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Age-induced methylmalonic acid accumulation promotes cancer aggressiveness and metastatic disease

ABSTRACT: TMT protein abundance profiling of human serum from 30 young and 30 older adults.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: John Blenis Noah Dephoure

PROVIDER: MSV000084974 | MassIVE | Tue Feb 18 11:09:00 GMT 2020

SECONDARY ACCESSION(S): PXD017599

REPOSITORIES: MassIVE

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Age-induced accumulation of methylmalonic acid promotes tumour progression.

Gomes Ana P AP Ilter Didem D Low Vivien V Endress Jennifer E JE Fernández-García Juan J Rosenzweig Adam A Schild Tanya T Broekaert Dorien D Ahmed Adnan A Planque Melanie M Elia Ilaria I Han Julie J Kinzig Charles C Mullarky Edouard E Mutvei Anders P AP Asara John J de Cabo Rafael R Cantley Lewis C LC Dephoure Noah N Fendt Sarah-Maria SM Blenis John J

Nature 20200819 7824

The risk of cancer and associated mortality increases substantially in humans from the age of 65 years onwards<sup>1-6</sup>. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy<sup>2,3,7,8</sup>. For decades, this link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the established role of diet, exercise and small molecules that target the pace of metabolic agei ...[more]

PMID: 32814897

Similar Datasets

Age-induced methylmalonic acid accumulation promotes tumor progression

Project description:From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.

2020-07-03 | GSE127001 | GEO

Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness

Project description:The skeletal muscle system plays an important role in the independence of older adults. In this study we examine differences in the skeletal muscle transcriptome between healthy young and older subjects and (pre‐)frail older adults. Additionally, we examine the effect of resistance‐type exercise training on the muscle transcriptome in healthy older subjects and (pre‐)frail older adults. Baseline transcriptome profiles were measured in muscle biopsies collected from 53 young, 73 healthy older subjects, and 61 frail older subjects. Follow‐up samples from these frail older subjects (31 samples) and healthy older subjects (41 samples) were collected after 6 months of progressive resistance‐type exercise training. Frail older subjects trained twice per week and the healthy older subjects trained three times per week. At baseline genes related to mitochondrial function and energy metabolism were differentially expressed between older and young subjects, as well as between healthy and frail older subjects. Three hundred seven genes were differentially expressed after training in both groups. Training affected expression levels of genes related to extracellular matrix, glucose metabolism, and vascularization. Expression of genes that were modulated by exercise training was indicative of muscle strength at baseline. Genes that strongly correlated with strength belonged to the protocadherin gamma gene cluster (r = −0.73). Our data suggest significant remaining plasticity of ageing skeletal muscle to adapt to resistance‐type exercise training. Some age‐related changes in skeletal muscle gene expression appear to be partially reversed by prolonged resistance‐type exercise training. The protocadherin gamma gene cluster may be related to muscle denervation and re‐innervation in ageing muscle.

2018-07-24 | GSE117525 | GEO

Age-induced accumulation of methylmalonic acid promotes tumour progression.

Project description: Not available

| S-EPMC7785256 | biostudies-literature

A unique adipocyte progenitor population that promotes age-related adiposity

Project description:The average fat (adipose tissue) mass in adults increases dramatically with age, and older people often suffer from visceral obesity and related adverse metabolic disorders. Unfortunately, how aging leads to adipose accumulation is poorly understood. It is known that fat cell (adipocyte) turnover is very low in young mice, similar to that in young humans. Single-cell RNA sequencing analyses reveal that aging globally remodels APCs. Herein, we identify a novel, age-specific committed APC population as CP-A cells, existing both in mice and humans, with a global activation of proliferation and adipogenesis pathways. CP-A cells display high proliferation and adipogenesis activity, both in vivo and in vitro. M1 macrophages may regulate the remodeling of APCs and the generation of CP-A cells during aging.

2021-12-02 | GSE189783 | GEO

Human myofiber-enriched aging-induced lncRNA FRAIL1 promotes muscle atrophy

Project description:The loss of skeletal muscle mass during aging is a significant health concern linked to adverse outcomes in older individuals. Understanding the molecular basis of age-related muscle loss is crucial for developing strategies to prevent or reverse this debilitating condition. Long non-coding RNAs (lncRNAs) are a largely uncharacterized class of biomolecules that have been implicated in cellular homeostasis and dysfunction across a wide variety of tissues and cell types. To identify lncRNAs that might contribute to skeletal muscle aging we screened for lncRNAs whose expression was altered in vastus lateralis muscle from older compared to young adults. We identified FRAIL1 as an aging-induced lncRNA with high abundance in human skeletal muscle. In a cohort of healthy young and older adults, skeletal muscle FRAIL1 was most strongly expressed in older females and negatively associated with measures of muscle strength and mass. Forced expression of FRAIL1 in mouse tibialis anterior muscle elicits a dose-dependent reduction in skeletal muscle fiber size that is independent of changes in muscle fiber type. Furthermore, this reduction in muscle size is dependent on an intact region of FRAIL1 that is highly conserved across non-human primates. Unbiased transcriptional and proteomic profiling of the effects of FRAIL1 expression in mouse skeletal muscle revealed widespread changes in mRNA and protein abundance that recapitulate age-related changes in pathways and processes that are known to be altered in aging skeletal muscle. Taken together, these findings shed light on the intricate molecular mechanisms underlying skeletal muscle aging and implicate FRAIL1 in the reduction of muscle mass during this process.

2024-02-24 | GSE249356 | GEO

Age-induced methylmalonic acid accumulation promotes tumor progression

Project description:Age-induced methylmalonic acid accumulation promotes tumor progression

| PRJNA524129 | ENA

Age-Dependent Changes in the Plasma Proteome of Healthy Adults

Project description:Human blood plasma is a complex which communicates with most parts of the body and reflects changes in the state of the organism, therefore identifying age-related biomarkers can help to predict and monitor age-related physiological decline and diseases, as well as to find new treatments for diseases. In this study, TMT-LC-MS/MS was utilized to screen for the differentially expressed plasma proteins in 118 healthy adults with different ages. Participants were divided into three groups: 21-30 (Young), 41-50 (Middle) and ≥60 (Old), the number of differentially expressed proteins when Young vs Middle, Middle vs Old and Young vs Old were 82, 22 and 99, respectively. These proteins were found to be involved in numerous physiological processes such as “negative regulation of smooth muscle cell proliferation” and “blood coagulation”. Meanwhile when Young vs Middle or Old, “Complement and coagulation cascades” was confirmed the top enriched pathway by KEGG pathway enrichment analysis. Functional phenotyping of the proteome demonstrated that the plasma proteomic profiles of Young adults were strikingly dissimilar to the Middle or Old adults. The results of this study mapped the variation in expression of plasma proteins, and provided information about possible biomarkers/treatments for different kinds of age-related function disorders.

2020-10-19 | PXD016199 | Pride

Age-associated accumulation of B cells promotes macrophage inflammation and inhibits lipolysis in adipose tissue during sepsis

Project description:Noncanonical lipolysis induced by inflammatory cytokines or toll-like receptor ligands is required for the regulation of inflammation during endotoxemia and sepsis. Canonical lipolysis induced by catecholamines declines during aging, but the extent to which the noncanonical pathway of lipolysis is active during aging remains unknown. The immune compartment of visceral white adipose tissue (vWAT) changes during aging, including an expansion of lymphocytes, pro-inflammatory macrophage polarization, and an increase in chronic low-grade inflammation, all of which influence canonical lipolysis in old vWAT. Therefore, we aimed to define the extent to which immune cells from older hosts influence noncanonical lipolysis induced by sepsis. Here we show that models of polymicrobial sepsis and lipopolysaccharide (LPS)-induced endotoxemia induce vWAT lipolysis in young mice but fail to activate lipolytic pathways in vWAT from old mice. Characterization of vWAT B cells revealed an accumulation of dysfunctional B1 B cells and an amplified inflammatory signature induced by LPS in old B1 B cells compared to old B2 B cells. Short term depletion of B2 B cells from old mice and adoptive transfer of peritoneal B cells from old mice into young recipient mice were insufficient to alter LPS-stimulated lipolysis. However, life-long deficiency of B cells increased LPS-stimulated lipolysis, suggesting the suppressive role of B cells may be indirect and requires other cell types. Pro-inflammatory macrophages and NLRP3 inflammasome activation were significantly reduced in the old B cell knockout mice. These data collectively reveal a decline in noncanonical lipolysis in vWAT during aging that is regulated by resident immune cells. Additionally, our study suggests the B cell-macrophage signaling axis may offer new approaches to resolve metabolic dysfunction in aged vWAT and attenuate septic severity in older individuals.

2024-03-18 | GSE250371 | GEO

LC-MS/MS of different developmental stages of human pancreas

Project description:Mass spectrometry-based quantitative proteomics was used to delineate proteome-wide and extracellular matrix (ECM) alterations at four age groups in human pancreas: fetal (18-20 weeks gestation), juvenile (5-16 years old), young adults (21-29 years old) and older adults (50-61 years old).

2021-01-06 | PXD020130 | Pride

The murine metastatic microenvironment of experimental brain metastases in breast cancer differs by host age in vivo: A proteomic study.

Project description:Breast cancer in young patients is known to exhibit more aggressive biological behavior and is associated with a less favorable prognosis than the same disease in older patients, owing in part to an increased incidence of brain metastases, the mechanistic explanations behind which remain poorly understood. We recently reported that young mice, compared to older mice, showed about a three-fold increase in the development of brain metastases in mouse models of triple-negative and luminal B breast cancer. Here we have performed a quantitative mass spectrometry-based proteomic analysis to identify proteins contributing to age-related disparities in the development of breast cancer brain metastases. Using a mouse model of brain-tropic (MDA-MB-231BR) triple-negative breast cancer, we harvested subpopulations of tumor metastases, the tumor-adjacent metastatic microenvironment, and uninvolved brain tissues via laser microdissection followed by quantitative proteomic analysis using high resolution mass spectrometry to characterize differentially abundant proteins contributing to age-dependent rates of brain metastasis.

2024-01-11 | PXD042346 | Pride

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