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The accumulation of damaged mitochondria has long been considered a hallmark of the aging process. Among various factors, age-related mitochondrial alterations comprise bioenergetic impairments and disturbances in reactive oxygen species (ROS) control, thereby negatively affecting mitochondrial performance and ultimately accelerating aging. Previous studies have revealed that polyamine spermidine appears to exert health-protective and lifespan-promoting effects. Notably, recent findings have also described a spermidine-induced improvement in age-associated mitochondrial dysfunction, but the beneficial effects of spermidine on aged mitochondria have not been entirely examined yet. Here, we show that spermidine positively regulates several parameters related to mitochondrial bioenergetics and mitochondrial redox homeostasis in young and aged human-induced pluripotent stem cell-derived neurons. We report that spermidine treatment increases adenosine triphosphate production and mitochondrial membrane potential, which is accompanied by an attenuation in mitochondrial ROS levels in both age groups. Furthermore, we demonstrate a spermidine-mediated amelioration in mitochondrial respiration in both young and aged neurons. Overall, our findings suggest that nutritional spermidine supplementation might represent an attractive therapeutic approach to enhance mitochondrial function, consequently decelerating aging.

A substantial challenge in human brain aging is to find a suitable model to mimic neuronal aging in vitro as accurately as possible. Using directly converted neurons (iNs) from human fibroblasts is considered a promising tool in human aging since it retains the aging-associated mitochondrial donor signature. Still, using iNs from aged donors can pose certain restrictions due to their lower reprogramming and conversion efficacy than those from younger individuals. To overcome these limitations, our study aimed to establish an in vitro neuronal aging model mirroring features of in vivo aging by acute exposure on young iNs to either human stress hormone cortisol or the mitochondrial stressor rotenone, considering stress as a trigger of in vivo aging. The impact of rotenone was evident in mitochondrial bioenergetic properties by showing aging-associated deficits in mitochondrial respiration, cellular ATP, and MMP and a rise in glycolysis, mitochondrial superoxide, and mitochondrial ROS; meanwhile, cortisol only partially induced an aging-associated mitochondrial dysfunction. To replicate the in vivo aging-associated mitochondrial dysfunctions, using rotenone, a mitochondrial complex I inhibitor, proved to be superior to the cortisol model. This work is the first to use stress on young iNs to recreate aging-related mitochondrial impairments.

Neuron-to-neuron transmission of aggregation-prone, misfolded proteins may potentially explain the spatiotemporal accumulation of pathological lesions in the brains of patients with neurodegenerative protein-misfolding diseases (PMDs). However, little is known about protein transmission from the central nervous system to the periphery, or how this propagation contributes to PMD pathology. To deepen our understanding of these processes, we established two functional neuromuscular systems derived from human iPSCs. One was suitable for long-term high-throughput live-cell imaging and the other was adapted to a microfluidic system assuring that connectivity between motor neurons and muscle cells was restricted to the neuromuscular junction. We show that the Huntington's disease (HD)-associated mutant HTT exon 1 protein (mHTTEx1) is transmitted from neurons to muscle cells across the human neuromuscular junction. We found that transmission is an active and dynamic process that starts before aggregate formation and is regulated by synaptic activity. We further found that transmitted mHTTEx1 causes HD-relevant pathology at both molecular and functional levels in human muscle cells, even in the presence of the ubiquitous expression of mHTTEx1. In conclusion, we have uncovered a causal link between mHTTEx1 synaptic transmission and HD pathology, highlighting the therapeutic potential of blocking toxic protein transmission in PMDs.

The accumulation of damaged mitochondria has long been considered a hallmark of the aging process. Among various factors, age-related mitochondrial alterations comprise bioenergetic impairments and disturbances in reactive oxygen species (ROS) control, thereby negatively affecting mitochondrial performance and ultimately accelerating aging. Previous studies have revealed that polyamine spermidine appears to exert health-protective and lifespan-promoting effects. Notably, recent findings have also described a spermidine-induced improvement in age-associated mitochondrial dysfunction, but the beneficial effects of spermidine on aged mitochondria have not been entirely examined yet. Here, we show that spermidine positively regulates several parameters related to mitochondrial bioenergetics and mitochondrial redox homeostasis in young and aged human-induced pluripotent stem cell-derived neurons. We report that spermidine treatment increases adenosine triphosphate production and mitochondrial membrane potential, which is accompanied by an attenuation in mitochondrial ROS levels in both age groups. Furthermore, we demonstrate a spermidine-mediated amelioration in mitochondrial respiration in both young and aged neurons. Overall, our findings suggest that nutritional spermidine supplementation might represent an attractive therapeutic approach to enhance mitochondrial function, consequently decelerating aging. [ABSTRACT FROM AUTHOR]

By introducing a ribosomal ambiguity mutation into mice, Moore et al. establish an in-vivo model to investigate how age-related diseases are related to decreasing accuracy in protein synthesis. Their findings potentially offer new insights into the pathological changes observed in age-related diseases, such as muscle atrophy

Pathological abnormalities in the tau protein give rise to a variety of neurodegenerative diseases, conjointly termed tauopathies. Several tau mutations have been identified in the tau-encoding gene MAPT, affecting either the physical properties of tau or resulting in altered tau splicing. At early disease stages, mitochondrial dysfunction was highlighted with mutant tau compromising almost every aspect of mitochondrial function. Additionally, mitochondria have emerged as fundamental regulators of stem cell function. Here, we show that compared to the isogenic wild-type triple MAPT-mutant human-induced pluripotent stem cells, bearing the pathogenic N279K, P301L, and E10+16 mutations, exhibit deficits in mitochondrial bioenergetics and present altered parameters linked to the metabolic regulation of mitochondria. Moreover, we demonstrate that the triple tau mutations disturb the cellular redox homeostasis and modify the mitochondrial network morphology and distribution. This study provides the first characterization of disease-associated tau-mediated mitochondrial impairments in an advanced human cellular tau pathology model at early disease stages, ranging from mitochondrial bioenergetics to dynamics. Consequently, comprehending better the influence of dysfunctional mitochondria on the development and differentiation of stem cells and their contribution to disease progression may thus assist in the potential prevention and treatment of tau-related neurodegeneration.

Aging represents the leading risk factor for developing neurodegenerative disorders. One of the nine hallmarks of aging is mitochondrial dysfunction. Age-related mitochondrial alterations have been shown to affect mitochondrial energy metabolism, reduction-oxidation homeostasis, and mitochondrial dynamics. Previous reports have shown that induced pluripotent stem cells (iPSCs) from aged donors do not keep the aging signature at the transcriptomic level. However, not all aspects of aging have been investigated, and especially not the mitochondria-related aging signature. Therefore, the present study compared the mitochondrial function in iPSCs from healthy aged donors compared to those of young donors. We addressed whether aged iPSCs may be used as drug-screening models of "aging in a dish" to identify therapies alleviating mitochondria aging. Compared to iPSCs from young donors, we demonstrate that iPSCs from aged donors show impaired mitochondrial bioenergetics and exhibit a rise in reactive oxygen species generation. Furthermore, aged iPSCs present a lower mitochondrial mass and alterations in the morphology of the mitochondrial network when compared to iPSCs from young donors. This study provides the first evidence that the aging phenotype is present at the mitochondrial level in iPSCs from aged donors, ranging from bioenergetics to mitochondrial network morphology. This model might be used to screen mitochondria-targeting drugs to promote healthy aging at the mitochondrial level. [ABSTRACT FROM AUTHOR]

A substantial challenge in human brain aging is to find a suitable model to mimic neuronal aging in vitro as accurately as possible. Using directly converted neurons (iNs) from human fibroblasts is considered a promising tool in human aging since it retains the aging-associated mitochondrial donor signature. Still, using iNs from aged donors can pose certain restrictions due to their lower reprogramming and conversion efficacy than those from younger individuals. To overcome these limitations, our study aimed to establish an in vitro neuronal aging model mirroring features of in vivo aging by acute exposure on young iNs to either human stress hormone cortisol or the mitochondrial stressor rotenone, considering stress as a trigger of in vivo aging. The impact of rotenone was evident in mitochondrial bioenergetic properties by showing aging-associated deficits in mitochondrial respiration, cellular ATP, and MMP and a rise in glycolysis, mitochondrial superoxide, and mitochondrial ROS; meanwhile, cortisol only partially induced an aging-associated mitochondrial dysfunction. To replicate the in vivo aging-associated mitochondrial dysfunctions, using rotenone, a mitochondrial complex I inhibitor, proved to be superior to the cortisol model. This work is the first to use stress on young iNs to recreate aging-related mitochondrial impairments. [ABSTRACT FROM AUTHOR]

Intercellular mitochondria transfer is a novel form of cell signalling in which whole mitochondria are transferred between cells in order to enhance cellular functions or aid in the degradation of dysfunctional mitochondria. Recent studies have observed intercellular mitochondria transfer between glia and neurons in the brain, and mitochondrial transfer has emerged as a key neuroprotective mechanism in a range of neurological conditions. In particular, artificial mitochondria transfer has sparked widespread interest as a potential therapeutic strategy for brain disorders. In this review, we discuss the mechanisms and effects of intercellular mitochondria transfer in the brain. The role of mitochondrial transfer in neurological conditions, including neurodegenerative disease, brain injury, and neurodevelopmental disorders, is discussed as well as therapeutic strategies targeting mitochondria transfer in the brain.

Translational errors frequently arise during protein synthesis, producing misfolded and dysfunctional proteins. Chronic stress resulting from translation errors may be particularly relevant in tissues that must synthesize and secrete large amounts of secretory proteins. Here, we studied the proteostasis networks in the liver of mice that express the Rps2-A226Y ribosomal ambiguity (ram) mutation to increase the translation error rate across all proteins. We found that Rps2-A226Y mice lack activation of the eIF2 kinase/ATF4 pathway, the main component of the integrated stress response (ISR), as well as the IRE1 and ATF6 pathways of the ER unfolded protein response (ER-UPR). Instead, we found downregulation of chronic ER stress responses, as indicated by reduced gene expression for lipogenic pathways and acute phase proteins, possibly via upregulation of Sirtuin-1. In parallel, we observed activation of alternative proteostasis responses, including the proteasome and the formation of stress granules. Together, our results point to a concerted response to error-prone translation to alleviate ER stress in favor of activating alternative proteostasis mechanisms, most likely to avoid cell damage and apoptotic pathways, which would result from persistent activation of the ER and integrated stress responses.

The brain is the most energy-consuming organ of the body and impairments in brain energy metabolism will affect neuronal functionality and viability. Brain aging is marked by defects in energetic metabolism. Abnormal tau protein is a hallmark of tauopathies, including Alzheimer’s disease (AD). Pathological tau was shown to induce bioenergetic impairments by affecting mitochondrial function. Although it is now clear that mutations in the tau-coding gene lead to tau pathology, the causes of abnormal tau phosphorylation and aggregation in non-familial tauopathies, such as sporadic AD, remain elusive. Strikingly, both tau pathology and brain hypometabolism correlate with cognitive impairments in AD. The aim of this review is to discuss the link between age-related decrease in brain metabolism and tau pathology. In particular, the following points will be discussed: (i) the common bioenergetic features observed during brain aging and tauopathies; (ii) how age-related bioenergetic defects affect tau pathology; (iii) the influence of lifestyle factors known to modulate brain bioenergetics on tau pathology. The findings compiled here suggest that age-related bioenergetic defects may trigger abnormal tau phosphorylation/aggregation and cognitive impairments after passing a pathological threshold. Understanding the effects of aging on brain metabolism may therefore help to identify disease-modifying strategies against tau-induced neurodegeneration.

Recent data indicate that Alzheimer’s disease (AD) is associated with disturbances of the circadian rhythm in patients. We examined the effect of amyloid-β (Aβ) peptide, the main component of the senile plaques playing a critical role in the deregulation of calcium (Ca 2+ ) homeostasis in AD, on the circadian oscillation of cytosolic calcium (Ca 2+ ) levels in vitro . The experiments we carried out in human primary skin fibroblasts. This cell line was previously shown to exhibit circadian rhythms of clock genes. Moreover, the basic clock properties of these peripheral cells closely mimic those measured physiologically and behaviorally in human and do not change during aging. In this study we showed that i) cytosolic Ca 2+ oscillations depend on the activation of purinergic P2X7 receptors; and ii) these oscillations are abolished in the presence of Aβ. In total, our new findings may help to deepen our understanding of the molecular mechanisms involved in AD-related circadian alterations.

Neurosteroids are steroids synthetized in the nervous system, with the first step of steroidogenesis taking place within mitochondria with the synthesis of pregnenolone. They exert important brain-specific functions by playing a role in neurotransmission, learning and memory processes, and neuroprotection. Here, we show for the first time that mitochondrial neurosteroidogenesis follows a circadian rhythm and correlates with the rhythmic changes in mitochondrial morphology. We used synchronized human A172 glioma cells, which are steroidogenic cells with a functional core molecular clock, to show that pregnenolone levels and translocator protein (TSPO) are controlled by the clock, probably via circadian regulation of mitochondrial fusion/fission. Key findings were recapitulated in mouse brains. We also showed that genetic or pharmacological abrogation of fusion/fission activity, as well as disturbing the core molecular clock, abolished circadian rhythms of pregnenolone and TSPO. Our findings provide new insights into the crosstalk between mitochondrial function (here, neurosteroidogenesis) and circadian cycles.

Recently, nutritional interventions have received attention as promising approaches to promote human health during a lifespan. The Mediterranean and Okinawan diets have been associated with longevity and decreasing risk for age-related diseases in contrast to the Western diet. The effect might be due to several antioxidative bioactive compounds highly consumed in both diets, namely, resveratrol, hydroxytyrosol, oleuropein, curcumin, and spermidine. This review aims to address the underlying mechanisms of these compounds to enhance mental fitness throughout life with a focus on brain mitophagy. Mitophagy is the autophagic clearance of dysfunctional, redundant, and aged mitochondria. In aging and neurodegenerative disorders, mitophagy is crucial to preserve the autophagy mechanism of the whole cell, especially during oxidative stress. Growing evidence indicates that curcumin, astaxanthin, resveratrol, hydroxytyrosol, oleuropein, and spermidine might exert protective functions via antioxidative properties and as well the enhanced induction of mitophagy mediators. The compounds seem to upregulate mitophagy and thereby alleviate the clearance of dysfunctional and aged mitochondria as well as mitogenesis. Thus, the Mediterranean or Okinawan diet could represent a feasible nutritional approach to reduce the risk of developing age-related cognitive impairment and corresponding disorders via the stimulation of mitophagy and thereby ensure a balanced redox state of brain cells.

BackgroundStandardized Ginkgo biloba extract (GBE) has demonstrated efficacy in the cognitive functional neuropsychiatric symptoms of patients with Alzheimer's disease (AD). With regard to its underlying molecular mode of action, first evidence was provided that GBE was able to modulate neuronal outgrowth in vitro, but the mechanisms underlying GBE effects on neuroplasticity remain unclear.Methodology/principal findingsIn this study, we investigated the effect of GBE on neurite outgrowth using SH-SY5Y neuroblastoma cells in a 2D and 3D surface culture. The effects of the GBE LI1370 on neuroplasticity and neurite outgrowth were compared to those of nerve growth factor (NGF, 50 ng/ml) which was used as a positive control. We evaluated several parameters of neurite outgrowth such as the neurite number, total neurite length and extend of branching. Our findings showed that GBE (10 and 100 μg/ml) significantly increased neurite outgrowth in the 2D as well as 3D culture model after 3 days of treatment with a comparable effect than that NGF. The use of the 3D cell culture allowed us to better reproduce the in vivo neuronal microenvironment for the evaluation the neurite formation after GBE treatment. In addition, we assessed the effects of GBE on the Akt/mTOR pathway, which is known to promote neuroplasticity induced by nerve growth factors. We showed that GBE treatment induced an increase of phosphorylated IGF1R (Tyr1135/Tyr1136), Akt (Ser473), TSC2 (Ser939), mTOR (Ser2448), PTEN (Ser380) and GSK3β (Ser9).ConclusionTogether, these findings indicate that GBE promotes neurite growth and activates the PI3K/Akt/mTOR pathway suggesting that this plant extract supports neuronal plasticity.

Mitochondria play an essential role in the generation of steroid hormones including the female sex hormones. These hormones are, in turn, able to modulate mitochondrial activities. Mitochondria possess crucial roles in cell maintenance, survival and well-being, because they are the main source of energy as well as of reactive oxygen species (ROS) within the cell. The impairment of these important organelles is one of the central features of aging. In women’s health, estrogen plays an important role during adulthood not only in the estrous cycle, but also in the brain via neuroprotective, neurotrophic and antioxidant modes of action. The hypestrogenic state in the peri- as well as in the prolonged postmenopause might increase the vulnerability of elderly women to brain degeneration and age-related pathologies. However, the underlying mechanisms that affect these processes are not well elucidated. Understanding the relationship between estrogen and mitochondria might therefore provide better insights into the female aging process. Thus, in this review, we first describe mitochondrial dysfunction in the aging brain. Second, we discuss the estrogen-dependent actions on the mitochondrial activity, including recent evidence of the estrogen—brain-derived neurotrophic factor and estrogen—sirtuin 3 (SIRT3) pathways, as well as their potential implications during female aging.

Gelsemium dynamized dilutions (GDD) are known as a remedy for a wide range of behavioral and psychological symptoms of depression and anxiety at ultra-low doses, yet the underlying mechanisms of the mode of action of G. sempervirens itself are not well understood. The present study was designed to examine the neuroprotective effects of Gelsemium preparations in counteracting stress-related mitochondrial dysfunctions in neuronal cells. We started by studying how serum deprivation affects the mitochondrial functions of human neuroblastoma (SH-SY5Y) cells. Next, we looked into the potential of various Gelsemium dilutions to improve cell survival and ATP levels. After identifying the most effective dilutions, 3C and 5C, we tested their ability to protect SH-SY5Y cells from stress-induced mitochondrial deficits. We measured total and mitochondrial superoxide anion radicals using fluorescent dyes dihydroethidium (DHE) and the red mitochondrial superoxide indicator (MitoSOX). Additionally, we assessed total nitric oxide levels with 4,5-diaminofluorescein diacetate (DAF-2DA), examined the redox state using pRA305 cells stably transfected with a plasmid encoding a redox-sensitive green fluorescent protein, and analyzed mitochondrial network morphology using an automated high-content analysis device, Cytation3. Furthermore, we investigated bioenergetics by measuring ATP production with a bioluminescence assay (ViaLighTM HT) and evaluated mitochondrial respiration (OCR) and glycolysis (ECAR) using the Seahorse Bioscience XF24 Analyzer. Finally, we determined cell survival using an MTT reduction assay. Our research indicates that Gelsemium dilutions (3C and 5C) exhibited neuroprotective effects by: - Normalizing total and mitochondrial superoxide anion radicals and total nitric oxide levels. - Regulating the mitochondrial redox environment and mitochondrial networks morphology. - Increasing ATP generation as well as OCR and ECAR levels, thereby reducing the viability loss induced by serum withdrawal stress. These findings highlight that dynamized Gelsemium preparations may have neuroprotective effects against stress-induced cellular changes in the brain by regulating mitochondrial functions, essential for the survival, plasticity, and function of neurons in depression. [Display omitted] • Stress induced by serum deprivation (Sd) exacerbated mitochondrial dysfunctions in human neuroblastoma SH-SY5Y cells. • Gelsemium dynamized dilutions protected against a stress-induced rise of ROS, a drop in NO and an oxidized redox state. • Gelsemium dynamized dilutions prevented stress-induced mitochondrial network impairments, cell death, and a decrease in ATP. • Gelsemium preparations mitigated the stress-induced drop of mitochondrial respiration and glycolysis. • Our results emphasize a novel potential mode of action of Gelsemium on stress-induced mechanisms underlying depression. [ABSTRACT FROM AUTHOR]