression, cellular homeostasis, and the aging trajectory. Dysregulation of DNA methyltransferases (DNMTs)-the enzymes catalyzing this process-has been implicated in a wide spectrum of chronic conditions, including cancer, cardiovascular and metabolic disorders, and neurodegenerative diseases. Emerging evidence suggests that food-derived bioactive compounds can act as DNMT inhibitors, reshaping epigenetic landscapes. This systematic review, registered in PROSPERO (CRD42022320316), critically evaluated in vitro, in vivo animal, and ex vivo studies investigating the effects of dietary bioactives on DNMT expression and activity. A thorough search of PubMed up to 23 May, 2025, yielded 103 studies, of which 76 met the inclusion criteria. Eligible publications were original, peer-reviewed, and provided evidence from in vitro, in vivo animal, or ex vivo models. Frequently studied bioactives included epigallocatechin-3-gallate, curcumin, genistein, resveratrol, sulforaphane, and folate. Notably, nearly 90% of studies reported DNMT inhibition-often dose- and time-dependent. Approximately 21% defined minimal effective concentrations, predominantly for isolated compounds. Several studies described synergistic interactions between bioactives, and emerging data highlighted the gut microbiota's mediating role in epigenetic modulation. Despite promising outcomes, the predominance of preclinical evidence and variability in experimental protocols and dosing limit the immediate translational impact. Nonetheless, current findings underscore the promise of dietary DNMT modulators as foundational elements for precision nutrition strategies aimed at promoting healthy aging and mitigating age-associated disease risk. The potential application of DNA methylation age as a biomarker of biological aging has been increasingly supported by recent literature, reinforcing its relevance in future nutritional epigenetics research. Further well-designed clinical trials are warranted to assess long-term efficacy, safety, and bioavailability of these compounds and to validate their use in personalized epigenetic interventions using biological aging markers. This review was funded by the European Union-Next Generation EU, PNRR Project Age-It (DM 1557 11.10.2022), and the University of Padua SID Grant (2024DCTV1SIDPROGETTI-00194).

Aging is driven by fundamental mechanisms like oxidative stress, telomere shortening and changes in DNA methylation, which together prepare the ground for age-related diseases. Botanical extracts, rich in bioactive phytoconstituents, represent a promising resource for developing therapies that target these mechanisms to promote healthy aging. This study explores the geroprotective potential of Monarda didyma L. extract. In vitro analyses revealed the extract's strong antioxidant activity, ability to reduce telomere shortening, and capacity to protect against DNA damage, thereby decreasing cellular senescence and improving endothelial function. The randomized, double-blind clinical trial demonstrated that daily oral supplementation with the extract significantly improved leukocyte telomere length (LTL) and stabilized DNA methylation age (DNAmAge) in the intervention group, while the placebo group experienced accelerated epigenetic aging and hypermethylation of critical age-related genes (ELOVL2 and FHL2). The intervention group also reported enhanced quality of life, particularly in the physical domain, along with improved movement and quality sleep indices detected by questionnaire and wearable sensors. These compelling findings position Monarda didyma L. extract as a powerful candidate for future geroprotective therapies, with the potential to significantly impact healthy aging.

This study explores the role of inflammation and oxidative stress, hallmarks of COVID-19, in accelerating cellular biological aging. We investigated early molecular markers—DNA methylation age (DNAmAge) and telomere length (TL)—in blood leukocytes, nasal cells (NCs), and induced sputum (IS) one year post-infection in pauci- and asymptomatic healthcare workers (HCWs) infected during the first pandemic wave (February–May 2020), compared to COPD patients, model for “aged lung”. Data from questionnaires, Work Ability Index (WAI), blood analyses, autonomic cardiac balance assessments, heart rate variability (HRV), and pulmonary function tests were collected. Elevated leukocyte DNAmAge significantly correlated with advancing age, male sex, daytime work, and an aged phenotype characterized by chronic diseases, elevated LDL and glycemia levels, medications affecting HRV, and declines in lung function, WAI, lymphocyte count, hemoglobin levels, and HRV (p < 0.05). Increasing age, LDL levels, job positions involving intensive patient contact, and higher leukocyte counts collectively contributed to shortened leukocyte TL (p < 0.05). Notably, HCWs exhibited accelerated biological aging in IS cells compared to both blood leukocytes (p ≤ 0.05) and NCs (p < 0.001) and were biologically older than COPD patients (p < 0.05). These findings suggest the need to monitor aging in pauci- and asymptomatic COVID-19 survivors, who represent the majority of the general population.

Abstract Background Manipulations to decelerate biological aging and extend health span are major challenges for health given the social and healthcare costs of aging population. Excessive oxidative stress and inflammation are primary drivers in biological aging and age-related diseases. Didymin, a natural bioactive flavonoid and the major polyphenol of Monarda didyma L., has showed a crucial anti-inflammatory role. This clinical study aims to investigate the potential benefits of a 12-weeks supplementation of Monarda didyma L. extract on reducing / delaying the biological aging of a susceptible population of aging workers. Methods This is a randomized, placebo-controlled, double-blind, parallel design and monocentric clinical trial. Study population will comprise 80 participants, aged 45–65 years, randomly allocated to both Intervention group (supplementation of Monarda didyma L. extract) and placebo control group (placebo supplementation) for a 12-weeks period of treatment. All study participants, who will be enrolled at the Occupational Medicine Unit – Azienda Ospedale Università of Padova providing a written informed consent, will undergo clinical examination, an interview with structured questionnaires (demographic data, lifestyle, information quality of life and sleeping patterns) and collection of fasting blood for evaluation of indicators of biological aging as primary outcomes (DNA methylation age, telomere length, mitochondrial DNA copy number), as well as secondary outcomes including basic biochemistry and inflammation markers (emocrome, glycemia, insulin, total cholesterol, low and high density lipoproteins, triglycerides, creatinine, telomerase expression, C-reactive protein, interleukin6, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase) and salivary sample for cortisol analysis. Clinical examination and sample collection, to assess primary and secondary outcomes, will be performed at enrollment and at the follow up after of this treatment. Tracking of additional parameters (heart rate, sleep, mobility) will be performed along the study period by using a wearable MiBand 7 watch and a daily diary to determine compliance and record effects on stress, well-being and health status. Discussion The success of this research could represent a turning point in the healthy aging research, leading to rejuvenation by means of a sustainable and safe intervention, accessible to everybody in order to extend health span. Trial registration: ClinicalTrials.gov PRS (NCT05399966), registration date: May 17, 2022.

Sarcopenia, a musculoskeletal disease characterized by the progressive loss of skeletal muscle mass, strength, and physical performance, presents significant challenges to global public health due to its adverse effects on mobility, morbidity, mortality, and healthcare costs. This comprehensive review explores the intricate connections between sarcopenia and low birth weight (LBW), emphasizing the developmental origins of health and disease (DOHaD) hypothesis, inflammatory processes (inflammaging), mitochondrial dysfunction, circadian rhythm disruptions, epigenetic mechanisms, and genetic variations revealed through genome-wide studies (GWAS). A systematic search strategy was developed using PubMed to identify relevant English-language publications on sarcopenia, LBW, DOHaD, inflammaging, mitochondrial dysfunction, circadian disruption, epigenetic mechanisms, and GWAS. The publications consist of 46.2% reviews, 21.2% cohort studies, 4.8% systematic reviews, 1.9% cross-sectional studies, 13.4% animal studies, 4.8% genome-wide studies, 5.8% epigenome-wide studies, and 1.9% book chapters. The review identified key factors contributing to sarcopenia development, including the DOHaD hypothesis, LBW impact on muscle mass, inflammaging, mitochondrial dysfunction, the influence of clock genes, the role of epigenetic mechanisms, and genetic variations revealed through GWAS. The DOHaD theory suggests that LBW induces epigenetic alterations during foetal development, impacting long-term health outcomes, including the early onset of sarcopenia. LBW correlates with reduced muscle mass, grip strength, and lean body mass in adulthood, increasing the risk of sarcopenia. Chronic inflammation (inflammaging) and mitochondrial dysfunction contribute to sarcopenia, with LBW linked to increased oxidative stress and dysfunction. Disrupted circadian rhythms, regulated by genes such as BMAL1 and CLOCK, are associated with both LBW and sarcopenia, impacting lipid metabolism, muscle mass, and the ageing process. Early-life exposures, including LBW, induce epigenetic modifications like DNA methylation (DNAm) and histone changes, playing a pivotal role in sarcopenia development. Genome-wide studies have identified candidate genes and variants associated with lean body mass, muscle weakness, and sarcopenia, providing insights into genetic factors contributing to the disorder. LBW emerges as a potential early predictor of sarcopenia development, reflecting the impact of intrauterine exposures on long-term health outcomes. Understanding the complex interplay between LBW with inflammaging, mitochondrial dysfunction, circadian disruption, and epigenetic factors is essential for elucidating the pathogenesis of sarcopenia and developing targeted interventions. Future research on GWAS and the underlying mechanisms of LBW-associated sarcopenia is warranted to inform preventive strategies and improve public health outcomes.

The growing phenomenon of population aging is redefining demographic dynamics, intensifying age-related conditions, especially dementia, projected to triple by 2050 with an enormous global economic burden. This study investigates visual arts-mediated Cognitive Activation Therapy (CAT) as a non-pharmacological CAT intervention targets both biological aging [leukocyte telomere length (LTL), DNA methylation age (DNAmAge)] and cognitive functionality. Aligning with a broader trend of integrating non-pharmacological approaches into dementia care. The longitudinal study involved 20 patients with mild to moderate neurocognitive disorders. Cognitive and functional assessments, and biological aging markers -i.e., LTL and DNAmAge- were analyzed before and after CAT intervention. Change in LTL was positively correlated with days of treatment (p =0.0518). LTL significantly elongated after intervention (p =0.0269), especially in men (p =0.0142), correlating with younger age (p =0.0357), and higher education (p =0.0008). DNAmAge remained instead stable post-treatment. Cognitive and functional improvements were observed for Copy of complex geometric figure, Progressive Silhouettes, Position Discrimination, Communication Activities of Daily Living—Second edition, Direct Functional Status (p < 0.0001) and Object decision (p =0.0594), but no correlations were found between LTL and cognitive gains. Visual arts-mediated CAT effectively mitigates cellular aging, especially in men, by elongating LTL. These findings underscore the potential of non-pharmacological interventions in enhancing cognitive and functional status and general well-being in dementia care. Further research with larger and longer-term studies is essential for validation.

Astronauts returning from space missions often exhibit health issues mirroring age-related conditions, suggesting spaceflight as a potential driver of biological ageing and age-related diseases. To unravel the underlying mechanisms of these conditions, this comprehensive review explores the impact of the space “exposome” on the twelve hallmarks of ageing. Through a meticulous analysis encompassing both space environments and terrestrial analogs, we aim to decipher how different conditions influence ageing hallmarks. Utilizing PubMed, we identified 189 studies and 60 meet screening criteria. Research on biological ageing in space has focused on genomic instability, chronic inflammation, and deregulated nutrient sensing. Spaceflight consistently induces genomic instability, linked to prolonged exposure to ionizing radiation, triggers pro-inflammatory and immune alterations, resembling conditions in isolated simulations. Nutrient sensing pathways reveal increased systemic insulin-like growth-factor-1. Microbiome studies indicate imbalances favoring opportunistic species during spaceflight. Telomere dynamics present intriguing patterns, with lengthening during missions and rapid shortening upon return. Despite a pro-ageing trend, some protective mechanisms emerge. Countermeasures, encompassing dietary adjustments, prebiotics, postbiotics, symbiotics, tailored exercises, meditation, and anti-inflammatory supplements, exhibit potential. Spaceflight's impact on ageing is intricate, with diverse findings challenging established beliefs. Multidisciplinary studies provide guidance for future research in this field.

Background Further knowledge on modifiable aging risk factors is required to mitigate the increasing burden of age-related diseases in a rapidly growing global demographic of elderly individuals. We explored the effect of everyday exposure to polycyclic aromatic hydrocarbons (PAHs), which are fundamental constituents of air pollution, on cellular biological aging. This was determined via the analysis of leukocyte telomere length (LTL), mitochondrial DNA copy number (LmtDNAcn), and by the formation of anti- benzo[a]pyrene diolepoxide (B[a]PDE–DNA) adducts. Methods The study population consisted of 585 individuals living in North-East Italy. PAH exposure (diet, indoor activities, outdoor activities, traffic, and residential exposure) and smoking behavior were assessed by questionnaire and anti-B[a]PDE–DNA] by high-perfomance-liquid-chromatography. LTL, LmtDNAcn and genetic polymorphisms [glutathione S-transferase M1 and T1 (GSTM1; GSTT1)] were measured by polymerase chain reaction. Structural equation modelling analysis evaluated these complex relationships. Results Anti-B[a]PDE–DNA enhanced with PAH exposure (p=0.005) and active smoking (p=0.0001), whereas decreased with detoxifying GSTM1 (p=0.021) and in female (p=0.0001). Subsequently, LTL and LmtDNAcn reduced with anti-B[a]PDE–DNA (p=0.028 and p=0.018), particularly in males (p=0.006 and p=0.0001). Only LTL shortened with age (p=0.001) while elongated with active smoking (p =0.0001). Besides this, the most significant determinants of PAH exposure that raised anti-B[a]PDE–DNA were indoor and diet (p=0.0001 ), the least was outdoor (p=0.003). Conclusion New findings stemming from our study suggest that certain preventable everyday life exposures to PAHs reduce LTL and LmtDNAcn. In particular, the clear association with indoor activities, diet, and gender opens new perspectives for tailored preventive measures in age-related diseases. Capsule Everyday life exposure to polycyclic aromatic hydrocarbons reduces leukocyte telomere length and mitochondrial DNA copy number through anti-B[a]PDE-DNA adduct formation.

Abstract Background: Manipulations to decelerate biological aging and extend health span are major challenges for health given the social and healthcare costs of aging population. Excessive oxidative stress and inflammation are primary drivers in biological aging and age-related diseases. Didymin, a natural bioactive flavonoid and the major polyphenol of Monarda didyma L., has showed a crucial anti-inflammatory role. This clinical study aims to investigate the potential benefits of a 12-weeks supplementation of Monarda didyma L. extract on reducing / delaying the biological aging of a susceptible population of aging workers. Methods: This is a randomized, placebo-controlled, double-blind, parallel design and monocentric pilot study. Study population will comprise 80 participants, aged 45-65 years, randomly allocated to both Intervention group (supplementation of Monarda didyma L. extract) and placebo control group (placebo supplementation) for a 12-weeks period of treatment. All study participants, who will be enrolled at the Occupational Medicine Unit – Azienda Ospedale Università of Padova providing a written informed consent, will undergo clinical examination, an interview with structured questionnaires (demographic data, lifestyle, information quality of life and sleeping patterns) and collection of fasting blood for evaluation of indicators of biological aging as primary outcomes (DNA methylation age, telomere length, mitochondrial DNA copy number), as well as secondary outcomes including basic biochemistry and inflammation markers (emocrome, glycemia, insulin, total cholesterol, low and high density lipoproteins, triglycerides, creatinine, telomerase expression, C-reactive protein, interleukin6, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase) and salivary sample for cortisol analysis. Clinical examination and sample collection, to assess primary and secondary outcomes, will be performed at enrollment and at the follow up after of this treatment. Tracking of additional parameters (heart rate, sleep, mobility) will be performed along the study period by using a wearable MiBand 6 watch and a daily diary to determine compliance and record effects on stress, well-being and health status. Discussion: The success of this research could represent a turning point in the healthy aging research, leading to rejuvenation by means of a sustainable and safe intervention, accessible to everybody in order to extend health span. Trial registration: ClinicalTrials.gov PRS (NCT05399966), registration date: May 17, 2022. https://clinicaltrials.gov/ct2/about-studies/learn#WhatIs

The biological age of an organ may represent a valuable tool for assessing its quality, especially in the elder. We examined the biological age of the kidneys [right (RK) and left kidney (LK)] and blood leukocytes in the same subject and compared these to assess whether blood mirrors kidney biological aging. Biological age was studied in n = 36 donors (median age: 72 years, range: 19-92; male: 42%) by exploring mitotic and non-mitotic pathways, using telomere length (TL) and age-methylation changes (DNAmAge) and its acceleration (AgeAcc). RK and LK DNAmAge are older than blood DNAmAge (RK vs. Blood, p = 0.0271 and LK vs. Blood, p = 0.0245) and RK and LK AgeAcc present higher score (this mean the AgeAcc is faster) than that of blood leukocytes (p = 0.0271 and p = 0.0245) in the same donor. TL of RK and LK are instead longer than that of blood (p = 0.0011 and p = 0.0098) and the increase in Remuzzi-Karpinski score is strongly correlated with kidney TL attrition (p = 0.0046). Finally, blood and kidney TL (p < 0.01) and DNAmAge (p < 0.001) were correlated. These markers can be evaluated in further studies as indicators of biological age of donor organ quality and increase the usage of organs from donors of advanced age therefore offering a potential translational research inkidney transplantation.

Although kidney transplantation improves patient survival and quality of life, long-term results are hampered by both immune- and non-immune-mediated complications. Current biomarkers of post-transplant complications, such as allograft rejection, chronic renal allograft dysfunction, and cutaneous squamous cell carcinoma, have a suboptimal predictive value. DNA methylation is an epigenetic modification that directly affects gene expression and plays an important role in processes such as ischemia/reperfusion injury, fibrosis, and alloreactive immune response. Novel techniques can quickly assess the DNA methylation status of multiple loci in different cell types, allowing a deep and interesting study of cells’ activity and function. Therefore, DNA methylation has the potential to become an important biomarker for prediction and monitoring in kidney transplantation. The aim of this study was to evaluate the role of DNA methylation as a potential biomarker of graft survival and complications development in kidney transplantation. A systematic review of several databases has been conducted. The Newcastle–Ottawa scale and the Jadad scale have been used to assess the risk of bias for observational and randomized studies, respectively. Twenty articles reporting on DNA methylation as a biomarker for kidney transplantation were included, all using DNA methylation for prediction and monitoring. DNA methylation pattern alterations in cells isolated from different tissues, such as kidney biopsies, urine, and blood, have been associated with ischemia–reperfusion injury and chronic renal allograft dysfunction. These alterations occurred in different and specific loci. DNA methylation status has also proved to be important for immune response modulation, having a crucial role in regulatory T cell definition and activity. Research also focused on a better understanding of the role of this epigenetic modification assessment for regulatory T cells isolation and expansion for future tolerance induction-oriented therapies. Studies included in this review are heterogeneous in study design, biological samples, and outcome. More coordinated investigations are needed to affirm DNA methylation as a clinically relevant biomarker important for prevention, monitoring, and intervention.

Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease destined to increase as a sequel of the Severe Acute Respiratory Syndrome Coronavirus-2. Several studies implicate telomere shortening as hallmark in the pathomechanism of IPF. Our understanding of disease pathogenesis remains, however, incomplete, which hampers also the development of more effective drugs. Aims of this study are: 1) to analyze telomere length in blood leukocytes (LTL) in well phenotypically characterized IPF patients at diagnosis, before treatment with antifibrotic drugs, Pirfenidone and Nintedanib (T0); 2) to investigate in follow up (T1) a possible change in the rate of LTL by combining data on clinic, hematochemical tests, respiratory function and occupational exposure. We examined a group of 24 IPF patients that underwent to a therapy follow up (T1) (mean±SD 297±124 days). We observed an increase in LTL at T1 compared to LTL at T0 (mean±SD LTL (T/S), T1 vs T0, 1.29 ± 0.26 vs 1.19 ± 0.27; p=0.051). Multiple linear regression analysis reveals that the LTL increase, at T1, is significantly related to the time of treatment (p=0.002), LTL at T0 (p<0.0001) and to a slowing in lung function decline (FVC%pred) (p=0.054). The other variables considered including occupational exposure, pack-years, occupational risk factor, gender and body mass index are not significantly related. Our research would indicate a rejuvenation effect of the antifibrotic therapy by measuring the LTL that correlates with lung function improvement. This suggests that targeting fundamental mechanisms of cellular aging has the potential to interfere with the severity of the disease.

Leukocyte telomere length (LTL) represents a key integrating component of the cumulative effects of environmental, lifestyle, and genetic factors. A question, however, remains on whether LTL can be considered predictive for a longer and healthier life. Within the elderly prospective TRELONG cohort (n = 612), we aimed to investigate LTL as a predictor of longevity and identify the main determinants of LTL among many different factors (physiological and lifestyle characteristics, physical performance and frailty measures, chronic diseases, biochemical measurements and apolipoprotein E genotyping). We found an ever-increasing relationship between LTL quartiles and survival. Hazard ratio analysis showed that for each unit increase in LTL and Short Physical Performance Battery (SPPB) scores, the mortality risk was reduced by 22.41% and 8.78%, respectively. Conversely, male gender, Charlson Comorbidity Index, and age threatened survival, with mortality risk growing by 74.99%, 16.57% and 8.5%, respectively. Determinants of LTL elongation were SPPB scores (OR = 1.1542; p = 0.0066) and years of education (OR = 1.0958; p = 0.0065), while male gender (OR = 0.4388; p = 0.0143) and increased Disease Count Index (OR = 0.6912; p = 0.0066) were determinants of LTL attrition. Longer LTL predicts a significant survival advantage in elderly people. By identifying determinants of LTL elongation, we provided additional knowledge that could offer a potential translation into prevention strategies.

The battle against the new coronavirus that continues to kill millions of people will be still long. Novel strategies are demanded to control infection, mitigate symptoms and treatment of COVID-19. This is even more imperative given the long sequels that the disease has on the health of the infected. The discovery that S protein includes two ankyrin binding motifs (S-ARBMs) and that the transient receptor potential vanilloid subtype 1 (TRPV-1) cation channels contain these ankyrin repeat domains (TRPs-ARDs) suggest that TRPV-1, the most studied member of the TRPV channel family, can play a role in binding SARS-CoV-2. This hypothesis is strengthened by studies showing that other respiratory viruses bind the TRPV-1 on sensory nerves and epithelial cells in the airways. Furthermore, the pathophysiology in COVID-19 patients is similar to the effects generated by TRPV-1 stimulation. Lastly, treatment with agonists that down-regulate or inactivate TRPV-1 can have a beneficial action on impaired lung functions and clearance of infection. In this review, we explore the role of the TRPV-1 channel in the infection, susceptibility, pathogenesis, and treatment of COVID-19, with the aim of looking at novel strategies to control infection and mitigate symptoms, and trying to translate this knowledge into new preventive and therapeutic interventions.

Aging is the predominant risk factor for most degenerative diseases, including chronic obstructive pulmonary disease (COPD). This process is however very heterogeneous. Defining the biological aging of individual tissues may contribute to better assess this risky process. In this study, we examined the biological age of induced sputum (IS) cells, and peripheral blood leukocytes in the same subject, and compared these to assess whether biological aging of blood leukocytes mirrors that of IS cells. Biological aging was assessed in 18 COPD patients (72.4 ± 7.7 years; 50% males). We explored mitotic and non-mitotic aging pathways, using telomere length (TL) and DNA methylation-based age prediction (DNAmAge) and age acceleration (AgeAcc) (i.e., difference between DNAmAge and chronological age). Data on demographics, life style and occupational exposure, lung function, and clinical and blood parameters were collected. DNAmAge (67.4 ± 5.80 vs. 61.6 ± 5.40 years; p = 0.0003), AgeAcc (−4.5 ± 5.02 vs. −10.8 ± 3.50 years; p = 0.0003), and TL attrition (1.05 ± 0.35 vs. 1.48 ± 0.21 T/S; p = 0.0341) are higher in IS cells than in blood leukocytes in the same patients. Blood leukocytes DNAmAge ( r = 0.927245; p = 0.0026) and AgeAcc ( r = 0.916445; p = 0.0037), but not TL, highly correlate with that of IS cells. Multiple regression analysis shows that both blood leukocytes DNAmAge and AgeAcc decrease (i.e., younger) in patients with FEV 1 % enhancement ( p = 0.0254 and p = 0.0296) and combined inhaled corticosteroid (ICS) therapy ( p = 0.0494 and p = 0.0553). In conclusion, new findings from our work reveal a differential aging in the context of COPD, by a direct quantitative comparison of cell aging in the airway with that in the more accessible peripheral blood leukocytes, providing additional knowledge which could offer a potential translation into the disease management.

Background: A neurogenic pathway, involving TRPV1 expressed in the airways, has been hypothesized to be implicated in acute cardiovascular events occurring after peaks of air pollution. Aims: To test whether inhaled prostaglandin E2 (PGE2) and bradykinin (BK) modulate TRPV1 activity in vivo by changing cough response to capsaicin (CPS) and whether sensitization of TRPV1 by PGE2 and BK affects heart rate variability (HRV). Methods: 17 healthy volunteers (median age 35 IQR, 29.5-47) inhaled 100 μg PGE2, 200 μg BK or diluent in a randomized double-blind fashion. Subsequently, the response to CPS was assessed by cough challenge. The results were expressed as n° of coughs caused by 30 μM of CPS. HRV, expressed by low (0.04–0.15 Hz) and high (0.15–0.40 Hz) normalized frequency components (nLF, sympathetic component, and nHF, vagal component), as well as nLF/nHF ratio (sympathovagal balance), was evaluated after inhalation of diluent, PGE2 and BK. Results: Inhalations of PGE2 and BK were associated with a highly significant increase in cough response induced by CPS: PGE2 (n° cough=4.20±0.42; p<0.001) and BK (n° cough =3.64±0.37; p<0.01), compared to diluent (n° cough=2.77±0.29). Inhalations of PGE2 and BK lead to a significant sympathetic upregulation and vagal downregulation (nLF/nHF after PGE2 = 6.1, p< 0.01; nLF/nHF after BK = 4.2, p<0.05), compared to diluent (nLF/nHF ratio = 2.5-3.3). Conclusion: Inhalation of PGE2 and BK sensitizes TRPV1 and is associated with autonomic dysregulation of cardiac rhythm in healthy subjects.

The aim of the PhD project is to explore molecular mechanisms that characterize the process of biological aging with the main focus on the two most prominent early hallmarks of biological aging such as telomere length (TL) and epigenetic age, also defined as DNA methylation age (DNAmAge), in order to answer the following main questions: 1) If environmental and occupational exposures accelerate the biological aging in healthy subjects and in subjects affected by age-relate disease. 2) If, on the other hand, correct lifestyle including an intensive meditation/relaxing training in healthy subjects and patients with cardiovascular diseases, and heart transplantation in patients suffering from end-stage heart failure, slow down biological aging. To this aims we analyzed biological aging indicators in easily available human tissue (blood leucocytes) and in target organ (i.e., heart of donors and recipients and lung from induced sputum of Chronic Obstructive Pulmonary Disease (COPD) patients). Study populations consist of: 1) HEALTHY SUBJECTS EXPOSED TO GERONTOGENIC ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES a) 71 night-shift workers and 84 day workers as control exposed to circadian rhythm disruption. b) 585 individuals from general population living in North-East Italy exposed to everyday exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs), which are fundamental constituents of air pollution. c) A prospective cohort study of women and men aged 70 years and older from the area of Treviso, which is characterized by the highest longevity in Italy. TRELONG longitudinal study population comprises 576 subjects at baseline, 300 and 200 subjects at T1 and T2 respectively, exposed to lifestyle and occupational exposures. 2) SUBJECTS AFFECTED BY AGE-RELATE DISEASES a) Bladder cancer (BC), a chronic disease characterized by the interaction between environmental/occupational and genetic risk factors. Study population includes newly diagnosed, histologically confirmed BC patients, admitted to the Urology Departments of two large hospitals from 1997 to 2000. Controls are 94 non-neoplastic urological patients matched to cases by age, period and hospital of admission. b) Idiopathic pulmonary fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD) as the most common manifestations of aging-mediated diseases. Study population consists of n=101 IPF patients (ATS/ERS/JRS/ALAT guidelines) and n=18 moderate COPD patients (GOLD 2019) all enrolled at the ambulatory of Pneumology and Respiratory Physiopathology Wards – Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova. 3) HEALTHY SUBJECTS AND PATIENTS EXPOSED TO REJUVENATING FACTORS a) Patients after myocardial infarction (n=20) and healthy control individuals (n=10), age- and gender-matched, trained to meditation and relax for 60 days. b) 17 recipients receiving the heart from 17 donors in the period February 2018 - February 2019. The local Ethics Committee - University of Padova, approved the study protocols (3843/AO/16 and 3054/AO/14). Main finding stemming from our results revels that: 1) HEALTHY SUBJECTS EXPOSED TO GERONTOGENIC ENVIRONMENTAL AND OCCUPATIONAL EXPOSURES - Night-shift work is associated with increased systemic inflammation as proved by higher C-reactive protein (CRP) levels among night shift workers. LTL is reduced by CRP, while is positively associated with long pentraxin 3 (PTX3) that, by orchestrating an efficient governance of inflammatory processes, may protect telomere from attrition. This would make nocturnal workers more susceptible to premature LTL shortening and aging. - Certain preventable everyday life exposures to PAHs diminish LTL and even LmtDNAcn, in particular in males, acting through anti-B[a]PDE–DNA adduct formation. Our findings show that indoor activities and diet represent the primary determinants of PAHs exposure in increasing anti-B[a]PDE–DNA adduct levels that in turn decrease in presence of detoxifying GSTM1. - In TRELONG population LTL significantly declines over the years, from baseline to follow up, also considering only n=161 subjects whit all measurements at three different time points. 2) SUBJECTS AFFECTED BY AGE-RELATE DISEASES - LTL attrition is a critical event in BC. In particular, BC risk is increased directly by LTL attrition that depends on some preventable everyday life exposures genetically modulated. Furthermore, indirect effects on BC risk are evidenced via LTL reduction through age and genetic polymorphisms involved in modulating response to environmental exposure. - IPF patients in follow up present an increase in LTL positively related to the duration of antifibrotic treatment, with both pirfenidone and nintedanib, and with a decrease in lung function decline. These results would suggest that telomere shortening in IPF patients treated with antifibrotic drugs may be reversed leading to an increase in LTL. - In COPD patients: a) lung, i.e., pulmonary cells obtained from induced sputum, is biologically older than blood, as determined by TL and DNAmAge; b) blood age acceleration (AgeAcc) defined as the difference between DNAmAge and chronological age, but not TL, highly correlates with lung AgeAcc; c) blood AgeAcc significantly correlates with the main clinical features (CRP and FEV1) of COPD. 3) HEALTHY SUBJECTS AND PATIENTS EXPOSED TO REJUVENATING FACTORS - In healthy subjects but not in patients, DNAmAge is reduced after an intensive relaxing training. Differently, LTL is preserved in healthy subjects, while in patients it continues to decrease. However, the correlation between LTL and chronological age becomes positive after training in both groups. These findings would suggest that intensive relaxing practices influence different aging molecular mechanisms, i.e., DNAmAge and LTL, with a rejuvenating effect. - Biological donors’ heart age is found to be younger than chronological age, suggesting that donors’ cardiac tissues are biologically younger than chronologically measured. Furthermore, biological donors’ left atrium age is 5 years younger than recipients’ left atrium age. This would indicate that patients who underwent heart transplantation have received a younger heart. Further results and comments are described in each work reported in the specific Chapters. Our results contribute to reinforce the concept that biological aging may be modulated by a multiplicity of factors (environmental, occupational, lifestyle) making people more susceptible to premature aging or inducing an accelerated aging or, interestingly, eliciting a rejuvenation effect. In the era of the silver tsunami, identifying gerontogenic and rejuvenating factors is of paramount importance to develop anti-aging strategies for extending the number of healthy years of life.