Sex- and age-specific normative values of lower extremity muscle power in Italian community-dwellers.

BACKGROUND: Muscle power is associated with health-related parameters. Simple equations were validated to estimate lower extremity muscle power measures based on the time to complete the five-repetition sit-to-stand test. The present study was conducted to provide lower extremity muscle power estimates and produce centile values in a large and relatively unselected population across a wide age spectrum. METHODS: Data were from the Longevity Check-up 7+ (Lookup 7+) project, an ongoing initiative conducted in unconventional settings (e.g., exhibitions, shopping centres and health promotion campaigns) across Italy to foster adoption of healthy lifestyles. Absolute, relative, allometric and specific muscle power measures of the lower extremities were estimated using validated formulas. Cross-sectional centile and normative values for muscle power measures from 18 to 81+ years were produced for the two sexes. Smoothed normative curves for men and women were constructed using the lambda-mu-sigma method. RESULTS: From 1 June 2015 to 31 October 2021, 13 515 participants were enrolled of whom 12 864 were eligible for the present study. Mean age was 55.9 years (standard deviation: 14.8 years; range: 18-98 years), and 7217 (56.%) were women. Absolute, relative, allometric and specific muscle power declined significantly with age. Specific patterns of decline were observed according to sex and muscle power parameter. Absolute muscle power peaked at 41-50 and 31-40 years in men and women, respectively. Afterwards, a decline rate of approximately 12% per decade was observed, regardless of sex. Relative muscle power showed the largest reduction with age, such that it was 40.6% and 46.4% smaller in men and women older than 80, respectively, compared with those aged 18-30 years. Age-related changes in allometric and specific muscle power measures were similar between men and women. CONCLUSIONS: Data from the Lookup 7+ project indicate that lower extremity muscle power estimated using simple equations is significantly associated with age. Sex-specific patterns of decline in absolute and relative muscle power were observed with age. Allometric and specific muscle power declined at a similar rate in men and women.

A simple medical device development according to normative values of calf circumference across ages: results from the Italian Longevity Check-up 7+ (Lookup 7+) project.

BACKGROUND: Wide consensus exists on the notion that low muscle mass is a predictor of negative health-related events, such as disability, morbidity, and mortality. Indeed, the European Working Group on Sarcopenia in Older People 2 had identified muscle mass as the key component to confirm the diagnosis of sarcopenia. However, the lack of normative values for muscle mass across ages hampers the practical assessment of this important parameter. The aim of the present study was to produce cross-sectional centile and normative values for calf circumference (a surrogate estimation of muscle mass) across a wide spectrum of ages using a large and unselected sample of community-dwellers enrolled in the Longevity Check-up 7+ (Lookup 7+) project. METHODS: This is a cross-sectional study using the data of Lookup 7+ project, an ongoing study started in June 2015 and conducted in unconventional settings (i.e., exhibitions, malls, and health promotion campaigns). Candidate participants were considered eligible for enrolment if they were at least 45 years of age and provided written informed consent. Calf circumference was measured using an inextensible but flexible plastic tape in a sitting position with the knee and ankle at a right angle and the feet resting on the floor. Normative values for calf circumference from ages 45 to 80 + years were generated. RESULTS: A total of 11 814 participants were enrolled from 1 June 2015 to 30 September 2022. The mean age of participants included in the analyses was 61.8 years (standard deviation; 10.2 years; range: 45-98 years), and 6686 (57%) were women. Normative values for calf circumference were obtained for men and women, stratified by age groups. Accordingly, a calf circumference tape, with colour bands that demarcate the centiles range into which the patient falls, was created and validated. CONCLUSIONS: Our study established age- and gender-specific centile reference values for calf circumference. The calf circumference tape can be used to easily interpret the assessment in every-day practice for the early detection of individuals with or at risk of sarcopenia and malnutrition.

The contribution of mitochondrial DNA alterations to aging, cancer, and neurodegeneration.

Mitochondrial DNA (mtDNA) is as a double-stranded molecule existing in hundreds to thousands copies in cells depending on cell metabolism and exposure to endogenous and/or environmental stressors. The coordination of mtDNA replication and transcription regulates the pace of mitochondrial biogenesis to guarantee the minimum number of organelles per cell. mtDNA inheritance follows a maternal lineage, although bi-parental inheritance has been reported in some species and in the case of mitochondrial diseases in humans. mtDNA mutations (e.g., point mutations, deletions, copy number variations) have been identified in the setting of several human diseases. For instance, sporadic and inherited rare disorders involving the nervous system as well higher risk of developing cancer and neurodegenerative conditions, including Parkinson's and Alzheimer's disease, have been associated with polymorphic mtDNA variants. An accrual of mtDNA mutations has also been identified in several tissues and organs, including heart and muscle, of old experimental animals and humans, which may contribute to the development of aging phenotypes. The role played by mtDNA homeostasis and mtDNA quality control pathways in human health is actively investigated for the possibility of developing targeted therapeutics for a wide range of conditions.

Amino Acid Profiles in Older Adults with Frailty: Secondary Analysis from MetaboFrail and BIOSPHERE Studies.

An altered amino acid metabolism has been described in frail older adults which may contribute to muscle loss and functional decline associated with frailty. In the present investigation, we compared circulating amino acid profiles of older adults with physical frailty and sarcopenia (PF&S, n = 94), frail/pre-frail older adults with type 2 diabetes mellitus (F-T2DM, n = 66), and robust non-diabetic controls (n = 40). Partial least squares discriminant analysis (PLS-DA) models were built to define the amino acid signatures associated with the different frailty phenotypes. PLS-DA allowed correct classification of participants with 78.2 ± 1.9% accuracy. Older adults with F-T2DM showed an amino acid profile characterized by higher levels of 3-methylhistidine, alanine, arginine, ethanolamine, and glutamic acid. PF&S and control participants were discriminated based on serum concentrations of aminoadipic acid, aspartate, citrulline, cystine, taurine, and tryptophan. These findings suggest that different types of frailty may be characterized by distinct metabolic perturbations. Amino acid profiling may therefore serve as a valuable tool for frailty biomarker discovery.

Effects of a 2-year exercise training on neuromuscular system health in older individuals with low muscle function.

BACKGROUND: Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration contribute to sarcopenia pathogenesis. Seeking for strategies able to slow down sarcopenia insurgence and progression, we investigated whether a 2-year mixed-model training involving aerobic, strength and balance exercises would be effective for improving or preserving motoneuronal health and NMJ stability, together with muscle mass, strength and functionality in an old, sarcopenic population. METHODS: Forty-five sarcopenic elderly (34 females; 11 males) with low dual-energy X-ray absorptiometry (DXA) lean mass and Short Physical Performance Battery (SPPB) score <9 were randomly assigned to either a control group [Healthy Aging Lifestyle Education (HALE), n = 21] or an intervention group [MultiComponent Intervention (MCI), n = 24]. MCI trained three times per week for 2 years with a mix of aerobic, strength and balance exercises matched with nutritional advice. Before and after the intervention, ultrasound scans of the vastus lateralis (VL), SPPB and a blood sample were obtained. VL architecture [pennation angle (PA) and fascicle length (Lf)] and cross-sectional area (CSA) were measured. As biomarkers of neuronal health and NMJ stability status, neurofilament light chain (NfL) and C-terminal agrin fragment (CAF) concentrations were measured in serum. Differences in ultrasound parameters, NfL and CAF concentration and physical performance between baseline and follow-up were tested with mixed ANOVA or Wilcoxon test. The relationship between changes in physical performance and NfL or CAF concentration was assessed through correlation analyses. RESULTS: At follow-up, MCI showed preserved VL architecture (PA, Lf) despite a reduced CSA (-8.4%, P < 0.001), accompanied by maintained CAF concentration and ameliorated overall SPPB performance (P = 0.007). Conversely, HALE showed 12.7% decrease in muscle CSA (P < 0.001), together with 5.1% and 5.5% reduction in PA and Lf (P < 0.001 and P = 0.001, respectively), and a 6.2% increase in CAF (P = 0.009) but improved SPPB balance score (P = 0.007). NfL concentration did not change in either group. In the population, negative correlations between changes in CAF concentration and SPPB total score were found (P = 0.047), whereas no correlation between NfL and SPPB variations was observed. CONCLUSIONS: The present findings suggest that our 2-year mixed aerobic, strength and balance training seemed effective for preventing the age and sarcopenia-related increases in CAF concentration, preserving NMJ stability as well as muscle structure (PA and Lf) and improving physical performance in sarcopenic older individuals.

Circulating Inflammatory, Mitochondrial Dysfunction, and Senescence-Related Markers in Older Adults with Physical Frailty and Sarcopenia: A BIOSPHERE Exploratory Study.

Multisystem derangements encompassing musculoskeletal, stress, and metabolic response have been described in older adults with physical frailty and sarcopenia (PF&S). Whether PF&S is also associated with markers of cellular senescence has yet to be explored. To address this research question, we quantified the serum levels of selected inflammatory, mitochondrial, and senescence-associated secretory phenotype (SASP)-related factors in 22 older adults with PF&S (mean age 75.5 ± 4.7 years; 81.8% women) and 27 nonPF&S controls (mean age 75.0 ± 4.4 years; 62.9% women) and evaluated their association with PF&S. Markers of inflammation (interleukin (IL)1-ß, IL6, and tumor necrosis factor α (TNF-α)), matrix remodeling (Serpin E1, intercellular adhesion molecule 1 (ICAM-1), and tissue inhibitor of metalloproteinases 1 (TIMP-1)), mitochondrial dysfunction (growth/differentiation factor 15 (GDF15) and fibroblast growth factor 21 (FGF21)), Activin A, and glial fibrillary acidic protein (GFAP) were assayed. Serum levels of TNF-α and those of the SASP-related factors ICAM-1 and TIMP-1 were found to be higher, while IL1-ß and IL6 were lower in PF&S participants compared with controls. Partial least squares discriminant analysis allowed discrimination of PF&S from nonPF&S participants with 74.0 ± 3.4% accuracy. Markers that significantly contributed to the classification were ICAM-1, TIMP-1, TNF-α, GFAP, and IL6. Future studies are warranted to establish whether inflammatory and SASP-related pathways are causally linked to the development and progression of PF&S, and may represent new targets for interventions.

Atypical Presentation of Pill Aspiration in Older Adults with Dysphagia: A Picture Not To Be Forgotten.

Nonconventional clinical presentations of diseases are common in older adults. Even dramatic events, such as foreign body (FB) inhalation, can occur in a subtle and non-specific manner. Pill aspiration is a rare yet overlooked cause of airway injury. It accounts for approximately 7% of all FB aspirations. In contrast, oral dysphagia and polypharmacology, mainly administrated in solid oral dosage forms (SDOF), like tablets and pills, are common conditions in older adults. Herein, we present a case of SDOF aspiration in a 78-year-old man. FB inhalation developed with general clinical deterioration and neurological impairment (delirium) rather than overt respiratory symptoms. Bronchoscopy provided remarkable images of this unexpected finding. Caregivers and healthcare workers must be aware of the risk of SDOF aspiration and adopt proper safety measures. Early recognition and bronchoscopy for diagnostic and therapeutic purposes can be lifesaving in such cases.

Effects of a New Multicomponent Nutritional Supplement on Muscle Mass and Physical Performance in Adult and Old Patients Recovered from COVID-19: A Pilot Observational Case-Control Study.

OBJECTIVE: The purpose of the present study was to assess the effect of a specific oral nutritional supplement among patients recovered from COVID-19 but suffering symptoms of fatigue. METHODS: This is an observational case-control study involving a sample of 66 COVID-19 survivors divided in two groups, 33 subjects in the intervention group who received the nutritional supplement and 33 subjects in the control group. The nutritional supplement received by subjects in the active group was based on amino acids; vitamin B6 and B1; and malic, succinic and citric acids. After an 8-week follow-up, the main outcomes considered were skeletal muscle index (measured by bioelectrical impedance analysis), physical performance measures (handgrip strength, one-minute chair-stand test, six-minute walking test), and quality of life (using EuroQol visual analogue scale). RESULTS: All the considered areas increased significantly in the subjects receiving the active treatment with oral nutritional supplement in comparison with the baseline values. After adjusting for age, gender, and baseline values, skeletal muscle index, handgrip strength test, the one-minute chair-stand test, and six-minute walking test values were higher among participants in the treatment group compared with subjects in control group. The oral nutritional supplement significantly improved the handgrip strength; similarly, participants in the active group showed a higher improvement in skeletal muscle index, the one-minute chair-stand test, the six-minute walking test, and in quality of life. CONCLUSION: The nutritional supplement containing nine essential amino acids plus cysteine; vitamin B6 and B1; and malic, succinic and citric acids had a positive effect on nutritional status, functional recovery, and quality of life in COVID-19 survivors still suffering from fatigue. Additional controlled clinical trials are required to corroborate these results.

Age-Associated Glia Remodeling and Mitochondrial Dysfunction in Neurodegeneration: Antioxidant Supplementation as a Possible Intervention.

Aging induces substantial remodeling of glia, including density, morphology, cytokine expression, and phagocytic capacity. Alterations of glial cells, such as hypertrophy of lysosomes, endosomes and peroxisomes, and the progressive accumulation of lipofuscin, lipid droplets, and other debris have also been reported. These abnormalities have been associated with significant declines of microglial processes and reduced ability to survey the surrounding tissue, maintain synapses, and recover from injury. Similarly, aged astrocytes show reduced capacity to support metabolite transportation to neurons. In the setting of reduced glial activity, stressors and/or injury signals can trigger a coordinated action of microglia and astrocytes that may amplify neuroinflammation and contribute to the release of neurotoxic factors. Oxidative stress and proteotoxic aggregates may burst astrocyte-mediated secretion of pro-inflammatory cytokines, thus activating microglia, favoring microgliosis, and ultimately making the brain more susceptible to injury and/or neurodegeneration. Here, we discuss the contribution of microglia and astrocyte oxidative stress to neuroinflammation and neurodegeneration, highlight the pathways that may help gain insights into their molecular mechanisms, and describe the benefits of antioxidant supplementation-based strategies.

Sarcopenia as potential biological substrate of long COVID-19 syndrome: prevalence, clinical features, and risk factors.

BACKGROUND: Severe clinical pictures and sequelae of COVID-19 disease are immune mediated and characterized by a 'cytokine storm'. Skeletal muscle has emerged as a potent regulator of immune system function. The aim of the present study is to define the prevalence of sarcopenia among COVID-19 survivors and the negative impact of sarcopenia on the post-acute COVID-19 syndrome and its related risk factors. METHODS: A total of 541 subjects recovered from COVID-19 disease were enrolled in the Gemelli Against COVID-19 Post-Acute Care between April 2020 and February 2021. They underwent a multidisciplinary clinical evaluation and muscle strength and physical performance assessment. RESULTS: Mean age was 53.1 years (SD 15.2, range from 18 to 86 years), and 274 (51%) were women. The prevalence of sarcopenia was 19.5%, and it was higher in patients with a longer hospital stay and lower in patients who were more physically active and had higher levels of serum albumin. Patients with sarcopenia had a higher number of persistent symptoms than non-sarcopenic patients (3.8 ± 2.9 vs. 3.2 ± 2.8, respectively; P = 0.06), in particular fatigue, dyspnoea, and joint pain. CONCLUSIONS: Sarcopenia identified according to the EWGSOP2 criteria is high in patients recovered from COVID-19 acute illness, particularly in those who had experienced the worst clinical picture reporting the persistence of fatigue and dyspnoea. Our data suggest that sarcopenia, through the persistence of inflammation, could be the biological substrate of long COVID-19 syndrome. Physical activity, especially if associated with adequate nutrition, seems to be an important protective factor.

Twelve-year sarcopenia trajectories in older adults: results from a population-based study.

BACKGROUND: The dynamic nature of sarcopenia, including possible transitions between its different stages, is currently unknown. We aimed to explore 12 year transitions through sarcopenia stages and identify factors associated with different sarcopenia trajectories in older adults. METHODS: We included 3219 participants (aged ≥60 years, 35.8% men, 96.4% community-dwelling) from the SNAC-K study. No sarcopenia (normal muscle strength and mass), probable sarcopenia (low muscle strength and normal muscle mass), and sarcopenia (low muscle strength and mass) were assessed at baseline and up to 12 years. Such conditions were defined based on a modified version of the EWGSOP2 criteria with muscle strength evaluated through handgrip or chair stand tests, and muscle mass from calf circumference. We estimated 1, 5, and 10 year transition probabilities through continuous-time multistage Markov modelling. Sociodemographic, lifestyle, and medical factors associated with the likelihood of different transitions were evaluated with proportional intensity models, and the associations' strength was expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Participants with no sarcopenia had 10-year probabilities of 17.1% and 5.1% to develop probable sarcopenia and sarcopenia, and a 40.4% chance of not transitioning. Those with probable sarcopenia had similar 5-year chances of developing sarcopenia (10.3%) and reverting to no sarcopenia (10.7%). Participants with sarcopenia had chances to revert to probable sarcopenia ranging from 8.2% (at 5 years) to 4.7% (at 10 years), and a 70.9% chance of dying after 10 years. Older age (HR = 1.11, 95% CI: 1.07-1.14), male sex (HR = 1.84, 95% CI: 1.16-2.91), current smoking (HR = 1.84, 95% CI: 1.16-2.91), and higher number of chronic diseases (HR = 1.07, 95% CI: 1.00-1.14) were associated with sarcopenia development, while higher levels of physical activity (HR = 1.84, 95% CI: 1.19-2.84) and cognitive function (HR = 1.17, 95% CI: 1.05-1.31 per each 1-point increase in the Mini-Mental State Examination) were associated with subsequent higher reversion rates from probable sarcopenia to no sarcopenia (P < 0.05 for all). None of the explored characteristics were associated with sarcopenia reversion to healthier stages. CONCLUSIONS: Sarcopenia appears to be a dynamic condition with possible two-way transitions between different sarcopenia stages, especially the earliest ones. Timely interventions to improve physical and cognitive function and better control individuals' chronic conditions could help counteract sarcopenia progression.

Circulating extracellular vesicles: friends and foes in neurodegeneration.

Extracellular vesicles have been identified as pivotal mediators of intercellular communication with critical roles in physiological and pathological conditions. Via this route, several molecules (e.g., nucleic acids, proteins, metabolites) can be transferred to proximal and distant targets to convey specific information. Extracellular vesicle-associated cargo molecules have been proposed as markers of several disease conditions for their potential of tracking down the generating cell. Indeed, circulating extracellular vesicles may represent biomarkers of dysfunctional cellular quality control systems especially in conditions characterized by the accrual of intracellular misfolded proteins. Furthermore, the identification of extracellular vesicles as tools for the delivery of nucleic acids or other cargo molecules to diseased tissues makes these circulating shuttles possible targets for therapeutic development. The increasing interest in the study of extracellular vesicles as biomarkers resides mainly in the fact that the identification of peripheral levels of extracellular vesicle-associated proteins might reflect molecular events occurring in hardly accessible tissues, such as the brain, thereby serving as a "brain liquid biopsy". The exploitation of extracellular vesicles for diagnostic and therapeutic purposed might offer unprecedented opportunities to develop personalized approaches. Here, we discuss the bright and dark sides of extracellular vesicles in the setting of two main neurodegenerative diseases (i.e., Parkinson's and Alzheimer's diseases). A special focus will be placed on the possibility of using extracellular vesicles as biomarkers for the two conditions to enable disease tracking and treatment monitoring.

Biomarkers shared by frailty and sarcopenia in older adults: A systematic review and meta-analysis.

BACKGROUND: Physical frailty and sarcopenia show extensive clinical similarities. Whether biomarkers exist that are shared by the two conditions is presently unclear. METHODS: We conducted a systematic review and meta-analysis of cross-sectional and longitudinal studies that investigated the association of frailty and/or sarcopenia with biomarkers as a primary or secondary outcome in adults aged 60 years and older. Only studies published in English that defined frailty using a validated scale and/or questionnaire and diagnosed sarcopenia according to the presence of muscle atrophy plus dynapenia or low physical function were included. Studies were identified from a systematic search of MEDLINE and SCOPUS databases from inception through August 2020. The quality of reporting of each study was assessed by using the Quality Assessment Tool for Observational Cohort, Cross-Sectional and Case-Control studies of the National Institute of Health. A meta-analysis was conducted when at least three studies investigated the same biomarker in both frailty and sarcopenia. Pooled effect size was calculated based on standard mean differences and random-effect models. Sensitivity analysis was performed based on age and the setting where the study was conducted. RESULTS: Eighty studies (58 on frailty and 22 on sarcopenia) met the inclusion criteria and were included in the qualitative analysis. Studies on frailty included 33,160 community-dwellers, hospitalized, or institutionalized older adults (60-88 years) from 21 countries. Studies on sarcopenia involved 4904 community-living and institutionalized older adults (68-87.6 years) from 9 countries. Several metabolic, inflammatory, and hematologic markers were found to be shared between the two conditions. Albumin and hemoglobin were negatively associated with both frailty and sarcopenia. Interleukin 6 was associated with frailty and sarcopenia only in people aged < 75. Community-dwelling older adults with frailty and sarcopenia had higher levels of tumor necrosis factor alpha compared with their robust and non-sarcopenic counterparts. CONCLUSIONS: A set of metabolic, hematologic, and inflammatory biomarkers was found to be shared by frailty and sarcopenia. These findings fill a knowledge gap in the quest of biomarkers for these conditions and provide a rationale for biomarker selection in studies on frailty and sarcopenia.

Extracellular Vesicles and Pancreatic Cancer: Insights on the Roles of miRNA, lncRNA, and Protein Cargos in Cancer Progression.

Pancreatic cancer (PC) is among the most devastating digestive tract cancers worldwide. This cancer is characterized by poor diagnostic detection, lack of therapy, and difficulty in predicting tumorigenesis progression. Although mutations of key oncogenes and oncosuppressor involved in tumor growth and in immunosurveillance escape are known, the underlying mechanisms that orchestrate PC initiation and progression are poorly understood or still under debate. In recent years, the attention of many researchers has been concentrated on the role of extracellular vesicles and of a particular subset of extracellular vesicles, known as exosomes. Literature data report that these nanovesicles are able to deliver their cargos to recipient cells playing key roles in the pathogenesis and progression of many pancreatic precancerous conditions. In this review, we have summarized and discussed principal cargos of extracellular vesicles characterized in PC, such as miRNAs, lncRNAs, and several proteins, to offer a systematic overview of their function in PC progression. The study of extracellular vesicles is allowing to understand that investigation of their secretion and analysis of their content might represent a new and potential diagnostic and prognostic tools for PC.

Sarcopenia and Menopause: The Role of Estradiol.

During aging and menopausal transition in women, a progressive muscle degeneration (i.e. decrease in quality and muscle function) occurs. This muscle dysfunction, caused by decreased proliferation of muscle satellite cells, increased levels of inflammatory markers, and altered levels of sex hormones, exposes women to a raised incidence of sarcopenia. In this regard, hormonal balance and, in particular, estradiol, seems to be essential in skeletal muscle function. The role of the estradiol on satellite cells and the release of inflammatory cytokines in menopausal women are reviewed. In particular, estradiol has a beneficial effect on the skeletal muscle by stimulating satellite cell proliferation. Skeletal muscle can respond to estrogenic hormonal control due to the presence of specific receptors for estradiol at the level of muscle fibers. Additionally, estradiol can limit inflammatory stress damage on skeletal muscle. In this review, we primarily focused on the role of estradiol in sarcopenia and on the possibility of using Estradiol Replacement Therapy, which combined with nutritional and physical activity programs, can counteract this condition representing a valid tool to treat sarcopenia in women.

Cell Death and Inflammation: The Role of Mitochondria in Health and Disease.

Mitochondria serve as a hub for a multitude of vital cellular processes. To ensure an efficient deployment of mitochondrial tasks, organelle homeostasis needs to be preserved. Mitochondrial quality control (MQC) mechanisms (i.e., mitochondrial dynamics, biogenesis, proteostasis, and autophagy) are in place to safeguard organelle integrity and functionality. Defective MQC has been reported in several conditions characterized by chronic low-grade inflammation. In this context, the displacement of mitochondrial components, including mitochondrial DNA (mtDNA), into the extracellular compartment is a possible factor eliciting an innate immune response. The presence of bacterial-like CpG islands in mtDNA makes this molecule recognized as a damaged-associated molecular pattern by the innate immune system. Following cell death-triggering stressors, mtDNA can be released from the cell and ignite inflammation via several pathways. Crosstalk between autophagy and apoptosis has emerged as a pivotal factor for the regulation of mtDNA release, cell's fate, and inflammation. The repression of mtDNA-mediated interferon production, a powerful driver of immunological cell death, is also regulated by autophagy-apoptosis crosstalk. Interferon production during mtDNA-mediated inflammation may be exploited for the elimination of dying cells and their conversion into elements driving anti-tumor immunity.

The Role of Artificial Intelligence in Managing Multimorbidity and Cancer.

Traditional healthcare paradigms rely on the disease-centered approach aiming at reducing human nature by discovering specific drivers and biomarkers that cause the advent and progression of diseases. This reductive approach is not always suitable to understand and manage complex conditions, such as multimorbidity and cancer. Multimorbidity requires considering heterogeneous data to tailor preventing and targeting interventions. Personalized Medicine represents an innovative approach to address the care needs of multimorbid patients considering relevant patient characteristics, such as lifestyle and individual preferences, in opposition to the more traditional "one-size-fits-all" strategy focused on interventions designed at the population level. Integration of omic (e.g., genomics) and non-strictly medical (e.g., lifestyle, the exposome) data is necessary to understand patients' complexity. Artificial Intelligence can help integrate and manage heterogeneous data through advanced machine learning and bioinformatics algorithms to define the best treatment for each patient with multimorbidity and cancer. The experience of an Italian research hospital, leader in the field of oncology, may help to understand the multifaceted issue of managing multimorbidity and cancer in the framework of Personalized Medicine.

Extracellular Vesicles and Damage-Associated Molecular Patterns: A Pandora's Box in Health and Disease.

Sterile inflammation develops as part of an innate immunity response to molecules released upon tissue injury and collectively indicated as damage-associated molecular patterns (DAMPs). While coordinating the clearance of potential harmful stimuli, promotion of tissue repair, and restoration of tissue homeostasis, a hyper-activation of such an inflammatory response may be detrimental. The complex regulatory pathways modulating DAMPs generation and trafficking are actively investigated for their potential to provide relevant insights into physiological and pathological conditions. Abnormal circulating extracellular vesicles (EVs) stemming from altered endosomal-lysosomal system have also been reported in several age-related conditions, including cancer and neurodegeneration, and indicated as a promising route for therapeutic purposes. Along this pathway, mitochondria may dispose altered components to preserve organelle homeostasis. However, whether a common thread exists between DAMPs and EVs generation is yet to be clarified. A deeper understanding of the highly complex, dynamic, and variable intracellular and extracellular trafficking of DAMPs and EVs, including those of mitochondrial origin, is needed to unveil relevant pathogenic pathways and novel targets for drug development. Herein, we describe the mechanisms of generation of EVs and mitochondrial-derived vesicles along the endocytic pathway and discuss the involvement of the endosomal-lysosomal in cancer and neurodegeneration (i.e., Alzheimer's and Parkinson's disease).

Fourier-Transform Infrared Spectroscopy of Skeletal Muscle Tissue: Expanding Biomarkers in Primary Mitochondrial Myopathies.

Primary mitochondrial myopathies (PMM) are a group of mitochondrial disorders characterized by a predominant skeletal muscle involvement. The aim of this study was to evaluate whether the biochemical profile determined by Fourier-transform infrared (FTIR) spectroscopic technique would allow to distinguish among patients affected by progressive external ophthalmoplegia (PEO), the most common PMM presentation, oculopharyngeal muscular dystrophy (OPMD), and healthy controls. Thirty-four participants were enrolled in the study. FTIR spectroscopy was found to be a sensitive and specific diagnostic marker for PEO. In particular, FTIR spectroscopy was able to distinguish PEO patients from those affected by OPMD, even in the presence of histological findings similar to mitochondrial myopathy. At the same time, FTIR spectroscopy differentiated single mtDNA deletion and mutations in POLG, the most common nuclear gene associated with mitochondrial diseases, with high sensitivity and specificity. In conclusion, our data suggest that FTIR spectroscopy is a valuable biodiagnostic tool for the differential diagnosis of PEO with a high ability to also distinguish between single mtDNA deletion and mutations in POLG gene based on specific metabolic transitions.

Altered Expression of Mitoferrin and Frataxin, Larger Labile Iron Pool and Greater Mitochondrial DNA Damage in the Skeletal Muscle of Older Adults.

Mitochondrial dysfunction and iron (Fe) dyshomeostasis are invoked among the mechanisms contributing to muscle aging, possibly via a detrimental mitochondrial-iron feed-forward loop. We quantified the labile Fe pool, Fe isotopes, and the expression of mitochondrial Fe handling proteins in muscle biopsies obtained from young and older adults. The expression of key proteins of mitochondrial quality control (MQC) and the abundance of the mitochondrial DNA common deletion (mtDNA4977) were also assessed. An inverse association was found between total Fe and the heavier Fe isotope (56Fe), indicating an increase in labile Fe abundance in cells with greater Fe content. The highest levels of labile Fe were detected in old participants with a Short Physical Performance Battery (SPPB) score ≤ 7 (low-functioning, LF). Protein levels of mitoferrin and frataxin were, respectively, higher and lower in the LF group relative to young participants and older adults with SPPB scores ≥ 11 (high-functioning, HF). The mtDNA4977 relative abundance was greater in old than in young participants, regardless of SPPB category. Higher protein levels of Pink1 were detected in LF participants compared with young and HF groups. Finally, the ratio between lipidated and non-lipidated microtubule-associated protein 1A/1B-light chain 3 (i.e., LC3B II/I), as well as p62 protein expression was lower in old participants regardless of SPPB scores. Our findings indicate that cellular and mitochondrial Fe homeostasis is perturbed in the aged muscle (especially in LF older adults), as reflected by altered levels of mitoferrin and frataxin, which, together with MQC derangements, might contribute to loss of mtDNA stability.