DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

Neurodegenerative disorders, metabolic icebergs, and mitohormesis.

Neurodegenerative disorders are typically "split" based on their hallmark clinical, anatomical, and pathological features, but they can also be "lumped" by a shared feature of impaired mitochondrial biology. This leads us to present a scientific framework that conceptualizes Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington's disease (HD) as "metabolic icebergs" comprised of a tip, a bulk, and a base. The visible tip conveys the hallmark neurological symptoms, neurodegenerative regions, and neuronal protein aggregates for each disorder. The hidden bulk depicts impaired mitochondrial biology throughout the body, which is multifaceted and may be subdivided into impaired cellular metabolism, cell-specific mitotypes, and mitochondrial behaviours, functions, activities, and features. The underlying base encompasses environmental factors, especially modern industrial toxins, dietary lifestyles, and cognitive, physical, and psychosocial behaviours, but also accommodates genetic factors specific to familial forms of AD, PD, and ALS, as well as HD. Over years or decades, chronic exposure to a particular suite of environmental and genetic factors at the base elicits a trajectory of impaired mitochondrial biology that maximally impacts particular subsets of mitotypes in the bulk, which eventually surfaces as the hallmark features of a particular neurodegenerative disorder at the tip. We propose that impaired mitochondrial biology can be repaired and recalibrated by activating "mitohormesis", which is optimally achieved using strategies that facilitate a balanced oscillation between mitochondrial stressor and recovery phases. Sustainably harnessing mitohormesis may constitute a potent preventative and therapeutic measure for people at risk of, or suffering with, neurodegenerative disorders.

Can stable introns and noncoding RNAs be harnessed to improve health through activation of mitohormesis?

Ever since their introduction a decade ago, stable introns, a type of noncoding (nc)RNAs, are found to be key players in different important cellular processes acting through regulation of gene expression and feedback loops to maintain cellular homeostasis. Despite being commonly regarded as useless byproducts, recent studies in yeast suggested that stable introns are essential for cell survivability under starvation. In Drosophila, we found that a stable intron, sisR-1, has a direct effect in regulating mitochondrial dynamics during short-term fasting and subsequently improved overall oocyte quality. We speculated that the beneficial effects implicated by sisR-1 is through the activation of mitohormesis, an interesting phenomenon in mitochondrial biology. Mitohormesis is suggested to improve health span and lifespan of cells and organisms, but the involvement of ncRNAs is not well-documented. Here, we discuss the potential role of sisR-1 and other ncRNAs in activating mitohormesis and the possible applications in improving cellular and organismal health.

[Mitohormesis: a key driver of the therapy resistance in cancer cells]. / Mitohormesis : la clé de voûte de la résistance thérapeutique des cellules cancéreuses.

A large body of literature highlights the importance of energy metabolism in the response of haematological malignancies to therapy. In this review, we are particularly interested in acute myeloid leukaemia, where mitochondrial metabolism plays a key role in response and resistance to treatment. We describe the new concept of mitohormesis in the response to therapy-induced stress and in the initiation of relapse in this disease.

De nombreux travaux de la littérature illustrent l'importance de l'étude du métabolisme énergétique pour la compréhension de la réponse aux thérapies des hémopathies malignes. Dans cette revue, nous nous sommes particulièrement intéressés aux leucémies aiguës myéloïdes pour lesquelles le métabolisme mitochondrial joue un rôle clé dans la réponse et la résistance aux traitements. Nous avons décrit le nouveau concept de mitohormesis dans la réponse aux stress induits par les thérapies et dans l'initiation des rechutes dans cette pathologie.

Are Aminoglycoside Antibiotics TRPing Your Metabolic Switches?

Transient receptor potential (TRP) channels are broadly implicated in the developmental programs of most tissues. Amongst these tissues, skeletal muscle and adipose are noteworthy for being essential in establishing systemic metabolic balance. TRP channels respond to environmental stimuli by supplying intracellular calcium that instigates enzymatic cascades of developmental consequence and often impinge on mitochondrial function and biogenesis. Critically, aminoglycoside antibiotics (AGAs) have been shown to block the capacity of TRP channels to conduct calcium entry into the cell in response to a wide range of developmental stimuli of a biophysical nature, including mechanical, electromagnetic, thermal, and chemical. Paradoxically, in vitro paradigms commonly used to understand organismal muscle and adipose development may have been led astray by the conventional use of streptomycin, an AGA, to help prevent bacterial contamination. Accordingly, streptomycin has been shown to disrupt both in vitro and in vivo myogenesis, as well as the phenotypic switch of white adipose into beige thermogenic status. In vivo, streptomycin has been shown to disrupt TRP-mediated calcium-dependent exercise adaptations of importance to systemic metabolism. Alternatively, streptomycin has also been used to curb detrimental levels of calcium leakage into dystrophic skeletal muscle through aberrantly gated TRPC1 channels that have been shown to be involved in the etiology of X-linked muscular dystrophies. TRP channels susceptible to AGA antagonism are critically involved in modulating the development of muscle and adipose tissues that, if administered to behaving animals, may translate to systemwide metabolic disruption. Regenerative medicine and clinical communities need to be made aware of this caveat of AGA usage and seek viable alternatives, to prevent contamination or infection in in vitro and in vivo paradigms, respectively.

Synergistic Cellular Responses Conferred by Concurrent Optical and Magnetic Stimulation Are Attenuated by Simultaneous Exposure to Streptomycin: An Antibiotic Dilemma.

Concurrent optical and magnetic stimulation (COMS) combines extremely low-frequency electromagnetic and light exposure for enhanced wound healing. We investigated the potential mechanistic synergism between the magnetic and light components of COMS by comparing their individual and combined cellular responses. Lone magnetic field exposure produced greater enhancements in cell proliferation than light alone, yet the combined effects of magnetic fields and light were supra-additive of the individual responses. Reactive oxygen species were incrementally reduced by exposure to light, magnetics fields, and their combination, wherein statistical significance was only achieved by the combined COMS modality. By contrast, ATP production was most greatly enhanced by magnetic exposure in combination with light, indicating that mitochondrial respiratory efficiency was improved by the combination of magnetic fields plus light. Protein expression pertaining to cell proliferation was preferentially enhanced by the COMS modality, as were the protein levels of the TRPC1 cation channel that had been previously implicated as part of a calcium-mitochondrial signaling axis invoked by electromagnetic exposure and necessary for proliferation. These results indicate that light facilitates functional synergism with magnetic fields that ultimately impinge on mitochondria-dependent developmental responses. Aminoglycoside antibiotics (AGAs) have been previously shown to inhibit TRPC1-mediated magnetotransduction, whereas their influence over photomodulation has not been explored. Streptomycin applied during exposure to light, magnetic fields, or COMS reduced their respective proliferation enhancements, whereas streptomycin added after the exposure did not. Magnetic field exposure and the COMS modality were capable of partially overcoming the antagonism of proliferation produced by streptomycin treatment, whereas light alone was not. The antagonism of photon-electromagnetic effects by streptomycin implicates TRPC1-mediated calcium entry in both magnetotransduction and photomodulation. Avoiding the prophylactic use of AGAs during COMS therapy will be crucial for maintaining clinical efficacy and is a common concern in most other electromagnetic regenerative paradigms.

Harnessing Mitochondrial Stress for Health and Disease: Opportunities and Challenges.

Mitochondria, essential organelles orchestrating cellular metabolism, have emerged as central players in various disease pathologies. Recent research has shed light on mitohormesis, a concept proposing an adaptive response of mitochondria to minor disturbances in homeostasis, offering novel therapeutic avenues for mitochondria-related diseases. This comprehensive review explores the concept of mitohormesis, elucidating its induction mechanisms and occurrence. Intracellular molecules like reactive oxygen species (ROS), calcium, mitochondrial unfolded proteins (UPRmt), and integrated stress response (ISR), along with external factors such as hydrogen sulfide (H2S), physical stimuli, and exercise, play pivotal roles in regulating mitohormesis. Based on the available evidence, we elucidate how mitohormesis maintains mitochondrial homeostasis through mechanisms like mitochondrial quality control and mitophagy. Furthermore, the regulatory role of mitohormesis in mitochondria-related diseases is discussed. By envisioning future applications, this review underscores the significance of mitohormesis as a potential therapeutic target, paving the way for innovative interventions in disease management.

Phloretin prolongs lifespan of Caenorhabditis elegans via inhibition of NDUFS1 and NDUFS6 at mitochondrial complex â .

Phloretin has been widely perceived as an antioxidant. However, the bioavailability of phloretin in vivo is generally far too low to elicit a direct antioxidant effect by scavenging reactive oxygen species (ROS). Here we showed that administration of phloretin of apple polyphenols extended lifespan of Caenorhabditis elegans and promoted fitness. Specially phloretin enhanced the survival rates of nematodes under oxidants in an inverted U-shaped dose-response manner. The lifespan-extending effects of phloretin were mediated by ROS via mitochondrial complex I inhibition. The increase of ROS stimulated p38 MAPK/PMK-1 as well as transcription factors of NRF2/SKN-1 and FOXO/DAF-16. Consistent with the involvement of NRF2/SKN-1 and FOXO/DAF-16 in lifespan-extending effects, activities of superoxide dismutase (SOD) and catalase (CAT) were enhanced by phloretin. The exogenous application of antioxidants butylated hydroxyanisole and N-acetylcysteine abolished the increase of ROS, the enhancement of SOD and CAT activities, and the lifespan extending effects of phloretin. Meanwhile, with the inhibition of mitochondrial complex I, ATP was instantly decreased. Both energy sensors of AMPK/AAK-2 and SIRT1/SIR-2.1 were involved in the lifespan extension by phloretin. Transcriptomic, real-time qPCR and molecular docking analyses demonstrated that the binding of phloretin at complex I located at NDUFS1/NUO-5, NDUFS2/GAS-1, and NDUFS6/NDUF-6. The molecular dynamic simulation and binding free energy calculations showed that phloretin had high binding affinities towards NDUFS1 (-7.21 kcal/mol) and NDUFS6 (-7.02 kcal/mol). Collectively, our findings suggested phloretin had effects of life expectancy enhancement and fitness promotion via redox regulations in vivo. NDUFS1/NUO-5 and NDUFS6/NDUF-6 might be new targets in the lifespan and wellness regulations.

Brown adipose tissue CoQ deficiency activates the integrated stress response and FGF21-dependent mitohormesis.

Coenzyme Q (CoQ) is essential for mitochondrial respiration and required for thermogenic activity in brown adipose tissues (BAT). CoQ deficiency leads to a wide range of pathological manifestations, but mechanistic consequences of CoQ deficiency in specific tissues, such as BAT, remain poorly understood. Here, we show that pharmacological or genetic CoQ deficiency in BAT leads to stress signals causing accumulation of cytosolic mitochondrial RNAs and activation of the eIF2α kinase PKR, resulting in activation of the integrated stress response (ISR) with suppression of UCP1 but induction of FGF21 expression. Strikingly, despite diminished UCP1 levels, BAT CoQ deficiency displays increased whole-body metabolic rates at room temperature and thermoneutrality resulting in decreased weight gain on high-fat diets (HFD). In line with enhanced metabolic rates, BAT and inguinal white adipose tissue (iWAT) interorgan crosstalk caused increased browning of iWAT in BAT-specific CoQ deficient animals. This mitohormesis-like effect depends on the ATF4-FGF21 axis and BAT-secreted FGF21, revealing an unexpected role for CoQ in the modulation of whole-body energy expenditure with wide-ranging implications for primary and secondary CoQ deficiencies.

Impact of Mitochondrial Architecture, Function, Redox Homeostasis, and Quality Control on Organismic Aging: Lessons from a Fungal Model System.

Significance: Mitochondria are eukaryotic organelles with various essential functions. They are both the source and the targets of reactive oxygen species (ROS). Different branches of a mitochondrial quality control system (mQCS), such as ROS balancing, degradation of damaged proteins, or whole mitochondria, can mitigate the adverse effects of ROS stress. However, the capacity of mQCS is limited. Overwhelming this capacity leads to dysfunctions and aging. Strategies to interfere into mitochondria-dependent human aging with the aim to increase the healthy period of life, the health span, rely on the precise knowledge of mitochondrial functions. Experimental models such as Podospora anserina, a filamentous fungus with a clear mitochondrial aging etiology, proved to be instrumental to reach this goal. Recent Advances: Investigations of the P. anserina mQCS revealed that it is constituted by a complex network of different branches. Moreover, mitochondrial architecture and lipid homeostasis emerged to affect aging. Critical Issues: The regulation of the mQCS is only incompletely understood. Details about the involved signaling molecules and interacting pathways remain to be elucidated. Moreover, most of the currently generated experimental data were generated in well-controlled experiments that do not reflect the constantly changing natural life conditions and bear the danger to miss relevant aspects leading to incorrect conclusions. Future Directions: In P. anserina, the precise impact of redox signaling as well as of molecular damaging for aging remains to be defined. Moreover, natural fluctuation of environmental conditions needs to be considered to generate a realistic picture of aging mechanisms as they developed during evolution.

The African killifish: A short-lived vertebrate model to study the biology of sarcopenia and longevity.

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish-an extremely short-lived vertebrate-revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span. In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Brain transcriptomic, metabolic and mitohormesis properties associated with N-propargylglycine treatment: A prevention strategy against neurodegeneration.

INTRODUCTION: There is an urgent need for new or repurposed therapeutics that protect against or significantly delay the clinical progression of neurodegenerative diseases, such as Huntington's disease (HD), Parkinson's disease and Alzheimer's disease. In particular, preclinical studies are needed for well tolerated and brain-penetrating small molecules capable of mitigating the proteotoxic mitochondrial processes that are hallmarks of these diseases. We identified a unique suicide inhibitor of mitochondrial proline dehydrogenase (Prodh), N-propargylglycine (N-PPG), which has anticancer and brain-enhancing mitohormesis properties, and we hypothesize that induction of mitohormesis by N-PPG protects against neurodegenerative diseases. We carried out a series of mouse studies designed to: i) compare brain and metabolic responses while on oral N-PPG treatment (50 mg/kg, 9-14 days) of B6CBA wildtype (WT) and short-lived transgenic R6/2 (HD) mice; and ii) evaluate potential brain and systemwide stress rebound responses in WT mice 2 months after cessation of extended mitohormesis induction by well-tolerated higher doses of N-PPG (100-200 mg/kg x 60 days). WT and HD mice showed comparable global evidence of N-PPG induced brain mitohormesis characterized by Prodh protein decay and increased mitochondrial expression of chaperone and Yme1l1 protease proteins. Interestingly, transcriptional analysis (RNAseq) showed partial normalization of HD whole brain transcriptomes toward those of WT mice. Comprehensive metabolomic profiles performed on control and N-PPG treated blood, brain, and kidney samples revealed expected N-PPG-induced tissue increases in proline levels in both WT and HD mice, accompanied by surprising parallel increases in hydroxyproline and sarcosine. Two months after cessation of the higher dose N-PPG stress treatments, WT mouse brains showed robust rebound increases in Prodh protein levels and mitochondrial transcriptome responses, as well as altered profiles of blood amino acid-related metabolites. Our HD and WT mouse preclinical findings point to the brain penetrating and mitohormesis-inducing potential of the drug candidate, N-PPG, and provide new rationale and application insights supporting its further preclinical testing in various models of neurodegenerative diseases characterized by loss of mitochondrial proteostasis.

Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging.

Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way to rapidly reduce age-related disease incidence in society. Several recent studies have found that a class of drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed as treatments for cancers and human immunodeficiency virus (HIV) infection, could be repurposed to slow the aging process. Interestingly, these studies propose complementary mechanisms that target multiple hallmarks of aging. At the molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting the hallmark of aging of 'Genomic Instability'. At the organellar level, NRTIs inhibit mitochondrial translation, activate ATF-4, suppress cytosolic translation, and extend lifespan in worms in a manner related to the 'Loss of Proteostasis' hallmark of aging. Meanwhile, at the cellular level, NRTIs inhibit the P2X7-mediated activation of the inflammasome, reducing inflammation and improving the hallmark of aging of 'Altered Intercellular Communication'. Future development of NRTIs for human aging health will need to balance out toxic side effects with the beneficial effects, which may occur in part through hormesis.

The bridge between cell survival and cell death: reactive oxygen species-mediated cellular stress.

As a requirement of aerobic metabolism, regulation of redox homeostasis is indispensable for the continuity of living homeostasis and life. Since the stability of the redox state is necessary for the maintenance of the biological functions of the cells, the balance between the pro-oxidants, especially ROS and the antioxidant capacity is kept in balance in the cells through antioxidant defense systems. The pleiotropic transcription factor, Nrf2, is the master regulator of the antioxidant defense system. Disruption of redox homeostasis leads to oxidative and reductive stress, bringing about multiple pathophysiological conditions. Oxidative stress characterized by high ROS levels causes oxidative damage to biomolecules and cell death, while reductive stress characterized by low ROS levels disrupt physiological cell functions. The fact that ROS, which were initially attributed as harmful products of aerobic metabolism, at the same time function as signal molecules at non-toxic levels and play a role in the adaptive response called mithormesis points out that ROS have a dose-dependent effect on cell fate determination. See also Figure 1(Fig. 1).

The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention.

Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment.

Transient inhibition of mitochondrial function by chrysin and apigenin prolong longevity via mitohormesis in C. elegans.

Mild inhibition of mitochondrial function leads to longevity. Genetic disruption of mitochondrial respiratory components either by mutation or RNAi greatly extends the lifespan in yeast, worms, and drosophila. This has given rise to the idea that pharmacologically inhibiting mitochondrial function would be a workable strategy for postponing aging. Toward this end, we used a transgenic worm strain that expresses the firefly luciferase enzyme widely to evaluate compounds by tracking real-time ATP levels. We identified chrysin and apigenin, which reduced ATP production and increased the lifespan of worms. Mechanistically, we discovered that chrysin and apigenin transiently inhibit mitochondrial respiration and induce an early ROS, and the lifespan-extending effect is dependent on transient ROS formation. We also show that AAK-2/AMPK, DAF-16/FOXO, and SKN-1/NRF-2 are required for chrysin or apigenin-mediated lifespan extension. Temporary increases in ROS levels trigger an adaptive response in a mitohormetic way, thereby increasing oxidative stress capacity and cellular metabolic adaptation, finally leading to longevity. Thus, chrysin and apigenin represent a class of compounds isolated from natural products that delay senescence and improve age-related diseases by inhibiting mitochondrial function and shed new light on the function of additional plant-derived polyphenols in enhancing health and delaying aging. Collectively, this work provides an avenue for pharmacological inhibition of mitochondrial function and the mechanism underlining their lifespan-extending properties.

Suboptimal Mitochondrial Activity Facilitates Nuclear Heat Shock Responses for Proteostasis and Genome Stability.

Thermal stress induces dynamic changes in nuclear proteins and relevant physiology as a part of the heat shock response (HSR). However, how the nuclear HSR is fine-tuned for cellular homeostasis remains elusive. Here, we show that mitochondrial activity plays an important role in nuclear proteostasis and genome stability through two distinct HSR pathways. Mitochondrial ribosomal protein (MRP) depletion enhanced the nucleolar granule formation of HSP70 and ubiquitin during HSR while facilitating the recovery of damaged nuclear proteins and impaired nucleocytoplasmic transport. Treatment of the mitochondrial proton gradient uncoupler masked MRP-depletion effects, implicating oxidative phosphorylation in these nuclear HSRs. On the other hand, MRP depletion and a reactive oxygen species (ROS) scavenger non-additively decreased mitochondrial ROS generation during HSR, thereby protecting the nuclear genome from DNA damage. These results suggest that suboptimal mitochondrial activity sustains nuclear homeostasis under cellular stress, providing plausible evidence for optimal endosymbiotic evolution via mitochondria-to-nuclear communication.

Mitochondrial stress and mitokines in aging.

Mitokines are signaling molecules that enable communication of local mitochondrial stress to other mitochondria in distant cells and tissues. Among those molecules are FGF21, GDF15 (both expressed in the nucleus) and several mitochondrial-derived peptides, including humanin. Their responsiveness to mitochondrial stress induces mitokine-signaling in response for example to exercise, following mitochondrial challenges in skeletal muscle. Such signaling is emerging as an important mediator of exercise-derived and dietary strategy-related molecular and systemic health benefits, including healthy aging. A compensatory increase in mitokine synthesis and secretion could preserve mitochondrial function and overall cellular vitality. Conversely, resistance against mitokine actions may also develop. Alterations of mitokine-levels, and therefore of mitokine-related inter-tissue cross talk, are associated with general aging processes and could influence the development of age-related chronic metabolic, cardiovascular and neurological diseases; whether these changes contribute to aging or represent "rescue factors" remains to be conclusively shown. The aim of the present review is to summarize the expanding knowledge on mitokines, the potential to modulate them by lifestyle and their involvement in aging and age-related diseases. We highlight the importance of well-balanced mitokine-levels, the preventive and therapeutic properties of maintaining mitokine homeostasis and sensitivity of mitokine signaling but also the risks arising from the dysregulation of mitokines. While reduced mitokine levels may impair inter-organ crosstalk, also excessive mitokine concentrations can have deleterious consequences and are associated with conditions such as cancer and heart failure. Preservation of healthy mitokine signaling levels can be achieved by regular exercise and is associated with an increased lifespan.

Insights on the role of L-lactate as a signaling molecule in skin aging.

L-lactate is a catabolite from the anaerobic metabolism of glucose, which plays a paramount role as a signaling molecule in various steps of the cell survival. Its activity, as a master tuner of many mechanisms underlying the aging process, for example in the skin, is still presumptive, however its crucial position in the complex cross-talk between mitochondria and the process of cell survival, should suggest that L-lactate may be not a simple waste product but a fine regulator of the aging/survival machinery, probably via mito-hormesis. Actually, emerging evidence is highlighting that ROS are crucial in the signaling of skin health, including mechanisms underlying wound repair, renewal and aging. The ROS, including superoxide anion, hydrogen peroxide, and nitric oxide, play both beneficial and detrimental roles depending upon their levels and cellular microenvironment. Physiological ROS levels are essential for cutaneous health and the wound repair process. Aberrant redox signaling activity drives chronic skin disease in elderly. On the contrary, impaired redox modulation, due to enhanced ROS generation and/or reduced levels of antioxidant defense, suppresses wound healing via promoting lymphatic/vascular endothelial cell apoptosis and death. This review tries to elucidate this issue.