Abl depletion via autophagy mediates the beneficial effects of quercetin against Alzheimer pathology across species.

Alzheimer's disease is the most common age-associated neurodegenerative disorder and the most frequent form of dementia in our society. Aging is a complex biological process concurrently shaped by genetic, dietary and environmental factors and natural compounds are emerging for their beneficial effects against age-related disorders. Besides their antioxidant activity often described in simple model organisms, the molecular mechanisms underlying the beneficial effects of different dietary compounds remain however largely unknown.

Mitochondria hormesis delays aging and associated diseases in impacting on key ferroptosis players.

Excessive iron accumulation or deficiency leads to a variety of pathologies in humans and developmental arrest in the nematode . Instead, sub-lethal iron depletion extends lifespan. Hypoxia preconditioning protects against severe hypoxia-induced neuromuscular damage across species but it has low feasible application.

Cobalt chloride has beneficial effects across species through a hormetic mechanism.

Severe oxygen and iron deficiencies have evolutionarily conserved detrimental effects, leading to pathologies in mammals and developmental arrest as well as neuromuscular degeneration in the nematode Yet, similar to the beneficial effects of mild hypoxia, non-toxic levels of iron depletion, achieved with the iron chelator bipyridine or through frataxin silencing, extend lifespan through hypoxia-like induction of mitophagy. While the positive health outcomes of hypoxia preconditioning are evident, its practical application is rather challenging. Here, we thus test the potential beneficial effects of non-toxic, preconditioning interventions acting on iron instead of oxygen availability.

Neuroligin-mediated neurodevelopmental defects are induced by mitochondrial dysfunction and prevented by lutein in C. elegans.

Complex-I-deficiency represents the most frequent pathogenetic cause of human mitochondriopathies. Therapeutic options for these neurodevelopmental life-threating disorders do not exist, partly due to the scarcity of appropriate model systems to study them. Caenorhabditis elegans is a genetically tractable model organism widely used to investigate neuronal pathologies.

Aryl Hydrocarbon Receptor-Dependent and -Independent Pathways Mediate Curcumin Anti-Aging Effects.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose activity can be modulated by polyphenols, such as curcumin. AhR and curcumin have evolutionarily conserved effects on aging. Here, we investigated whether and how the AhR mediates the anti-aging effects of curcumin across species.

Insights into cisplatin-induced neurotoxicity and mitochondrial dysfunction in Caenorhabditis elegans.

Cisplatin is the most common drug in first-line chemotherapy against solid tumors. We and others have previously used the nematode Caenorhabditis elegans to identify genetic factors influencing the sensitivity and resistance to cisplatin. In this study, we used C.

High-Content Screen Identifies Natural Compounds Impacting Mitochondria-Lipid Homeostasis and Promoting Healthspan.

The aging process is concurrently shaped by genetic and extrinsic factors. In this work, we screened a small library of natural compounds, many of marine origin, to identify novel possible anti-aging interventions in , a powerful model organism for aging studies. To this aim, we exploited a high-content microscopy platform to search for interventions able to induce phenotypes associated with mild mitochondrial stress, which is known to promote animal's health- and lifespan.

Dietary and environmental factors have opposite AhR-dependent effects on healthspan.

Genetic, dietary, and environmental factors concurrently shape the aging process. The aryl hydrocarbon receptor (AhR) was discovered as a dioxin-binding transcription factor involved in the metabolism of different environmental toxicants in vertebrates. Since then, the variety of pathophysiological processes regulated by the AhR has grown, ranging from immune response, metabolic pathways, and aging.

Mitophagy and iron: two actors sharing the stage in age-associated neuronal pathologies.

Aging is characterized by the deterioration of different cellular and organismal structures and functions. A typical hallmark of the aging process is the accumulation of dysfunctional mitochondria and excess iron, leading to a vicious cycle that promotes cell and tissue damage, which ultimately contribute to organismal aging. Accordingly, altered mitochondrial quality control pathways such as mitochondrial autophagy (mitophagy) as well as altered iron homeostasis, with consequent iron overload, can accelerate the aging process and the development and progression of different age-associated disorders.

AHR Signaling Dampens Inflammatory Signature in Neonatal Skin γδ T Cells.

Background Aryl hydrocarbon receptor (AHR)-deficient mice do not support the expansion of dendritic epidermal T cells (DETC), a resident immune cell population in the murine epidermis, which immigrates from the fetal thymus to the skin around birth. Material and Methods In order to identify the gene expression changes underlying the DETC disappearance in AHR-deficient mice, we analyzed microarray RNA-profiles of DETC, sorted from the skin of two-week-old AHR-deficient mice and their heterozygous littermates. In vitro studies were done for verification, and IL-10, AHR repressor (AHRR), and c-Kit deficient mice analyzed for DETC frequency.

Mitochondrial bioenergetic changes during development as an indicator of health-span.

Mild suppression of mitochondrial activity has beneficial effects across species. The nematode is a versatile, genetically tractable model organism widely employed for aging studies, which has led to the identification of many of the known evolutionarily conserved mechanisms regulating lifespan. In the pro-longevity effect of reducing mitochondrial function, for example by RNA interference, is only achieved if mitochondrial stress is applied during larval development.

BRCA1 and BARD1 mediate apoptotic resistance but not longevity upon mitochondrial stress in .

Interventions that promote healthy aging are typically associated with increased stress resistance. Paradoxically, reducing the activity of core biological processes such as mitochondrial or insulin metabolism promotes the expression of adaptive responses, which in turn increase animal longevity and resistance to stress. In this study, we investigated the relation between the extended lifespan elicited by reduction in mitochondrial functionality and resistance to genotoxic stress.

HDAC inhibition improves autophagic and lysosomal function to prevent loss of subcutaneous fat in a mouse model of Cockayne syndrome.

Cockayne syndrome (CS), a hereditary form of premature aging predominantly caused by mutations in the gene, affects multiple organs including skin where it manifests with hypersensitivity toward ultraviolet (UV) radiation and loss of subcutaneous fat. There is no curative treatment for CS, and its pathogenesis is only partially understood. Originally considered for its role in DNA repair, Cockayne syndrome group B (CSB) protein most likely serves additional functions.

Constitutive MAP-kinase activation suppresses germline apoptosis in NTH-1 DNA glycosylase deficient C. elegans.

Oxidation of DNA bases, an inevitable consequence of oxidative stress, requires the base excision repair (BER) pathway for repair. Caenorhabditis elegans is a well-established model to study phenotypic consequences and cellular responses to oxidative stress. To better understand how BER affects phenotypes associated with oxidative stress, we characterised the C.

Crosstalk of clock gene expression and autophagy in aging.

Autophagy and the circadian clock counteract tissue degeneration and support longevity in many organisms. Accumulating evidence indicates that aging compromises both the circadian clock and autophagy but the mechanisms involved are unknown. Here we show that the expression levels of transcriptional repressor components of the circadian oscillator, most prominently the human Period homologue , are strongly reduced in primary dermal fibroblasts from aged humans, while raising the expression of in the same cells partially restores diminished autophagy levels.

Iron-Starvation-Induced Mitophagy Mediates Lifespan Extension upon Mitochondrial Stress in C. elegans.

Frataxin is a nuclear-encoded mitochondrial protein involved in the biogenesis of Fe-S-cluster-containing proteins and consequently in the functionality of the mitochondrial respiratory chain. Similar to other proteins that regulate mitochondrial respiration, severe frataxin deficiency leads to pathology in humans--Friedreich's ataxia, a life-threatening neurodegenerative disorder--and to developmental arrest in the nematode C. elegans.

Mitochondrial stress extends lifespan in C. elegans through neuronal hormesis.

Progressive neuronal deterioration accompanied by sensory functions decline is typically observed during aging. On the other hand, structural or functional alterations of specific sensory neurons extend lifespan in the nematode Caenorhabditis elegans. Hormesis is a phenomenon by which the body benefits from moderate stress of various kinds which at high doses are harmful.

The interplay between mitochondria and autophagy and its role in the aging process.

Mitochondria are highly dynamic organelles which play a central role in cellular homeostasis. Mitochondrial dysfunction leads to life-threatening disorders and accelerates the aging process. Surprisingly, on the other hand, a mild reduction of mitochondria functionality can have pro-longevity effects in organisms spanning from yeast to mammals.

A de novo X;8 translocation creates a PTK2-THOC2 gene fusion with THOC2 expression knockdown in a patient with psychomotor retardation and congenital cerebellar hypoplasia.

Background And Aim: We identified a balanced de novo translocation involving chromosomes Xq25 and 8q24 in an eight year-old girl with a non-progressive form of congenital ataxia, cognitive impairment and cerebellar hypoplasia.

Methods And Results: Breakpoint definition showed that the promoter of the Protein Tyrosine Kinase 2 (PTK2, also known as Focal Adhesion Kinase, FAK) gene on chromosome 8q24.3 is translocated 2 kb upstream of the THO complex subunit 2 (THOC2) gene on chromosome Xq25.

Autophagy induction extends lifespan and reduces lipid content in response to frataxin silencing in C. elegans.

Severe mitochondria deficiency leads to a number of devastating degenerative disorders, yet, mild mitochondrial dysfunction in different species, including the nematode Caenorhabditis elegans, can have pro-longevity effects. This apparent paradox indicates that cellular adaptation to partial mitochondrial stress can induce beneficial responses, but how this is achieved is largely unknown. Complete absence of frataxin, the mitochondrial protein defective in patients with Friedreich's ataxia, is lethal in C.