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Quantitative Analysis of Age-dependent Albumin Modifications

ABSTRACT: Albumin, the most abundant plasma protein, plays critical roles in blood homeostasis by maintaining osmotic pressure, transporting diverse substances, and providing antioxidant defense. The function and regulation of albumin are influenced by its post-translational modifications (PTMs), yet how these modifications change with age remains incompletely understood. In the present study, we employed tandem mass spectrometry to quantitatively profile PTMs of human plasma albumin across different age groups. Specially, we characterized the redox state of Cys34, oxidation of methionine residues, the presence of the C-terminal cleavage product, and glycation of lysine residues. Our results showed that the reduced-to-oxidized ratio of Cys34 was approximately 40% higher in plasma from donors under 40 years old compared to older individuals. Consistently, oxidation of methionine residues（Met123, Met298, Met446 and Met548）was significantly increased with age. We also observed an age-dependent rise in intact C-terminal albumin and glycation of lysine residues (K64, K137, k262 and K525). Together, these findings provide a comprehensive profile of albumin modifications during aging and highlight potential biomarkers for tracking aging and its related health conditions.

ORGANISM(S): Homo Sapiens

SUBMITTER: Haiteng Deng

PROVIDER: PXD071353 | iProX | Fri Nov 28 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:Senolytic drugs are designed to selectively clear senescent cells (SnCs) that accumulate with injury or aging. In a mouse model of osteoarthritis (OA), senolysis yields a pro-regenerative response. However, recent research studies showed that the therapeutic benefit is reduced in aged mice. Increased oxidative stress (redox) mediates metabolic dysregulation and accumulation of posttranslational modifications (PTM) on proteins from the cartilage and is one of the major hallmarks of advanced age. This research investigated whether the senolytic treatment differentially affects oxidative load in the joints from young and aged animals. We employed label-free quantitative (LFQ) analysis of changes in the protein expression profiles and associated carbonylated PTMs in the extracted joint proteins. Our proteomic survey focused to a set of PTMs described as advanced glycation-end products (AGEs) or advanced lipooxidation-end products (ALEs), known to accumulate during aging and age-associated diseases. AGEs and ALEs are the result of non-enzymatic reactions of protein with reducing sugars, or with oxidized sugar or lipid degradation products, which may alter and sometimes crosslink the positively charged amino acids lysine and arginine on proteins. Our proteomic dataset supported detection of several AGEs and ALEs, including the adducts 4-ONE (4-oxononenal), 4-ONE+Delta:H(-2)O(-1) (dehydrated 4-oxononenal Michael adduct), carboxyethyl, carboxymethyl, 3-deoxyglucosone derived dihydroxyimidazoline, G-H1 (glyoxal-derived hydroimidazolone), HNE (4-hydroxynonenal), several carbonylated adducts including proline to pyrrolidinone or pyrrolidone Other detected modifications of note include mono-oxidation and di-oxidation products, including tryptophan to kynurenine. We also detected lysine-epsilon-gly-gly (GlyGly), which marks ubiquitylated sites, indicating potential substrates of proteasome-dependent degradation. The grand total PTM change was negative for treated aged OA mice but positive for treated young OA mice, regardless of whether summed across modifications or across proteins. In other words, senolytic treatment reduced oxidation associated PTMs more effectively in aged OA mice than in young OA mice. The LFQ proteomics analysis was complemented with new biophysical computational tools aimed to predict the stability of carbonylated proteins extracted from the joints. The biophysical model predicted divergent proteomic responses between young and aged animals. Altogether, our results showed that senolysis reduces overall oxidative stress in the aged arthritic joints in vivo.

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Quantitative Analysis of Age-dependent Albumin Modifications

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