scholarly journals Saccharomyces cerevisiae goes through distinct metabolic phases during its replicative lifespan

2018 ◽  
Author(s):  
Simeon Leupold ◽  
Georg Hubmann ◽  
Athanasios Litsios ◽  
Anne C. Meinema ◽  
Alexandros Papagiannakis ◽  
...  
Keyword(s):  
Metabolic Changes ◽  
Cellular Aging ◽  
Substrate Uptake ◽  
Comprehensive Description ◽  
Cellular Processes ◽  
Metabolic Fluxes ◽  
Age Related ◽  
Uptake Rates ◽  
Inference Methods ◽  
Holistic Description

A comprehensive description of the phenotypic changes during cellular aging is key towards unraveling its causal forces. Using recently developed experimental tools, which previously had enabled us to map age related changes in proteome and transcriptome (Janssens et al., 2015), and model-based inference methods, here, we generated a comprehensive account of the metabolic changes during the entire replicative life of Saecharomyces cerevisiae. With age, we found decreasing metabolite levels, decreasing growth and substrate uptake rates accompanied by a switch from aerobic fermentation to a respiratory metabolism, with increased glycerol and acetate production. The identification of intracellular metabolic fluxes revealed an increase in redox cofactor turnover, likely to combat the increased production of reactive oxygen species. The identified metabolic changes possibly reflect a dynamic adaptation to the age-associated, non- homeostatic increase in volume. With metabolism being an important factor of the cellular phenotype, this work complements our recent mapping of the transcriptomic and proteomic changes towards a holistic description of the cellular processes during aging.

scholarly journals Saccharomyces cerevisiae goes through distinct metabolic phases during its replicative lifespan

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Simeon Leupold ◽  
Georg Hubmann ◽  
Athanasios Litsios ◽  
Anne C Meinema ◽  
Vakil Takhaveev ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Metabolic Changes ◽  
Cellular Aging ◽  
Substrate Uptake ◽  
Cellular Phenotype ◽  
Experimental Procedure ◽  
Metabolic Fluxes ◽  
Age Related ◽  
Uptake Rates ◽  
Holistic Description

A comprehensive description of the phenotypic changes during cellular aging is key towards unraveling its causal forces. Previously, we mapped age-related changes in the proteome and transcriptome (Janssens et al., 2015). Here, employing the same experimental procedure and model-based inference, we generate a comprehensive account of metabolic changes during the replicative life of Saccharomyces cerevisiae. With age, we found decreasing metabolite levels, decreasing growth and substrate uptake rates accompanied by a switch from aerobic fermentation to respiration, with glycerol and acetate production. The identified metabolic fluxes revealed an increase in redox cofactor turnover, likely to combat increased production of reactive oxygen species. The metabolic changes are possibly a result of the age-associated decrease in surface area per cell volume. With metabolism being an important factor of the cellular phenotype, this work complements our recent mapping of the transcriptomic and proteomic changes towards a holistic description of the cellular phenotype during aging.

scholarly journals Crosstalk between Different DNA Repair Pathways Contributes to Neurodegenerative Diseases

Biology ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 163
Author(s):  
Swapnil Gupta ◽  
Panpan You ◽  
Tanima SenGupta ◽  
Hilde Nilsen ◽  
Kulbhushan Sharma
Keyword(s):  
Dna Repair ◽  
Neurodegenerative Diseases ◽  
3D Models ◽  
Model Systems ◽  
Spinocerebellar Ataxias ◽  
C Elegans ◽  
Cellular Processes ◽  
Age Related ◽  
Damage Response ◽  
Lateral Sclerosis

Genomic integrity is maintained by DNA repair and the DNA damage response (DDR). Defects in certain DNA repair genes give rise to many rare progressive neurodegenerative diseases (NDDs), such as ocular motor ataxia, Huntington disease (HD), and spinocerebellar ataxias (SCA). Dysregulation or dysfunction of DDR is also proposed to contribute to more common NDDs, such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Amyotrophic Lateral Sclerosis (ALS). Here, we present mechanisms that link DDR with neurodegeneration in rare NDDs caused by defects in the DDR and discuss the relevance for more common age-related neurodegenerative diseases. Moreover, we highlight recent insight into the crosstalk between the DDR and other cellular processes known to be disturbed during NDDs. We compare the strengths and limitations of established model systems to model human NDDs, ranging from C. elegans and mouse models towards advanced stem cell-based 3D models.

scholarly journals NAD+Metabolism in Aging and Cancer

2019 ◽  
Vol 3 (1) ◽  
pp. 105-130 ◽  
Author(s):  
Tyler G. Demarest ◽  
Mansi Babbar ◽  
Mustafa N. Okur ◽  
Xiuli Dan ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Accelerated Aging ◽  
Cancer Therapies ◽  
Nad Metabolism ◽  
Cellular Processes ◽  
Cancer Pathogenesis ◽  
Nicotinamide Mononucleotide ◽  
Age Related

Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

scholarly journals Lysosomal Exocytosis, Exosome Release and Secretory Autophagy: The Autophagic- and Endo-Lysosomal Systems Go Extracellular

2020 ◽  
Vol 21 (7) ◽  
pp. 2576 ◽  
Author(s):  
Sandra Buratta ◽  
Brunella Tancini ◽  
Krizia Sagini ◽  
Federica Delo ◽  
Elisabetta Chiaradia ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Cell Communication ◽  
Lysosomal Storage ◽  
Cellular Processes ◽  
Age Related ◽  
Extracellular Release ◽  
A Cell ◽  
Endosomal System

Beyond the consolidated role in degrading and recycling cellular waste, the autophagic- and endo-lysosomal systems play a crucial role in extracellular release pathways. Lysosomal exocytosis is a process leading to the secretion of lysosomal content upon lysosome fusion with plasma membrane and is an important mechanism of cellular clearance, necessary to maintain cell fitness. Exosomes are a class of extracellular vesicles originating from the inward budding of the membrane of late endosomes, which may not fuse with lysosomes but be released extracellularly upon exocytosis. In addition to garbage disposal tools, they are now considered a cell-to-cell communication mechanism. Autophagy is a cellular process leading to sequestration of cytosolic cargoes for their degradation within lysosomes. However, the autophagic machinery is also involved in unconventional protein secretion and autophagy-dependent secretion, which are fundamental mechanisms for toxic protein disposal, immune signalling and pathogen surveillance. These cellular processes underline the crosstalk between the autophagic and the endosomal system and indicate an intersection between degradative and secretory functions. Further, they suggest that the molecular mechanisms underlying fusion, either with lysosomes or plasma membrane, are key determinants to maintain cell homeostasis upon stressing stimuli. When they fail, the accumulation of undigested substrates leads to pathological consequences, as indicated by the involvement of autophagic and lysosomal alteration in human diseases, namely lysosomal storage disorders, age-related neurodegenerative diseases and cancer. In this paper, we reviewed the current knowledge on the functional role of extracellular release pathways involving lysosomes and the autophagic- and endo-lysosomal systems, evaluating their implication in health and disease.

scholarly journals Altered Nuclear Functions in Progeroid Syndromes: a Paradigm for Aging Research

2009 ◽  
Vol 9 ◽  
pp. 1449-1462 ◽  
Author(s):  
Baomin Li ◽  
Sonali Jog ◽  
Jose Candelario ◽  
Sita Reddy ◽  
Lucio Comai
Keyword(s):  
Werner Syndrome ◽  
Accelerated Aging ◽  
Natural Aging ◽  
Aging Research ◽  
Cellular Processes ◽  
Functional Connections ◽  
Age Related ◽  
Progeroid Syndromes ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Syndromes of accelerated aging could provide an entry point for identifying and dissecting the cellular pathways that are involved in the development of age-related pathologies in the general population. However, their usefulness for aging research has been controversial, as it has been argued that these diseases do not faithfully reflect the process of natural aging. Here we review recent findings on the molecular basis of two progeroid diseases, Werner syndrome (WS) and Hutchinson-Gilford progeria syndrome (HGPS), and highlight functional connections to cellular processes that may contribute to normal aging.

scholarly journals Disparate Central and Peripheral Effects of Circulating IGF-1 Deficiency on Tissue Mitochondrial Function

2019 ◽  
Vol 57 (3) ◽  
pp. 1317-1331 ◽  
Author(s):  
Gavin Pharaoh ◽  
Daniel Owen ◽  
Alexander Yeganeh ◽  
Pavithra Premkumar ◽  
Julie Farley ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cognitive Function ◽  
Spatial Learning ◽  
Mitochondrial Function ◽  
Coupling Efficiency ◽  
Redox Status ◽  
Cellular Aging ◽  
Age Related ◽  
The Brain ◽  
Circulating Levels

AbstractAge-related decline in circulating levels of insulin-like growth factor (IGF)-1 is associated with reduced cognitive function, neuronal aging, and neurodegeneration. Decreased mitochondrial function along with increased reactive oxygen species (ROS) and accumulation of damaged macromolecules are hallmarks of cellular aging. Based on numerous studies indicating pleiotropic effects of IGF-1 during aging, we compared the central and peripheral effects of circulating IGF-1 deficiency on tissue mitochondrial function using an inducible liver IGF-1 knockout (LID). Circulating levels of IGF-1 (~ 75%) were depleted in adult male Igf1f/f mice via AAV-mediated knockdown of hepatic IGF-1 at 5 months of age. Cognitive function was evaluated at 18 months using the radial arm water maze and glucose and insulin tolerance assessed. Mitochondrial function was analyzed in hippocampus, muscle, and visceral fat tissues using high-resolution respirometry O2K as well as redox status and oxidative stress in the cortex. Peripherally, IGF-1 deficiency did not significantly impact muscle mass or mitochondrial function. Aged LID mice were insulin resistant and exhibited ~ 60% less adipose tissue but increased fat mitochondrial respiration (20%). The effects on fat metabolism were attributed to increases in growth hormone. Centrally, IGF-1 deficiency impaired hippocampal-dependent spatial acquisition as well as reversal learning in male mice. Hippocampal mitochondrial OXPHOS coupling efficiency and cortex ATP levels (~ 50%) were decreased and hippocampal oxidative stress (protein carbonylation and F2-isoprostanes) was increased. These data suggest that IGF-1 is critical for regulating mitochondrial function, redox status, and spatial learning in the central nervous system but has limited impact on peripheral (liver and muscle) metabolism with age. Therefore, IGF-1 deficiency with age may increase sensitivity to damage in the brain and propensity for cognitive deficits. Targeting mitochondrial function in the brain may be an avenue for therapy of age-related impairment of cognitive function. Regulation of mitochondrial function and redox status by IGF-1 is essential to maintain brain function and coordinate hippocampal-dependent spatial learning. While a decline in IGF-1 in the periphery may be beneficial to avert cancer progression, diminished central IGF-1 signaling may mediate, in part, age-related cognitive dysfunction and cognitive pathologies potentially by decreasing mitochondrial function.

scholarly journals Mitochondrial DNA Variants and Common Diseases: A Mathematical Model for the Diversity of Age-Related mtDNA Mutations

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 608 ◽  
Author(s):  
Huanzheng Li ◽  
Jesse Slone ◽  
Lin Fei ◽  
Taosheng Huang
Keyword(s):  
Mutation Rate ◽  
Nuclear Dna ◽  
Eukaryotic Cell ◽  
Cellular Aging ◽  
Mtdna Mutation ◽  
Proliferating Cells ◽  
Mtdna Mutations ◽  
Common Diseases ◽  
Age Related ◽  
Primary Driver

The mitochondrion is the only organelle in the human cell, besides the nucleus, with its own DNA (mtDNA). Since the mitochondrion is critical to the energy metabolism of the eukaryotic cell, it should be unsurprising, then, that a primary driver of cellular aging and related diseases is mtDNA instability over the life of an individual. The mutation rate of mammalian mtDNA is significantly higher than the mutation rate observed for nuclear DNA, due to the poor fidelity of DNA polymerase and the ROS-saturated environment present within the mitochondrion. In this review, we will discuss the current literature showing that mitochondrial dysfunction can contribute to age-related common diseases such as cancer, diabetes, and other commonly occurring diseases. We will then turn our attention to the likely role that mtDNA mutation plays in aging and senescence. Finally, we will use this context to develop a mathematical formula for estimating for the accumulation of somatic mtDNA mutations with age. This resulting model shows that almost 90% of non-proliferating cells would be expected to have at least 100 mutations per cell by the age of 70, and almost no cells would have fewer than 10 mutations, suggesting that mtDNA mutations may contribute significantly to many adult onset diseases.

[P1-432]: ANTERIOR CINGULATE CORTEX EXHIBITS AGE-RELATED METABOLIC CHANGES: CORRELATION WITH BEHAVIORAL PERFORMANCE IN ATTENTION TASK

2017 ◽  
Vol 13 (7S_Part_8) ◽  
pp. P446-P447
Author(s):  
Pui Wai Chiu ◽  
Hui Zhang ◽  
Wai Ho Savio Wong ◽  
Tianyan Liu ◽  
Gloria Hoi Yan Wong ◽  
...  
Keyword(s):  
Anterior Cingulate Cortex ◽  
Cingulate Cortex ◽  
Metabolic Changes ◽  
Anterior Cingulate ◽  
Behavioral Performance ◽  
Attention Task ◽  
Age Related

AMPKα2 deficiency uncovers time dependency in the regulation of contraction-induced palmitate and glucose uptake in mouse muscle

2011 ◽  
Vol 111 (1) ◽  
pp. 125-134 ◽  
Author(s):  
Marcia J. Abbott ◽  
Lindsey D. Bogachus ◽  
Lorraine P. Turcotte
Keyword(s):  
Skeletal Muscle ◽  
Protein Kinase ◽  
Muscle Contraction ◽  
Glucose Uptake ◽  
Time Dependent ◽  
Substrate Uptake ◽  
Dependent Manner ◽  
Mouse Muscle ◽  
Uptake Rates ◽  
Intracellular Ca

AMP-activated protein kinase (AMPK) is a fuel sensor in skeletal muscle with multiple downstream signaling targets that may be triggered by increases in intracellular Ca2+ concentration ([Ca2+]). The purpose of this study was to determine whether increases in intracellular [Ca2+] induced by caffeine act solely via AMPKα2 and whether AMPKα2 is essential to increase glucose uptake, fatty acid (FA) uptake, and FA oxidation in contracting skeletal muscle. Hindlimbs from wild-type (WT) or AMPKα2 dominant-negative (DN) transgene mice were perfused during rest ( n = 11), treatment with 3 mM caffeine ( n = 10), or muscle contraction ( n = 11). Time-dependent effects on glucose and FA uptake were uncovered throughout the 20-min muscle contraction perfusion period ( P < 0.05). Glucose uptake rates did not increase in DN mice during muscle contraction until the last 5 min of the protocol ( P < 0.05). FA uptake rates were elevated at the onset of muscle contraction and diminished by the end of the protocol in DN mice ( P < 0.05). FA oxidation rates were abolished in the DN mice during muscle contraction ( P < 0.05). The DN transgene had no effect on caffeine-induced FA uptake and oxidation ( P > 0.05). Glucose uptake rates were blunted in caffeine-treated DN mice ( P < 0.05). The DN transgene resulted in a greater use of intramuscular triglycerides as a fuel source during muscle contraction. The DN transgene did not alter caffeine- or contraction-mediated changes in the phosphorylation of Ca2+/calmodulin-dependent protein kinase I or ERK1/2 ( P > 0.05). These data suggest that AMPKα2 is involved in the regulation of substrate uptake in a time-dependent manner in contracting muscle but is not necessary for regulation of FA uptake and oxidation during caffeine treatment.

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