Research

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23 pages, 4508 KiB

Open AccessArticle

by Mateusz Mołoń, Karolina Stępień, Patrycja Kielar, Bela Vasileva, Bonka Lozanska, Dessislava Staneva, Penyo Ivanov, Monika Kula-Maximenko, Eliza Molestak, Marek Tchórzewski, George Miloshev and Milena Georgieva

Cells 2022, 11(17), 2754; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172754 - 03 Sep 2022

Cited by 1 | Viewed by 1953

Abstract

Ageing is accompanied by dramatic changes in chromatin structure organization and genome function. Two essential components of chromatin, the linker histone Hho1p and actin-related protein 4 (Arp4p), have been shown to physically interact in Saccharomyces cerevisiae cells, thus maintaining chromatin dynamics and function, [...] Read more.

Ageing is accompanied by dramatic changes in chromatin structure organization and genome function. Two essential components of chromatin, the linker histone Hho1p and actin-related protein 4 (Arp4p), have been shown to physically interact in Saccharomyces cerevisiae cells, thus maintaining chromatin dynamics and function, as well as genome stability and cellular morphology. Disrupting this interaction has been proven to influence the stability of the yeast genome and the way cells respond to stress during chronological ageing. It has also been proven that the abrogated interaction between these two chromatin proteins elicited premature ageing phenotypes. Alterations in chromatin compaction have also been associated with replicative ageing, though the main players are not well recognized. Based on this knowledge, here, we examine how the interaction between Hho1p and Arp4p impacts the ageing of mitotically active yeast cells. For this purpose, two sets of strains were used—haploids (WT(n), arp4, hho1Δ and arp4 hho1Δ) and their heterozygous diploid counterparts (WT(2n), ARP4/arp4, HHO1/hho1Δ and ARP4 HHO1/arp4 hho1Δ)—for the performance of extensive morphological and physiological analyses during replicative ageing. These analyses included a comparative examination of the yeast cells’ chromatin structure, proliferative and reproductive potential, and resilience to stress, as well as polysome profiles and chemical composition. The results demonstrated that the haploid chromatin mutants arp4 and arp4 hho1Δ demonstrated a significant reduction in replicative and total lifespan. These findings lead to the conclusion that the importance of a healthy interaction between Arp4p and Hho1p in replicative ageing is significant. This is proof of the concomitant importance of Hho1p and Arp4p in chronological and replicative ageing. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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21 pages, 4893 KiB

Open AccessArticle

Depletion of the Origin Recognition Complex Subunits Delays Aging in Budding Yeast

by Karolina Stępień, Adrianna Skoneczna, Monika Kula-Maximenko, Łukasz Jurczyk and Mateusz Mołoń

Cells 2022, 11(8), 1252; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11081252 - 07 Apr 2022

Cited by 5 | Viewed by 2391

Abstract

Precise DNA replication is pivotal for ensuring the accurate inheritance of genetic information. To avoid genetic instability, each DNA fragment needs to be amplified only once per cell cycle. DNA replication in eukaryotes starts with the binding of the origin recognition complex (ORC) [...] Read more.

Precise DNA replication is pivotal for ensuring the accurate inheritance of genetic information. To avoid genetic instability, each DNA fragment needs to be amplified only once per cell cycle. DNA replication in eukaryotes starts with the binding of the origin recognition complex (ORC) to the origins of DNA replication. The genes encoding ORC subunits have been conserved across eukaryotic evolution and are essential for the initiation of DNA replication. In this study, we conducted an extensive physiological and aging-dependent analysis of heterozygous cells lacking one copy of ORC genes in the BY4743 background. Cells with only one copy of the ORC genes showed a significant decrease in the level of ORC mRNA, a delay in the G1 phase of the cell cycle, and an extended doubling time. Here, we also show that the reducing the levels of Orc1-6 proteins significantly extends both the budding and average chronological lifespans. Heterozygous ORC/orcΔ and wild-type diploid cells easily undergo haploidization during chronological aging. This ploidy shift might be related to nutrient starvation or the inability to survive under stress conditions. A Raman spectroscopy analysis helped us to strengthen the hypothesis of the importance of lipid metabolism and homeostasis in aging. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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14 pages, 4213 KiB

Open AccessArticle

Iron Supplementation Delays Aging and Extends Cellular Lifespan through Potentiation of Mitochondrial Function

by Jovian Lin Jing, Trishia Cheng Yi Ning, Federica Natali, Frank Eisenhaber and Mohammad Alfatah

Cells 2022, 11(5), 862; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050862 - 02 Mar 2022

Cited by 9 | Viewed by 4089

Abstract

Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, [...] Read more.

Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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15 pages, 23943 KiB

Open AccessArticle

Flavonoids from Sacred Lotus Stamen Extract Slows Chronological Aging in Yeast Model by Reducing Oxidative Stress and Maintaining Cellular Metabolism

by Duangjai Tungmunnithum, Samantha Drouet and Christophe Hano

Cells 2022, 11(4), 599; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040599 - 09 Feb 2022

Cited by 10 | Viewed by 2669

Abstract

Nelumbo nucifera is one of the most valuable medicinal species of the Nelumbonaceae family that has been consumed since the ancient historic period. Its stamen is an indispensable ingredient for many recipes of traditional medicines, and has been proved as a rich source [...] Read more.

Nelumbo nucifera is one of the most valuable medicinal species of the Nelumbonaceae family that has been consumed since the ancient historic period. Its stamen is an indispensable ingredient for many recipes of traditional medicines, and has been proved as a rich source of flavonoids that may provide an antiaging action for pharmaceutical or medicinal applications. However, there is no intense study on antiaging potential and molecular mechanisms. This present study was designed to fill in this important research gap by: (1) investigating the effects of sacred lotus stamen extract (LSE) on yeast lifespan extension; and (2) determining their effects on oxidative stress and metabolism to understand the potential antiaging action of its flavonoids. A validated ultrasound-assisted extraction method was also employed in this current work. The results confirmed that LSE is rich in flavonoids, and myricetin-3-O-glucose, quercetin-3-O-glucuronic acid, kaempferol-3-O-glucuronic acid, and isorhamnetin-3-O-glucose are the most abundant ones. In addition, LSE offers a high antioxidant capacity, as evidenced by different in vitro antioxidant assays. This present study also indicated that LSE delayed yeast (Saccharomyces cerevisiae, wild-type strain DBY746) chronological aging compared with untreated control yeast and a positive control (resveratrol) cells. Moreover, LSE acted on central metabolism, gene expressions (SIR2 and SOD2), and enzyme regulation (SIRT and SOD enzymatic activities). These findings are helpful to open the door for the pharmaceutical and medical sectors to employ this potential lotus raw material in their future pharmaceutical product development. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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19 pages, 3331 KiB

Open AccessArticle

Aging of Podospora anserina Leads to Alterations of OXPHOS and the Induction of Non-Mitochondrial Salvage Pathways

by Verena Warnsmann, Jana Meisterknecht, Ilka Wittig and Heinz D. Osiewacz

Cells 2021, 10(12), 3319; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10123319 - 26 Nov 2021

Cited by 3 | Viewed by 1896

Abstract

The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of [...] Read more.

The accumulation of functionally impaired mitochondria is a key event in aging. Previous works with the fungal aging model Podospora anserina demonstrated pronounced age-dependent changes of mitochondrial morphology and ultrastructure, as well as alterations of transcript and protein levels, including individual proteins of the oxidative phosphorylation (OXPHOS). The identified protein changes do not reflect the level of the whole protein complexes as they function in-vivo. In the present study, we investigated in detail the age-dependent changes of assembled mitochondrial protein complexes, using complexome profiling. We observed pronounced age-depen-dent alterations of the OXPHOS complexes, including the loss of mitochondrial respiratory supercomplexes (mtRSCs) and a reduction in the abundance of complex I and complex IV. Additionally, we identified a switch from the standard complex IV-dependent respiration to an alternative respiration during the aging of the P. anserina wild type. Interestingly, we identified proteasome components, as well as endoplasmic reticulum (ER) proteins, for which the recruitment to mitochondria appeared to be increased in the mitochondria of older cultures. Overall, our data demonstrate pronounced age-dependent alterations of the protein complexes involved in energy transduction and suggest the induction of different non-mitochondrial salvage pathways, to counteract the age-dependent mitochondrial impairments which occur during aging. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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21 pages, 3970 KiB

Open AccessArticle

Mitochondrial Phospholipid Homeostasis Is Regulated by the i-AAA Protease PaIAP and Affects Organismic Aging

by Timo Löser, Aljoscha Joppe, Andrea Hamann and Heinz D. Osiewacz

Cells 2021, 10(10), 2775; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102775 - 16 Oct 2021

Cited by 7 | Viewed by 2313

Abstract

Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological [...] Read more.

Mitochondria are ubiquitous organelles of eukaryotic organisms with a number of essential functions, including synthesis of iron-sulfur clusters, amino acids, lipids, and adenosine triphosphate (ATP). During aging of the fungal aging model Podospora anserina, the inner mitochondrial membrane (IMM) undergoes prominent morphological alterations, ultimately resulting in functional impairments. Since phospholipids (PLs) are key components of biological membranes, maintenance of membrane plasticity and integrity via regulation of PL biosynthesis is indispensable. Here, we report results from a lipidomic analysis of isolated mitochondria from P. anserina that revealed an age-related reorganization of the mitochondrial PL profile and the involvement of the i-AAA protease PaIAP in proteolytic regulation of PL metabolism. The absence of PaIAP enhances biosynthesis of characteristic mitochondrial PLs, leads to significant alterations in the acyl composition of the mitochondrial signature PL cardiolipin (CL), and induces mitophagy. These alterations presumably cause the lifespan increase of the PaIap deletion mutant under standard growth conditions. However, PaIAP is required at elevated temperatures and for degradation of superfluous CL synthase PaCRD1 during glycolytic growth. Overall, our study uncovers a prominent role of PaIAP in the regulation of PL homeostasis in order to adapt membrane plasticity to fluctuating environmental conditions as they occur in nature. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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13 pages, 1988 KiB

Open AccessArticle

Identification of Tropical Plant Extracts That Extend Yeast Chronological Life Span

by Mandy Mun Yee Kwong, Jee Whu Lee, Mohammed Razip Samian, Habibah A. Wahab, Nobumoto Watanabe and Eugene Boon Beng Ong

Cells 2021, 10(10), 2718; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10102718 - 11 Oct 2021

Cited by 4 | Viewed by 2423

Abstract

Certain plant extracts (PEs) contain bioactive compounds that have antioxidant and lifespan-extending activities on organisms. These PEs play different roles in cellular processes, such as enhancing stress resistance and modulating longevity-defined signaling pathways that contribute to longevity. Here, we report the discovery of [...] Read more.

Certain plant extracts (PEs) contain bioactive compounds that have antioxidant and lifespan-extending activities on organisms. These PEs play different roles in cellular processes, such as enhancing stress resistance and modulating longevity-defined signaling pathways that contribute to longevity. Here, we report the discovery of PEs that extended chronological life span (CLS) in budding yeast from a screen of 222 PEs. We identified two PEs, the leaf extracts of Manihot esculenta and Wodyetia bifurcata that extended CLS in a dose-dependent manner. The CLS-extending PEs also conferred oxidative stress tolerance, suggesting that these PEs might extend yeast CLS through the upregulation of stress response pathways. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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17 pages, 2112 KiB

Open AccessArticle

MNase Digestion Protection Patterns of the Linker DNA in Chromatosomes

by Chang-Hui Shen and James Allan

Cells 2021, 10(9), 2239; https://0-doi-org.brum.beds.ac.uk/10.3390/cells10092239 - 29 Aug 2021

Viewed by 4238

Abstract

The compact nucleosomal structure limits DNA accessibility and regulates DNA-dependent cellular activities. Linker histones bind to nucleosomes and compact nucleosomal arrays into a higher-order chromatin structure. Recent developments in high throughput technologies and structural computational studies provide nucleosome positioning at a high resolution [...] Read more.

The compact nucleosomal structure limits DNA accessibility and regulates DNA-dependent cellular activities. Linker histones bind to nucleosomes and compact nucleosomal arrays into a higher-order chromatin structure. Recent developments in high throughput technologies and structural computational studies provide nucleosome positioning at a high resolution and contribute to the information of linker histone location within a chromatosome. However, the precise linker histone location within the chromatin fibre remains unclear. Using monomer extension, we mapped core particle and chromatosomal positions over a core histone-reconstituted, 1.5 kb stretch of DNA from the chicken adult β-globin gene, after titration with linker histones and linker histone globular domains. Our results show that, although linker histone globular domains and linker histones display a wide variation in their binding affinity for different positioned nucleosomes, they do not alter nucleosome positions or generate new nucleosome positions. Furthermore, the extra ~20 bp of DNA protected in a chromatosome is usually symmetrically distributed at each end of the core particle, suggesting linker histones or linker histone globular domains are located close to the nucleosomal dyad axis. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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Review

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16 pages, 2836 KiB

Open AccessEditor’s ChoiceReview

Yeast Chronological Lifespan: Longevity Regulatory Genes and Mechanisms

by Mario G. Mirisola and Valter D. Longo

Cells 2022, 11(10), 1714; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11101714 - 23 May 2022

Cited by 15 | Viewed by 4990

Abstract

S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has [...] Read more.

S. cerevisiae plays a pivotal role as a model system in understanding the biochemistry and molecular biology of mammals including humans. A considerable portion of our knowledge on the genes and pathways involved in cellular growth, resistance to toxic agents, and death has in fact been generated using this model organism. The yeast chronological lifespan (CLS) is a paradigm to study age-dependent damage and longevity. In combination with powerful genetic screening and high throughput technologies, the CLS has allowed the identification of longevity genes and pathways but has also introduced a unicellular “test tube” model system to identify and study macromolecular and cellular damage leading to diseases. In addition, it has played an important role in studying the nutrients and dietary regimens capable of affecting stress resistance and longevity and allowing the characterization of aging regulatory networks. The parallel description of the pro-aging roles of homologs of RAS, S6 kinase, adenylate cyclase, and Tor in yeast and in higher eukaryotes in S. cerevisiae chronological survival studies is valuable to understand human aging and disease. Here we review work on the S. cerevisiae chronological lifespan with a focus on the genes regulating age-dependent macromolecular damage and longevity extension. Full article

(This article belongs to the Special Issue Yeast as a Model in Aging Research)

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