1,721,119 research outputs found
The mitochondrial side of frailty
No full textPurpose of review. Frailty, a prevalent geriatric condition marked by reduced physiological reserve and greater vulnerability to stressors, is increasingly linked to mitochondrial dysfunction. This review summarizes current evidence on mitochondrial quality control, bioenergetics, and signaling in frailty, with emphasis on biomarker discovery and translational potential.
Recent findings. Preclinical and human studies have shown that impaired mitochondrial biogenesis, altered dynamics, and defective mitophagy contribute to frailty, sarcopenia, and immune dysregulation. Frail older adults exhibit reduced mitochondrial DNA content, diminished mitochondrial respiratory capacity, elevated reactive oxygen species generation, and distinctive metabolomic changes. Potential biomarkers include mitochondria-derived vesicles, circulating metabolites, and measures of peripheral blood mononuclear cell respiration, which may enable early detection of functional decline. Multivariate profiling approaches have identified sex-specific and shared molecular signatures converging on mitochondrial pathways. Interventions promoting mitochondrial health, including resistance training and targeted immunomodulation, hold promise in slowing frailty progression.
Summary. Mitochondrial dysfunction lies at the intersection of musculoskeletal, metabolic, and immune changes underpinning frailty. While integrative biomarker panels have defined metabolic signatures, early diagnosis and personalized therapies remain unmet needs. Longitudinal studies are required to establish causality, refine biomarker utility, and guide precision medicine strategies to preserve mitochondrial function, extend healthspan, and improve quality of life in aging populations
Regulation of mitochondrial biogenesis through TFAM-mitochondrial DNA interactions. Useful insights from aging and calorie restriction studies
Full text linkMitochondrial biogenesis is regulated to adapt mitochondrial population to cell energy demands. Mitochondrial transcription factor A (TFAM) performs several functions for mtDNA and interactions between TFAM and mtDNA participate to regulation of mitochondrial biogenesis. Such interactions are modulated through different mechanisms: regulation of TFAM expression and turnover, modulation of TFAM binding activity to mtDNA through post-translational modifications and differential affinity of TFAM, occurrence of TFAM sliding on mtDNA filaments and of cooperative binding among TFAM molecules, modulation of protein-protein interactions. The tissue-specific regulation of mitochondrial biogenesis in aging and calorie restriction (CR) highlights the relevance of modulation of TFAM-mtDNA interactions
Mitochondria-derived vesicles in neurodegeneration
Full text linkMitophagy is a well-characterized and redundant recycling system for damaged mitochondria and a marker of organelle quality (Picca et al., 2023). Yet, the assessment of mitophagy in vivo remains a challenge. The characterization of the endosomal-lysosomal pathways supporting the endocytic trafficking has provided invaluable information also into mitophagy signaling. The endocytic pathway has been implicated in preserving mitochondrial quality via generation of mitochondria-derived vesicles (MDVs) and, as such, has been related to mitophagy tasks (Ferrucci et al., 2024). Altered mitophagy and MDV signaling accompany brain aging and neurodegenerative conditions (Ferrucci et al., 2024). However, how MDVs can be best characterized to be exploited as hallmarks of health and disease is debated. MDVs may be a trait d’union between dysfunctional mitophagy and decline of cell homeostasis through shuttling and/or being themselves mitochondria-derived damage-associated molecular patterns. These latter by instigating chronic low-grade inflammation may support neuroinflammation and neurodegeneration (Ferrucci et al., 2024). Alternatively, MDVs may rescue mitochondrial bioenergetics of neighbouring cells and favour neuronal health by transferring functional organelles. However, what defines one or the other role of MDVs and whether the outcome is mediated by vesicle subpopulations released under different metabolic triggers remain to be defined. Herein, we discuss MDVs as surrogate and more accessible measures of
mitophagy. We also highlight the importance of addressing challenges in MDVs isolation and characterization to appreciate their signaling roles in neurodegeneration
Mitochondria break free: Mitochondria-derived vesicles in aging and associated conditions
No full textMitophagy is the intracellular recycling system that disposes damaged/inefficient mitochondria and allows biogenesis of new organelles to ensure mitochondrial quality is optimized. Dysfunctional mitophagy has been implicated in human aging and diseases. Multiple evolutionarily selected, redundant mechanisms of mitophagy have been identified, but their specific roles in human health and their potential exploitation as therapeutic targets are unclear. Recently, the characterization of the endosomal−lysosomal system has revealed additional mechanisms of mitophagy and mitochondrial quality control that operate via the production of mitochondria-derived vesicles (MDVs). Circulating MDVs can be isolated and characterized to provide an unprecedented opportunity to study this type of mitochondrial recycling in vivo and to relate it to human physiology and pathology. Defining the role of MDVs in human physiology, pathology, and aging is hampered by the lack of standardized methods to isolate, validate, and characterize these vesicles. Hence, some basic questions about MDVs remain unanswered. While MDVs are generated directly through the extrusion of mitochondrial membranes within the cell, a set of circulating extracellular vesicles leaking from the endosomal−lysosomal system and containing mitochondrial portions have also been identified and warrant investigation. Preliminary research indicates that MDV generation serves multiple biological roles and contributes to restoring cell homeostasis. However, studies have shown that MDVs may also be involved in pathological conditions. Therefore, further research is warranted to establish when/whether MDVs are supporting disease progression and/or are extracting damaged mitochondrial components to alleviate cellular oxidative burden and restore redox homeoastasis. This information will be relevant for exploiting these vesicles for therapeutic purpose. Herein, we provide an overview of preclinical and clinical studies on MDVs in aging and associated conditions and discuss the interplay between MDVs and some of the hallmarks of aging (mitophagy, inflammation, and proteostasis). We also outline open questions on MDV research that should be prioritized by future investigations
Exploring the role of intrinsic and extrinsic factors on the associations between sarcopenia and falls in older adults
No full textThe present study investigated the moderating effects of intrinsic and extrinsic factors on the association between sarcopenia and falls in older adults. This prospective cohort study was conducted among octogenarians residing in the mountainous Sirente geographic area of Central Italy. Sarcopenia was defined by the coexistence of low muscle mass and dynapenia. Data on fall history and incident falls were collected over a two-year period. A general linear model was used to assess whether intrinsic factors (i.e., multimorbidity, polypharmacy, cognitive function, vision status, nutritional status) and extrinsic factors (i.e., social functioning, environmental characteristics) moderated the relationship between sarcopenia (independent variable) and falls (dependent variable). Data of 364 individuals were examined. Fifty participants (13.7%) reported at least one fall event in the 90 days prior to data collection, while 36 participants (10%) reported having fallen during the follow-up period. Results revealed that intrinsic factors, but not extrinsic ones, significantly influenced this association. Specifically, multimorbidity and polypharmacy were associated with both fall history and incidence, while cognitive function and nutritional status emerged as significant moderators in the longitudinal analysis. In conclusion, these findings underscore the importance of addressing specific intrinsic health-related factors in order to more effectively mitigate the risk of falls among older adults with sarcopenia
Defective mitochondrial quality control in the aging of skeletal muscle
Full text linkAge-related skeletal muscle decline is a major contributor to frailty, functional impairment, and loss of independence in advanced age. This process is characterized by selective atrophy of type II fibers, impaired excitation–contraction coupling, and reduced regenerative capacity. Emerging evidence implicates mitochondrial dysfunction as a central mechanism in the disruption of muscle homeostasis with age. Beyond ATP production, mitochondria orchestrate redox signaling, calcium handling, and apoptotic pathways, which are increasingly compromised in aged muscle due to chronic oxidative stress and defective quality control. High-resolution respirometry has revealed intrinsic, lifestyle-independent declines in mitochondrial respiratory capacity, while large-scale phenotyping and transcriptomic profiling have established robust associations between mitochondrial integrity, physical performance, and mobility. These findings have prompted a paradigm shift from static descriptions of mitochondrial decline toward dynamic analyses of mitochondrial signaling networks and stress adaptability. Several quality control mechanisms, including mitochondrial biogenesis, dynamics, mitophagy, and vesicle trafficking, emerge as critical regulators of myocyte integrity. Understanding how these systems deteriorate with age will be pivotal for developing therapeutic targets to preserve muscle function, mitigate sarcopenia, and extend health span
Does eating less make you live longer and better? An update on calorie restriction
Full text linkAnna Picca,1 Vito Pesce,2 Angela Maria Serena Lezza2 1Department of Geriatrics, Neuroscience and Orthopedics, Catholic University of the Sacred Heart School of Medicine, Rome, 2Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, Bari, Italy Abstract: The complexity of aging is hard to be captured. However, apart from its tissue-specific features, a structural and functional progressive decline of the whole organism that leads to death, often preceded by a phase of chronic morbidity, characterizes the common process of aging. Therefore, the research goal of scientists in the field moved from the search for strategies able to extend longevity to those ensuring healthy aging associated with a longer lifespan referred to as “healthspan”. The aging process is plastic and can be tuned by multiple mechanisms including dietary and genetic interventions. To date, the most robust approach, efficient in warding off the cellular markers of aging, is calorie restriction (CR). Here, after a preliminary presentation of the major debate originated by CR, we concisely overviewed the recent results of CR treatment on humans. We also provided an update on the molecular mechanisms involved by CR and the effects on some of the age-associated cellular markers. We finally reviewed a number of tested CR mimetics and concluded with an evaluation of future applications of such dietary approach. Keywords: aging, calorie restriction, studies on humans, CR molecular mechanisms, CR mimetic
Immunological Landscape and Molecular Therapeutic Targets of the Tumor Microenvironment in Hepatocellular Carcinoma
No full textHepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed
Age-related changes of skeletal muscle mass and strength among Italian and Taiwanese older people: Results from the Milan EXPO 2015 survey and the I-Lan Longitudinal Aging Study
No full textBackground Muscle mass and strength ineluctably decline with advancing age. Yet, the impact of ethnicity on the pattern of changes and their magnitude is unclear. The aims of the present study were to analyze age- and gender-specific changes in measures of muscle mass and strength among community-living persons and to identify differences between Caucasian and Asian participants. Methods The Italian survey (“Longevity Check-up”), conducted during Milan EXPO 2015, consisted of a population assessment aimed at evaluating the prevalence of specific health metrics in persons outside of a conventional research setting (n = 1924), with a special focus on muscle mass and strength. The Taiwanese survey used the first-wave sampling from the I-Lan Longitudinal Aging Study (ILAS) collected from August 2011 to August 2013 (n = 1839). ILAS was designed to explore the interrelationship between sarcopenia and frailty in community-dwelling older people in Taiwan. In both studies, muscle mass was estimated by measuring the calf circumference (CC), whereas muscle strength was assessed by handgrip strength testing. Results The mean age of the 1924 Italian participants was 62.5 years (standard deviation 8.3, range from 50 to 98 years), of whom 1031 (53.6%) were women. Similarly, the mean age of the Taiwanese sample was 63.9 years (standard deviation 9.3, range from 50 to 92 years), with 966 (52.5%) women. CC declined with age in both genders and was significantly greater among Italian participants compared with Taiwanese people in all age groups. A similar effect of age was observed for muscle strength. As for CC, muscle strength was significantly greater among Italian persons relative to Taiwanese participants. Conclusion Muscle mass and strength declined with age in both ethnic groups. Caucasians showed greater muscle mass and performed better than their Asian counterparts. However, the age at which declines began to appear and the rate of decline during aging were comparable between the two populations
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