scholarly journals Clonal expansion of mitochondrial DNA deletions is a private mechanism of ageing in long-lived animals

2018 ◽  
Author(s):  
Lakshmi Narayanan Lakshmanan ◽  
Zhuangli Yee ◽  
Li Fang Ng ◽  
Rudiyanto Gunawan ◽  
Barry Halliwell ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Functional Decline ◽  
Computational Modelling ◽  
Clonal Expansion ◽  
Mtdna Mutation ◽  
C Elegans ◽  
Mtdna Deletions ◽  
Age Dependent ◽  
And Function

SummaryDisruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of ageing (López-Otín et al. 2013). Human ageing is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle ageing is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions co-localize with sites of fiber-breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age-dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans ageing. Here we report identification of 266 novel mtDNA deletions in ageing nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (1) mtDNA deletions in nematode is extremely rare, (2) there is no significant age-dependent increase in mtDNA deletions and (3) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age-dependent functional decline commonly observed in C. elegans. Computational modelling of mtDNA dynamics in C. elegans indicates that the lifespan of short-lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of ageing predominantly relevant in long-lived animals such as humans and rhesus monkey and possibly in rodents.

128 MITOCHONDRIAL DNA DELETIONS IN RHESUS MACAQUE OOCYTES, EMBRYOS, AND ADULT AND EMBRYONIC STEM CELLS

2006 ◽  
Vol 18 (2) ◽  
pp. 173
Author(s):  
T. Gibson ◽  
T. Quebedeaux ◽  
S. Rajasekaran ◽  
C. Brenner
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Mitochondrial Dna ◽  
Embryonic Stem Cells ◽  
Rhesus Macaque ◽  
Rhesus Macaques ◽  
Embryonic Stem ◽  
Immature Oocytes ◽  
Mtdna Deletions ◽  
Common Deletion

Mitochondria are the most abundant organelles in mammalian oocytes and early embryos. Previous data have shown that mitochondrial DNA (mtDNA) deletions are present both in human oocytes and in embryos from in vitro fertilization (IVF) patients and suggest that accumulation of these deletions may contribute to mitochondrial dysfunction and impaired ATP production. In addition, high levels of mitochondrial mutations are present in skeletal muscle fibers from aged rhesus macaques. The specific aims of this study were to determine whether the mitochondrial common deletion is present in non-human primate oocytes and embryos generated by IVF and to determine whether mtDNA mutations are already present in immature oocytes from rhesus ovaries. Using a nested primer polymerase chain reaction (PCR) strategy, we determined the frequency of the rhesus common deletion in immature oocytes compared with stimulated oocytes and embryos. There was a low incidence (21%) of the rhesus common deletion present in immature, unstimulated oocytes derived from necropsied ovaries of 2 to 10-yr-old rhesus macaques. However, there was >3-fold increase (71.4%) in the frequency of deleted mtDNA in stimulated oocytes and IVF embryos from age-matched fertile monkeys. We postulated that, in addition to skeletal muscle, a similar time-dependent accumulation of mtDNA deletions occurs in fertile rhesus macaque oocytes and embryos. We are now investigating the effects of culture and passage number on mtDNA deletions in primate adult and embryonic stem cells. We propose the rhesus monkey to be an excellent model to assess the quality of gametes and embryos, as well as stem cells, and their developmental competence in human and non-human primates. This study was supported by National Institutes of Health grants RR15395 and HD045966.

scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in Caenorhabditis elegans

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Chaolie Huang ◽  
Sara Wagner-Valladolid ◽  
Amberley D Stephens ◽  
Raimund Jung ◽  
Chetan Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Aging Process ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
Molecular Feature ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Tissue Aging ◽  
Different Tissues

Reduced protein homeostasis leading to increased protein instability is a common molecular feature of aging, but it remains unclear whether this is a cause or consequence of the aging process. In neurodegenerative diseases and other amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological aggregates in different tissues. More recently, widespread protein aggregation has been described during normal aging. Until now, an extensive characterization of the nature of age-dependent protein aggregation has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and have an amyloid-like structure resembling that of protein aggregates observed in disease. We then demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these findings imply that amyloid-like aggregates contribute to the aging process and therefore could be important targets for strategies designed to maintain physiological functions in the late stages of life.

scholarly journals A genetic screen identifies processes that couple oocyte maturation to proteostasis in the immortal C. elegans germ lineage

2020 ◽  
Author(s):  
Madhuja Samaddar ◽  
Jérôme Goudeau ◽  
Melissa Sanchez ◽  
David H. Hall ◽  
K. Adam Bohnert ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Cell Biology ◽  
Cell Lineage ◽  
Genetic Screen ◽  
Protein Aggregate ◽  
C Elegans ◽  
Age Dependent ◽  
Dependent Protein ◽  
Atp Generation ◽  
And Function

AbstractSomatic cells age and die, but the germ-cell lineage is immortal. In C. elegans, oocyte-maturation signals from sperm trigger the clearance of carbonylated proteins and protein aggregates. Here, we explore the cell biology of this proteostasis renewal in the context of a whole-genome RNAi screen for knockdowns that interfere with aggregate clearance. Oocyte-maturation signals are known to trigger protein-aggregate removal via lysosome acidification, and our findings suggest that lysosomes are acidified as a consequence of changes in ER morphology and function that permit assembly of the lysosomal V-ATPase. Once lysosomes are acidified, our genetic findings support the model that they remove aggregates by microautophagy. We also define two functions for mitochondria in this proteostasis renewal, both of which appear to be independent of mitochondrial ATP generation. Finally, many genes from the screen also regulate lysosome acidification and age-dependent protein aggregation in the soma, suggesting a fundamental mechanistic link between proteostasis renewal in the germline and the maintenance of the soma.

scholarly journals Metformin Preserves Mitochondrial Integrity at Old Age in Male Rats

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 690-690
Author(s):  
Jonathan Wanagat ◽  
Allen Herbst ◽  
Austin Hoang ◽  
Chiye Kim ◽  
Judd Aiken ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Copy Number ◽  
Male Rats ◽  
Metformin Treatment ◽  
Mtdna Copy Number ◽  
C Elegans ◽  
Mitochondrial Integrity ◽  
Mitochondrial Dna Copy Number ◽  
And Function ◽  
Deletion Frequency

Abstract Metformin is being deployed in clinical trials to ameliorate aging in older humans who do not have diabetes. In C. elegans, metformin treatment at old ages exacerbated mitochondrial dysfunction, led to respiratory failure, and shortened lifespan. Metformin is a commonly used, well-tolerated treatment for diabetes in older adults. Mitochondrial effects of metformin treatment in aged mammals has not been sufficiently investigated. We hypothesized that metformin treatment would not be toxic to older mammals. To define a therapeutic dose in aged hybrid rats, we evaluated two doses of metformin (0.1%, 0.75% of the diet) at 30-months of age. Body mass decreased at the 0.75% dose. Neither dose affected mortality between 30- and 34-months of age. We assessed mitochondrial quality, quantity, and function in aged rats treated with metformin at the 0.75% dose by measuring mitochondrial DNA copy number, deletion mutation frequency, and respirometry in skeletal muscle and heart. In skeletal muscle, we observed no effect of metformin on quadriceps mass, mtDNA copy number or deletion frequency. In the heart, metformin treated rats had higher mtDNA copy number, lower cardiac mass and no effect on deletion frequency. Metformin treatment resulted in lower mitochondrial complex I activity in both heart and quadriceps. Metformin did not compromise mitochondrial integrity, was well tolerated, and may have cardiac benefits to rats at old ages.

scholarly journals Intrinsically aggregation-prone proteins form amyloid-like aggregates and contribute to tissue aging in C. elegans

2018 ◽  
Author(s):  
C. Huang ◽  
S. Wagner-Valladolid ◽  
A.D. Stephens ◽  
R. Jung ◽  
C. Poudel ◽  
...  
Keyword(s):  
Protein Aggregation ◽  
Amyloid Fibrils ◽  
Functional Decline ◽  
C Elegans ◽  
Amyloid Aggregates ◽  
Age Dependent ◽  
Dependent Protein ◽  
Specific Proteins ◽  
Protein Instability ◽  
Tissue Aging

AbstractReduced protein homeostasis and increased protein instability is a common feature of aging. Yet it remains unclear whether protein instability is a cause of aging. In neurodegenerative diseases and amyloidoses, specific proteins self-assemble into amyloid fibrils and accumulate as pathological solid aggregates in a variety of tissues. More recently, widespread protein aggregation has been described during normal aging, in the absence of disease processes. Until now, an extensive characterization of the nature of age-dependent protein aggregation and its consequences for aging has been lacking. Here, we show that age-dependent aggregates are rapidly formed by newly synthesized proteins and contain amyloid-like structures similar to disease-associated protein aggregates. Moreover, we demonstrate that age-dependent protein aggregation accelerates the functional decline of different tissues in C. elegans. Together, these finding reveal that the formation of amyloid aggregates is a generic problem of aging and likely to be an important target for strategies designed to maintain physiological functions in later stages of life.

Secondary abnormalities of mitochondrial DNA associated with neurodegeneration

1999 ◽  
Vol 66 ◽  
pp. 99-110 ◽  
Author(s):  
S.J. Tabrizi ◽  
A.H.V. Schapira
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Complex I ◽  
Tricarboxylic Acid Cycle ◽  
Energy Requirement ◽  
Mitochondrial Protein ◽  
High Energy ◽  
Resonance Spectroscopy ◽  
Mtdna Mutation ◽  
Mitochondrial Iron

The central nervous system has a particularly high energy requirement, thus making it very susceptible to defects in mitochondrial function. A number of neurodegenerative diseases, in particular Parkinson's disease (PD), Huntington's disease (HD) and Friedreich's ataxia (FRDA), are associated with mitochondrial dysfunction. The identification of a mitochondrial complex-I defect in PD provides a link between toxin models of the disease, and clues to the pathogenesis of idiopathic PD. We have undertaken genomic transplantation studies involving the transfer of mitochondrial DNA (mtDNA) from PD patients with a complex-I defect to a novel nuclear background. Histochemical, immunohistochemical and functional analysis of the resulting cybrids all showed a pattern in the PD clones indicative of a mtDNA mutation. There is good evidence for the involvement of defective energy metabolism and excitotoxicity in the aetiology of HD. We, and others, have shown a severe deficiency of complex II/III confined to the striatum that mimics the toxin-induced animal models of HD. There is also a milder defect in complex IV in the caudate. The tricarboxylic acid cycle enzyme aconitase is particularly sensitive to inhibition by peroxynitrite and superoxide radicals. We have found this enzyme to be severely decreased in HD caudate, putamen and cortex in a pattern that parallels the severity of neuronal loss seen. We propose a scheme for the role of nitric oxide, free radicals and excitotoxicity in the pathogenesis of HD. FRDA is caused by an expanded GAA repeat in intron 1 of the X25 gene encoding a protein called frataxin. Frataxin is widely expressed and is a mitochondrial protein, although its function is unknown. We have found abnormal magnetic resonance spectroscopy in the skeletal muscle of FRDA patients, which parallels our biochemical findings of reduced complexes I-III in patients' heart and skeletal muscle. There is also reduced aconitase activity in these areas. Increased iron deposition was seen in patients' tissues in a pattern consistent with a mitochondrial location. The mitochondrial iron accumulation, defective respiratory chain activity and aconitase dysfunction suggest that frataxin may be involved in mitochondrial iron regulation. There is also evidence that oxidative stress contributes to cellular toxicity.

scholarly journals The understudied links of the retromer complex to age-related pathways

GeroScience ◽  
2021 ◽  
Author(s):  
Kenneth A. Wilson
Keyword(s):  
Disease Progression ◽  
Neurodegenerative Disorders ◽  
Memory Impairment ◽  
Functional Decline ◽  
Protein Aggregates ◽  
Structure And Function ◽  
Retromer Complex ◽  
Age Related ◽  
Age Dependent ◽  
And Function

AbstractNeuronal aging is associated with numerous diseases resulting in memory impairment and functional decline. A common hallmark of these disorders is the accumulation of intracellular and extracellular protein aggregates. The retromer complex plays a central role in sorting proteins by marking them for reuse rather than degradation. Retromer dysfunction has been shown to induce protein aggregates and neurodegeneration, suggesting that it may be important for age-related neuronal decline and disease progression. Despite this, little is known about how aging influences retromer stability and the proteins with which it interacts. Detailed insights into age-dependent changes in retromer structure and function could provide valuable information towards treating and preventing many age-related neurodegenerative disorders. Here, we visit age-related pathways which interact with retromer function that ought to be further explored to determine its role in age-related neurodegeneration.

A radical view of immunosenescence: Does chronic redox depletion interfere with immune cell signalling and function?

2000 ◽  
Vol 10 (1) ◽  
pp. 5-15 ◽  
Author(s):  
David A. Rider ◽  
Stephen P. Young
Keyword(s):  
Immune Cell ◽  
Cell Signalling ◽  
Functional Decline ◽  
Underlying Disease ◽  
Cell Mediated Immunity ◽  
Older Individuals ◽  
Helper T Lymphocytes ◽  
Age Dependent ◽  
Underlying Mechanisms ◽  
And Function

Many changes occur in the aging immune system, which culminate in its functional decline, but the underlying mechanisms have proved difficult to define. Wick and Grubeck-Loebenstein have recently classified the changes in function as either primary ‘those that occur in perfectly healthy older individuals’ as the result of ‘an age dependent intrinsic decline of immune responsiveness’ or secondary ‘those that are due to underlying disease or various environmental factors including diet, drug intake, physical activity, etc’. Both types of alteration are important when considering immune dysfunction in older people which seems to be centred on the loss of cell-mediated immunity, in particular the activity of CD4 helper T lymphocytes.

scholarly journals Ultrasensitive deletion detection links mitochondrial DNA replication, disease, and aging

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Scott A. Lujan ◽  
Matthew J. Longley ◽  
Margaret H. Humble ◽  
Christopher A. Lavender ◽  
Adam Burkholder ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Dna ◽  
Dna Polymerase ◽  
Late Onset ◽  
Nuclear Gene ◽  
Purifying Selection ◽  
Pathogenic Variants ◽  
Mtdna Deletions ◽  
Fork Stalling ◽  
Dna Polymerase Γ

Abstract Background Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. Results To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns. Conclusions These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.

scholarly journals Sarcopenia and Physical Activity Predict Falls in Older Adults from Amazonas, Brazil (La sarcopenia y la actividad física predicen caídas en adultos mayores de Amazonas, Brasil)

Retos ◽  
2021 ◽  
Vol 43 ◽  
pp. 215-222
Author(s):  
Kessketlen Alves Miranda ◽  
Élvio Rubio Gouveia ◽  
Bruna Gouveia ◽  
Adilson Marques ◽  
Pedro Campos ◽  
...  
Keyword(s):  
Physical Activity ◽  
Skeletal Muscle ◽  
Functional Decline ◽  
European Working ◽  
Risk Of Falls ◽  
Falls In Older Adults ◽  
Muscle Disorder ◽  
Las Mujeres ◽  
Risk Of Fall ◽  
And Function

Introduction: Sarcopenia is a progressive and widespread skeletal muscle disorder involving loss of muscle mass and function, and is associated with several outcomes, including falls, functional decline, frailty, and mortality. Therefore, this study aimed: (1) to estimate the prevalence of sarcopenia, falls, and the risk of falls considering age, sex, and the level of physical activity (PA), and (2) to identify which of these predictors better explained the likelihood that participants present risk of fall. A total of 701 participants (433 women) with a mean age of 70.4±6.9. Sarcopenia was determined according to the most recent guidelines from the European Working Group (EWGSOP2). The prevalence of falls and the level of physical activity were assessed by questionnaires. The risk of falls was assessed using the Fullerton Advance Balance (FAB) scale. This study provides evidence that women (OR: 2.5, p<0.001), the oldest people (OR: 1.1 p<0.001), and people who had identified sarcopenia (OR: 2.9 p<0.001), and lower level of physical activity (OR: 2.9 p<0.001), were more likely to present the risk of falls. Implications for vulnerable aging are discussed.  Resumen. Introducción: La sarcopenia es un trastorno del músculo esquelético generalizado y progresivo que implica pérdida de masa y función muscular y se asocia con varios resultados, que incluyen caídas, deterioro funcional, fragilidad y mortalidad. Por lo tanto, este estudio tuvo como objetivo: (1) estimar la prevalencia de sarcopenia, caídas y el riesgo de caídas considerando la edad, el sexo y el nivel de actividad física (AF), y (2) identificar cuál de estos predictores explicaba mejor la probabilidad que los participantes presentan riesgo de caída. Un total de 701 participantes (433 mujeres) con una edad media de 70,4 ± 6,9 años. La sarcopenia se determinó de acuerdo con las guías más recientes del Grupo de trabajo europeo (EWGSOP2). La prevalencia de caídas y el nivel de AF se evaluaron mediante cuestionarios. El riesgo de caídas se evaluó mediante la escala Fullerton Advance Balance (FAB). Este estudio proporciona evidencia de que las mujeres (OR: 2,5, p <0,001), las personas mayores (OR: 1,1 p <0,001) y las personas que habían identificado sarcopenia (OR: 2,9 p <0,001) y un nivel más bajo de AP (OR: 2,9 p <0,001), tenían más probabilidades de presentar riesgo de caídas. Se discuten las implicaciones para el envejecimiento vulnerable.

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