Extracellular Vesicles and Cellular Ageing.

Ageing is a complex process characterized by deteriorated performance at multiple levels, starting from cellular dysfunction to organ degeneration. Stem cell-based therapies aim to administrate stem cells that eventually migrate to the injured site to replenish the damaged tissue and recover tissue functionality. Stem cells can be easily obtained and cultured in vitro, and display several qualities such as self-renewal, differentiation, and immunomodulation that make them suitable candidates for stem cell-based therapies. Current animal studies and clinical trials are being performed to assess the safety and beneficial effects of stem cell engraftments for regenerative medicine in ageing and age-related diseases.Since alterations in cell-cell communication have been associated with the development of pathophysiological processes, new research is focusing on the modulation of the microenvironment. Recent research has highlighted the important role of some microenvironment components that modulate cell-cell communication, thus spreading signals from damaged ageing cells to neighbor healthy cells, thereby promoting systemic ageing. Extracellular vesicles (EVs) are small-rounded vesicles released by almost every cell type. EVs cargo includes several bioactive molecules, such as lipids, proteins, and genetic material. Once internalized by target cells, their specific cargo can induce epigenetic modifications and alter the fate of the recipient cells. Also, EV's content is dependent on the releasing cells, thus, EVs can be used as biomarkers for several diseases. Moreover, EVs have been proposed to be used as cell-free therapies that focus on their administration to slow or even reverse some hallmarks of physiological ageing. It is not surprising that EVs are also under study as next-generation therapies for age-related diseases.

Involvement of Aryl Hydrocarbon Receptor in Longevity and Healthspan: Insights from Humans, Mice, and C. elegans.

In previous studies, using transcriptomic analysis, we observed higher levels of aryl hydrocarbon receptor (AHR) gene expression in the peripheral blood cells of centenarians compared to octogenarians. This suggests the potential significance of this receptor in maintaining physiological balance and promoting healthy aging, possibly linked to its critical role in detoxifying xenobiotics. In our current study, we confirmed that AHR expression is indeed higher in centenarians. We employed C. elegans as a model known for its suitability in longevity studies to explore whether the AHR pathway has a significant impact on lifespan and healthspan. Our survival assays revealed that two different mutants of AHR-1 exhibited lower longevity. Additionally, we used a mouse model to examine whether supplementation with pomegranate extract modulates the expression of AHR pathway genes in the liver. Furthermore, we studied a nutritional strategy based on pomegranate extract administration to investigate its potential modulation of life- and healthspan in worms.

Telomerase reverse transcriptase delays aging in cancer-resistant mice.

Telomerase confers limitless proliferative potential to most human cells through its ability to elongate telomeres, the natural ends of chromosomes, which otherwise would undergo progressive attrition and eventually compromise cell viability. However, the role of telomerase in organismal aging has remained unaddressed, in part because of the cancer-promoting activity of telomerase. To circumvent this problem, we have constitutively expressed telomerase reverse transcriptase (TERT), one of the components of telomerase, in mice engineered to be cancer resistant by means of enhanced expression of the tumor suppressors p53, p16, and p19ARF. In this context, TERT overexpression improves the fitness of epithelial barriers, particularly the skin and the intestine, and produces a systemic delay in aging accompanied by extension of the median life span. These results demonstrate that constitutive expression of Tert provides antiaging activity in the context of a mammalian organism.

The Role of Extracellular Vesicles in Aging and Disease.

Cells are exposed to various internal and external factors that can cause damage over time [...].

Extracellular Vesicles as Therapeutic Resources in the Clinical Environment.

The native role of extracellular vesicles (EVs) in mediating the transfer of biomolecules between cells has raised the possibility to use them as therapeutic vehicles. The development of therapies based on EVs is now expanding rapidly; here we will describe the current knowledge on different key points regarding the use of EVs in a clinical setting. These points are related to cell sources of EVs, isolation, storage, and delivery methods, as well as modifications to the releasing cells for improved production of EVs. Finally, we will depict the application of EVs therapies in clinical trials, considering the impact of the COVID-19 pandemic on the development of these therapies, pointing out that although it is a promising therapy for human diseases, we are still in the initial phase of its application to patients.

The Potential Use of Mitochondrial Extracellular Vesicles as Biomarkers or Therapeutical Tools.

The mitochondria play a crucial role in cellular metabolism, reactive oxygen species (ROS) production, and apoptosis. Aberrant mitochondria can cause severe damage to the cells, which have established a tight quality control for the mitochondria. This process avoids the accumulation of damaged mitochondria and can lead to the release of mitochondrial constituents to the extracellular milieu through mitochondrial extracellular vesicles (MitoEVs). These MitoEVs carry mtDNA, rRNA, tRNA, and protein complexes of the respiratory chain, and the largest MitoEVs can even transport whole mitochondria. Macrophages ultimately engulf these MitoEVs to undergo outsourced mitophagy. Recently, it has been reported that MitoEVs can also contain healthy mitochondria, whose function seems to be the rescue of stressed cells by restoring the loss of mitochondrial function. This mitochondrial transfer has opened the field of their use as potential disease biomarkers and therapeutic tools. This review describes this new EVs-mediated transfer of the mitochondria and the current application of MitoEVs in the clinical environment.

Extracellular Vesicles: The Future of Diagnosis in Solid Organ Transplantation?

Solid organ transplantation (SOT) is a life-saving treatment for end-stage organ failure, but it comes with several challenges, the most important of which is the existing gap between the need for transplants and organ availability. One of the main concerns in this regard is the lack of accurate non-invasive biomarkers to monitor the status of a transplanted organ. Extracellular vesicles (EVs) have recently emerged as a promising source of biomarkers for various diseases. In the context of SOT, EVs have been shown to be involved in the communication between donor and recipient cells and may carry valuable information about the function of an allograft. This has led to an increasing interest in exploring the use of EVs for the preoperative assessment of organs, early postoperative monitoring of graft function, or the diagnosis of rejection, infection, ischemia-reperfusion injury, or drug toxicity. In this review, we summarize recent evidence on the use of EVs as biomarkers for these conditions and discuss their applicability in the clinical setting.

Therapeutic Potential of Extracellular Vesicles in Aging and Age-Related Diseases.

Aging is associated with an alteration of intercellular communication. These changes in the extracellular environment contribute to the aging phenotype and have been linked to different aging-related diseases. Extracellular vesicles (EVs) are factors that mediate the transmission of signaling molecules between cells. In the aging field, these EVs have been shown to regulate important aging processes, such as oxidative stress or senescence, both in vivo and in vitro. EVs from healthy cells, particularly those coming from stem cells (SCs), have been described as potential effectors of the regenerative potential of SCs. Many studies with different animal models have shown promising results in the field of regenerative medicine. EVs are now viewed as a potential cell-free therapy for tissue damage and several diseases. Here we propose EVs as regulators of the aging process, with an important role in tissue regeneration and a raising therapy for age-related diseases.

What Genetics Can Do for Oncological Imaging: A Systematic Review of the Genetic Validation Data Used in Radiomics Studies.

(1) Background: Radiogenomics is motivated by the concept that biomedical images contain information that reflects underlying pathophysiology. This review focused on papers that used genetics to validate their radiomics models and outcomes and assess their contribution to this emerging field. (2) Methods: All original research with the words radiomics and genomics in English and performed in humans up to 31 January 2022, were identified on Medline and Embase. The quality of the studies was assessed with Radiomic Quality Score (RQS) and the Cochrane recommendation for diagnostic accuracy study Quality Assessment 2. (3) Results: 45 studies were included in our systematic review, and more than 50% were published in the last two years. The studies had a mean RQS of 12, and the studied tumors were very diverse. Up to 83% investigated the prognosis as the main outcome, with the rest focusing on response to treatment and risk assessment. Most applied either transcriptomics (54%) and/or genetics (35%) for genetic validation. (4) Conclusions: There is enough evidence to state that new science has emerged, focusing on establishing an association between radiological features and genomic/molecular expression to explain underlying disease mechanisms and enhance prognostic, risk assessment, and treatment response radiomics models in cancer patients.

Garcinoic acid prevents ß-amyloid (Aß) deposition in the mouse brain.

Garcinoic acid (GA or δ-T3-13'COOH), is a natural vitamin E metabolite that has preliminarily been identified as a modulator of nuclear receptors involved in ß-amyloid (Aß) metabolism and progression of Alzheimer's disease (AD). In this study, we investigated GA's effects on Aß oligomer formation and deposition. Specifically, we compared them with those of other vitamin E analogs and the soy isoflavone genistein, a natural agonist of peroxisome proliferator-activated receptor γ (PPARγ) that has therapeutic potential for managing AD. GA significantly reduced Aß aggregation and accumulation in mouse cortical astrocytes. Similarly to genistein, GA up-regulated PPARγ expression and apolipoprotein E (ApoE) efflux in these cells with an efficacy that was comparable with that of its metabolic precursor δ-tocotrienol and higher than those of α-tocopherol metabolites. Unlike for genistein and the other vitamin E compounds, the GA-induced restoration of ApoE efflux was not affected by pharmacological inhibition of PPARγ activity, and specific activation of pregnane X receptor (PXR) was observed together with ApoE and multidrug resistance protein 1 (MDR1) membrane transporter up-regulation in both the mouse astrocytes and brain tissue. These effects of GA were associated with reduced Aß deposition in the brain of TgCRND8 mice, a transgenic AD model. In conclusion, GA holds potential for preventing Aß oligomerization and deposition in the brain. The mechanistic aspects of GA's properties appear to be distinct from those of other vitamin E metabolites and of genistein.

Lipid peroxidation as measured by chromatographic determination of malondialdehyde. Human plasma reference values in health and disease.

Free radicals and oxidants are involved in physiological signaling pathways, although an imbalance between pro-oxidant and anti-oxidant systems in favor of the former leads to major biomolecular damage. This is the so-called oxidative stress, a complex process that affects us all and is responsible for the development of many diseases. Lipids are very sensitive to oxidant attack and to-date, malondialdehyde (MDA), 4-hydroxy-2-nonenal (4-HNE) and F2-isoprostane are the main biomarkers for lipid peroxidation assessment. They all derive from polyunsaturated fatty acids (PUFAs) either by enzyme-catalyzed reactions (physiological) or by non-enzyme reactions (pathological). The profile of PUFAs present in the tissue will determine the proportion of each biomarker. In this review we aim to discuss the proper method for MDA determination using HPLC. We also offer reference MDA values in humans in physiological and pathological conditions.

Diagnostic Performance of Muscle Echo Intensity and Fractal Dimension for the Detection of Frailty Phenotype.

To determine the relationship between muscle echo intensity (EI) and fractal dimension (FD), and the diagnostic performance of both ultrasound parameters for the identification of frailty phenotype. A retrospective interpretation of ultrasound scans from a previous cohort (November 2014-February 2015) was performed. The sample included healthy participants <60 years old, and participants ≥60 divided into robust, pre-frail, and frail groups according to Fried frailty criteria. A region of interest of the rectus femoris from the ultrasound scan was segmented, and histogram function was applied to obtain EI. For fractal analysis, images were processed using two-dimensional box-counting techniques to calculate FD. Statistical analyses were performed with diagnostic performance tests. A total of 102 participants (mean age 63 ± 16, 57 men) were evaluated. Muscle fractal dimension correlated with EI (r = .38, p < .01) and showed different pattern in the scatter plots when participants were grouped by non-frail (control + robust) and frail (pre-frail + frail). The diagnostic accuracy for EI to categorize frailty was of 0.69 (95%CI: 0.59-0.78, p = .001), with high intra-rater (ICC: 0.98, 95%CI: 0.98-0.99); p < .001) and inter-rater (ICC: 0.89, 95%CI: 0.75-0.95; p < .001) reliability and low measurement error for both parameters (EI: -0.18, LOA95%: -10.8 to 10.5; FD: 0.00, LOA95%: -0.09 to 0.10) in arbitrary units. The ROC curve combining both parameters was not better than EI alone (p = .18). Muscle FD correlated with EI and showed different patterns according to frailty phenotype, with EI outperforming FD as a possible diagnostic tool for frailty.

Bcl-xL as a Modulator of Senescence and Aging.

Many features of aging result from the incapacity of cells to adapt to stress conditions. When cells are overwhelmed by stress, they can undergo senescence to avoid unrestricted growth of damaged cells. Recent findings have proven that cellular senescence is more than that. A specific grade of senescence promotes embryo development, tissue remodeling and wound healing. However, constant stresses and a weakening immune system can lead to senescence chronicity with aging. The accumulation of senescent cells is directly related to tissue dysfunction and age-related pathologies. Centenarians, the most aged individuals, should accumulate senescent cells and suffer from their deleterious effects, however, they enjoy a compression of morbidity. We have shown that they overexpress B-cell lymphoma-extra large (Bcl-xL). Bcl-xL could avoid an excessive burden of senescent cells through the regulation of intrinsic apoptosis, mitochondrial bioenergetics and oxidative stress. On the other hand, Bcl-xL maintains a fully functional immune system that ensures an efficient clearance of senescent cells. Moreover, there is a paradox, as inhibitors of Bcl-xL have been employed as senolytic agents, which have been shown to protect from aging in animal models. In this review, we aim to discuss how Bcl-xL could modulate senescence-associated harmful effects in centenarians, protecting them from the burden of accumulation of senescent cells.

BCL-xL, a Mitochondrial Protein Involved in Successful Aging: From C. elegans to Human Centenarians.

B-Cell Lymphoma-extra-large (BCL-xL) is involved in longevity and successful aging, which indicates a role for BCL-xL in cell survival pathway regulation. Beyond its well described role as an inhibitor of apoptosis by preventing cytochrome c release, BCL-xL has also been related, indirectly, to autophagy and senescence pathways. Although in these latter cases, BCL-xL has dual roles, either activating or inhibiting, depending on the cell type and the specific conditions. Taken together, all these findings suggest a precise mechanism of action for BCL-xL, able to regulate the crosstalk between apoptosis, autophagy, and senescence, thus promoting cell survival or cell death. All three pathways can be both beneficial or detrimental depending on the circumstances. Thus, targeting BCL-xL would in turn be a "double-edge sword" and therefore, additional studies are needed to better comprehend this dual and apparently contradictory role of BCL-XL in longevity.

Relevance of Oxygen Concentration in Stem Cell Culture for Regenerative Medicine.

The key hallmark of stem cells is their ability to self-renew while keeping a differentiation potential. Intrinsic and extrinsic cell factors may contribute to a decline in these stem cell properties, and this is of the most importance when culturing them. One of these factors is oxygen concentration, which has been closely linked to the maintenance of stemness. The widely used environmental 21% O2 concentration represents a hyperoxic non-physiological condition, which can impair stem cell behaviour by many mechanisms. The goal of this review is to understand these mechanisms underlying the oxygen signalling pathways and their negatively-associated consequences. This may provide a rationale for culturing stem cells under physiological oxygen concentration for stem cell therapy success, in the field of tissue engineering and regenerative medicine.

Unlocking the biochemical secrets of longevity: balancing healthspan and lifespan.

In an era of rising global life expectancies, research focuses on enhancing the quality of extended years. This review examines the link between mitochondrial function and aging, highlighting the importance of healthspan alongside lifespan. This involves significant human and economic challenges, with longer lifespans often accompanied by reduced well-being. Addressing mitochondrial decline, exploring targeted interventions, and understanding the complexities of research models are vital for advancing our knowledge in this field. Additionally, promoting physical exercise and adopting personalized supplementation strategies based on individual needs can contribute to healthy aging. The insights from this Perspective article offer a hopeful outlook for future advances in extending both lifespan and healthspan, aiming to improve the overall quality of life in aging populations.

Genistein, A Phytoestrogen, Delays the Transition to Dementia in Prodromal Alzheimer's Disease Patients.

Alzheimer's disease is recognized as a complex condition influenced by multiple factors, necessitating a similarly multifaceted approach to treatment. Ideally, interventions should prioritize averting the progression to dementia. Given the chronic nature of the disease, long-term management strategies are required. Within this framework, lifestyle modifications and dietary supplements emerge as appealing options due to their minimal toxicity, limited side effects, and cost-effectiveness. This study presents findings from a double-blind, placebo-controlled bicentric pilot clinical trial, demonstrating the significant cognitive preservation associated with genistein, a phytoestrogen found in soy and various other dietary sources, among individuals with prodromal Alzheimer's disease. Our prior investigation utilizing APP/PS1 mice elucidated the specific mechanisms through which genistein operates, including anti-amyloid-ß, antioxidant, anti-inflammatory, and antiapoptotic effects. These findings underscore the potential of identifying bioactive compounds from dietary sources for the management of Alzheimer's disease.

Free radicals in Alzheimer's disease: From pathophysiology to clinical trial results.

In this review, we examine the role of oxidative stress in the pathophysiology of Alzheimer's Disease (AD). Amyloid-beta (Aß) induces damage not only extracellularly but also within the intracellular environment. Mitochondria, a principal source of free radicals, are closely associated with Aß, as it binds to heme, thereby disrupting the normal electron flow in the respiratory chain. At the turn of the century, it was hypothesized that the majority, if not all, pathological events in AD are linked to free radical damage. Notably, free radicals also possess signaling capabilities that contribute to the disease's progression. A substantial body of evidence suggests that radical signaling is implicated in the relationship between amyloid-ß and tau hyperphosphorylation. Antioxidant therapy represents a potential strategy to delay the progression from cognitive impairment to overt dementia. Enhancing endogenous antioxidant defenses, for instance, through polyphenol supplementation, offers a promising approach to partially prevent dementia onset, particularly in at-risk populations. Understanding the redox-related pathophysiology of AD opens new avenues for prevention and treatment, providing a source of hope in the fight against Alzheimer's Disease.

A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.

The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity.

Delayed ageing through damage protection by the Arf/p53 pathway.

The tumour-suppressor pathway formed by the alternative reading frame protein of the Cdkn2a locus (Arf) and by p53 (also called Trp53) plays a central part in the detection and elimination of cellular damage, and this constitutes the basis of its potent cancer protection activity. Similar to cancer, ageing also results from the accumulation of damage and, therefore, we have reasoned that Arf/p53 could have anti-ageing activity by alleviating the load of age-associated damage. Here we show that genetically manipulated mice with increased, but otherwise normally regulated, levels of Arf and p53 present strong cancer resistance and have decreased levels of ageing-associated damage. These observations extend the protective role of Arf/p53 to ageing, revealing a previously unknown anti-ageing mechanism and providing a rationale for the co-evolution of cancer resistance and longevity.