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Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness. Quadriceps muscle from four mice per genotype were used (Control young (6 month-old), Mfn2KO young (6-month-old), control old (22-month-old) and Mfn2KO old (22-month-old)
2016-08-08 | E-GEOD-71501 | biostudies-arrayexpress
Project description:Metabolic dysfunction–associated steatohepatitis (MASH), marked by hepatic steatosis and inflammation, is a major risk for cirrhosis and liver cancer. Obesity-induced oxidative stress plays a central role in MASH promoting protein damage and dysfunction. Cysteine persulfidation (PSSH), a post-translational modification regulated by hydrogen sulfide (H2S), is involved in protein stability and cellular protection. However, the role of PSSH in MASH is poorly understood. We found that H2S-producing enzymes are downregulated in livers with fibrosis and inflammation, leading to decreased hepatic PSSH. Using dimedone-switch-based mass spectrometry, we mapped the alterations in the liver persulfidome during diet-induced fibrosis and inflammation. While the levels of H2S-producing enzymes dropped, some proteins, including protein tyrosine phosphatases (PTPs) and redox regulators, showed increased PSSH. This change suggests that H2S-mediated persulfidation helps protect proteins from oxidative damage. Overall, decreased H2S enzyme expression and reduced PSSH may impair protection against oxidative stress, contributing to liver dysfunction in obesity.
2025-08-04 | PXD057932 | Pride
Project description:Age-related hearing loss (presbycusis) affects more than one-third of Americans over the age of 60, with its prevalence and severity increasing with age. Pathological alterations to the cochlear lateral wall (CLW) disrupting the maintenance of the endocochlear potential (EP) are a major cause of (metabolic) presbycusis. Although molecular mediators of CLW degeneration are largely unknown, several cellular events, including oxidative stress, apoptosis, and inhibition of proliferation, are known to contribute to this dysfunction. Here we have analyzed mRNA and microRNA expression in CLW of young and old mice to profile transcriptional changes that occur as a function of aging. Our results reinforce prior findings about molecular processes and pathways affected by aging and implicate microRNAs that may be involved in influencing these changes.
2021-04-14 | GSE98070 | GEO
Project description:The decline of cognitive function is a feature of normal human aging and is exacerbated in AlzheimerM-bM-^@M-^Ys disease (AD). DNA repair declines in brain cells during normal aging and even more so in AD. Here we show that experimental reduction in levels of the base excision repair enzyme, DNA polymerase M-NM-2 (Polb) renders neurons vulnerable to age-related dysfunction and degeneration in a mouse model of AD. Whereas 3xTgAD mice exhibit age-related extracellular amyloid b-peptide (Ab) accumulation and cognitive deficits, but no neuronal death, 3xTg/Polb+/- mice accumulates intracellular Ab and neurons die in the hippocampus and cerebral cortex. The DNA repair-deficient 3xTgAD mice exhibited increased DNA strand breaks and apoptotic caspase activation with loss of hippocampal volume, and impaired synaptic plasticity and memory retention. Molecular profiling revealed remarkable similarities in gene expression alterations in brain cells of AD patients and 3xTgAD/Polb+/- mice including multiple abnormalities suggestive of impaired cellular bioenergetics. Our findings demonstrate that a modest decrement in oxidative DNA damage processing is sufficient to render neurons vulnerable to AD-related pathogenic molecular and cellular alterations that result in the dysfunction and death of neurons, and associated cognitive deficits. 4 mouse strains were used in these experiments, the 3xTgAD and Pol M-NM-2 (+/-) mice were bred at the National Institute on Aging (Baltimore, Maryland). The original line 3xTgAD line was generated as described previously (Oddo, et. al 2003) and possess APPswe, PS1M146V, and tauP301L mutations. DNA polymerase beta heterozygous mice, Pol M-NM-2 (+/-), were crossed with the 3xTgAD mice to generate a 3xTgAD/Pol M-NM-2 (+/-) mouse. The Wt strain is C57Bl/6. At 20 months of age these mice were euthanized by cervical dislocation, the brain removed from the skull and dissected into regions of interest, the prefrontal cortex was used for the microarray studies.
2015-01-05 | E-GEOD-60911 | biostudies-arrayexpress
Project description:Testicular aging commonly leads to testosterone deficiency and impaired spermatogenesis, yet the underlying mechanisms remain elusive. Here, a comprehensive analysis of senescence landscapes in mice testes during aging revealed that the Leydig cells (LCs) are particularly vulnerable to aging processes. Single-cell RNA sequencing identified the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme of ketogenesis, decreased significantly in LCs from aged mice. Additionally, the concentrations of ketone bodies β-hydroxybutyric acid (BHB) and acetoacetic acid (AcAc) in the young testes were substantially higher than that in serum, but significantly diminished in aged testes. Silencing of Hmgcs2 in young LCs resulted in decreased ketone body production, which in turn drove LCs senescence and accelerated testicular aging. Mechanistically, BHB acted as an endogenous inhibitor of histone deacetylase 1 to upregulate the expression of Foxo3a by promoting histone acetylation, thereby mitigating LCs senescence and promoting testosterone production. Consistently, enhanced ketogenesis by genetic manipulation or oral BHB supplementation alleviated LCs senescence and ameliorated testicular aging in aged mice. These findings highlight defective ketogenesis as a pivotal factor in testicular aging, suggesting novel therapeutic avenues for addressing age-related testicular dysfunction.
2025-03-27 | GSE287203 | GEO
Project description:Aging is characterized by a gradual decline in function, partly due to molecular damage that accumulates over time. Human skin is highly susceptible to both chronological aging and environmental damage in the form of UV photoaging. This results in detrimental structural and physiological changes with age. In this study we sought to comprehensively address both chronological and photoaging at the single-cell level, and to explore genetic and environmental factors, revealing their influences on the aging process. We included samples from young, middle-aged, and old individuals, and with these samples, we compared chronological aging and photoaging. Utilizing single-cell RNA sequencing, we created a comprehensive human skin cell atlas, that offers insights into the cellular composition and functions. We investigated the renewal ability of epidermis stem cells as they age and extended the study to fibroblasts, hair follicles, and endothelial cells. Examining the genetic landscape of aging in keratinocytes, we identified two distinct "gene modules" with altered gene expression during aging. Furthermore, we uncovered that skin aging involves interactions between epidermal keratinocytes and dermal fibroblasts, as well as extensive communication of keratinocytes with various other skin cell types as revealed through ligand-receptor pairs. Interactions, such as COL17A1-A1b1complex, highlighted a direct link between keratinocytes and fibroblast stimulation for collagen production. Most importantly, A key gene, MYO1, associated with skin aging was identified, leading to the development of an innovative mRNA treatment aimed at promoting skin rejuvenation by targeting this gene. Experimental results demonstrated that the mRNA treatment reduces basal stem cell senescence, increases basal stem cell proliferation, and enhances collagen production in fibroblasts via keratinocyte-fibroblast communication. The MYO1-targeted treatment is validated as an effective strategy for reversing skin aging by targeting cellular mechanisms.
2024-11-18 | GSE274955 | GEO
Project description:SIRT6 has been implicated in anti-aging at the organismal level; however, its role in pancreatic beta cell aging is unclear. This study investigated the role of SIRT6 in pancreatic beta cell aging using conditional SIRT6 transgenic overexpression mice at 10 and 16 months of age. Our data show that SIRT6 has a strong protective function against aging-associated oxidative stress, DNA damage, and multiple forms of cell death.
2025-08-23 | GSE287696 | GEO
Project description:Mitochondrial fusion and fission proteins regulate mitochondrial quality control and mitochondrial metabolism. In turn, mitochondrial dysfunction is associated with aging, although its causes are still under debate. Here, we show that aging is characterized by a progressive reduction of Mitofusin 2 (Mfn2) in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, muscle Mfn2-deficient mice show unhealthy aging characterized by altered metabolic homeostasis and sarcopenia. Mfn2 deficiency impairs mitochondrial quality control, which contributes to an exacerbated age-related mitochondrial dysfunction. Surprisingly, aging-induced Mfn2 deficiency triggers a ROS-dependent retrograde signaling pathway through induction of HIF1 transcription factor and BNIP3. This pathway ameliorates mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that repression of Mfn2 in skeletal muscle during aging is determinant for the loss of mitochondrial quality, contributing to age-associated metabolic alterations and loss of muscle fitness.
2016-08-08 | GSE71501 | GEO
Project description:Oxidative stress plays a key role in aging and related diseases, including neurodegeneration, cancer, and organ failure. Copper (Cu), a redox-active metal ion, generates reactive oxygen species (ROS), and its dysregulation contributes to aging. Here, we develop activity-based imaging probes for the sensitive detection of Cu(I) and show that labile hepatic Cu activity increases with age, paralleling a decline in ALDH1A1 activity, a protective hepatic enzyme. We also observe an age-related decrease in hepatic glutathione (GSH) activity through noninvasive photoacoustic imaging. Using these probes, we perform longitudinal studies in aged mice treated with ATN-224, a Cu chelator, and demonstrate that this treatment improves Cu homeostasis and preserves ALDH1A1 activity. Our findings uncover a direct link between Cu dysregulation and aging, providing insights into its role and offering a therapeutic strategy to mitigate its effects.
2025-01-16 | PXD059736 | JPOST Repository
Project description:The ectopic deposition of fat is thought to lead to lipotoxicity and has been associated with mitochondrial dysfunction and diabetic cardiomyopathy. We have measured mitochondrial respiratory capacities in the hearts of ob/ob and wild-type mice on either a regular chow (RCD) or high-fat (HFD) diet across four age groups to investigate the impact of diet and age on mitochondrial function alongside a comprehensive strategy for metabolic profiling of the tissue. Myocardial mitochondrial dysfunction was only evident in ob/ob mice on RCD at 14 months, but it was detectable at 3 months on the HFD. Liquid chromatography–mass spectrometry (LC–MS) was used to study the profiles of acylcarnitines and the accumulation of triglycerides, but neither class of lipid was associated with mitochondrial dysfunction. However, a targeted LC–MS/MS analysis of markers of oxidative stress demonstrated increases in GSSG/GSH and 8-oxoguanine, in addition to the accumulation of diacylglycerols, which are lipid species linked to lipotoxicity. Our results demonstrate that myocardial mitochondria in ob/ob mice on RCD maintained a similar respiratory capacity to that of wild type until a late stage in aging. However, on a HFD, unlike wild-type mice, ob/ob mice failed to increase mitochondrial respiration, which may be associated with a complex I defect following increased oxidative damage.
2015-11-17 | MTBLS173 | MetaboLights