为期两年的热量限制干预可降低血糖生物学年龄生物标志物。

A 2-year calorie restriction intervention reduces glycomic biological age biomarkers.

作者信息

Pribić Tea, Das Jayanta K, Đerek Lovorka, Belsky Daniel W, Orenduff Melissa, Huffman Kim M, Kraus William E, Deriš Helena, Šimunović Jelena, Štambuk Tamara, Hodžić Azra Frkatović, Kraus Virginia B, Das Sai Krupa, Racette Susan B, Banskota Nirad, Ferruci Luigi, Pieper Carl, Lewis Nathan E, Lauc Gordan, Krishnan Sridevi

机构信息

Genos Ltd, Glycoscience Research Laboratory, Zagreb, Croatia.

Longitudinal Studies Section, Translation Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, USA.

出版信息

medRxiv. 2024 Dec 5:2024.12.04.24318451. doi: 10.1101/2024.12.04.24318451.

BACKGROUND/OBJECTIVE: In a subset of participants from the CALERIE Phase 2 study we evaluated the effects of 2y of ~25% Calorie Restriction (CR) diet on IgG N-glycosylation (GlycAge), plasma and complement C3 N-glycome as markers of aging and inflammaging.

METHODS

Plasma samples from 26 participants in the CR group who completed the CALERIE2 trial and were deemed adherent to the intervention (~>10 % CR at 12 mo) were obtained from the NIA AgingResearchBiobank. Glycomic investigations using UPLC or LC-MS analyses were conducted on samples from baseline (BL), mid-intervention (12 mo) and post-intervention (24 mo), and changes resulting from the 2y CR intervention were examined. In addition, anthropometric, clinical, metabolic, DNA methylation (epigenetic) and skeletal muscle transcriptomic data were analyzed to identify aging-related changes that occurred in tandem with the N-glycome changes.

RESULTS

Following the 2y CR intervention, IgG galactosylation was higher at 24mo compared to BL (p = 0.051), digalactosylation and GlycAge (the IgG-based surrogate for biological age) were not different between BL and 12mo or BL and 24mo, but increased between 12mo and 24mo (p = 0.016, 0.027 respectively). GlycAge was also positively associated with TNF-α and ICAM-1 (p=0.030, p=0.017 respectively). Plasma highly branched glycans were decreased by the 2y intervention (BL vs 24 mo: p=0.013), but both plasma and IgG bisecting GlcNAcs were increased (BL vs 24mo: p<0.001, p = 0.01 respectively). Furthermore, total complement C3 protein concentrations were reduced (BL vs 24mo: p <0.001), as were Man9 glycoforms (BL vs 24mo: p<0.001), and Man10 (which is glucosylated) C3 glycoforms (BL vs 24mo: p = 0.046).

CONCLUSIONS

24-mos of CR was associated with several favorable, anti-aging, anti-inflammatory changes in the glycome: increased galactosylation, reduced branching glycans, and reduced GlycAge. These promising CR effects were accompanied by an increase in bisecting GlcNAc, a known pro-inflammatory biomarker. These intriguing findings linking CR, clinical, and glycomic changes may be anti-aging and inflammatory, and merit additional investigation.

背景/目的：在热量限制长期效应综合评估（CALERIE）2期研究的部分参与者中，我们评估了两年约25%热量限制（CR）饮食对IgG N-糖基化（糖龄）、血浆及补体C3 N-糖组的影响，这些指标作为衰老和炎症衰老的标志物。

方法

从美国国立衰老研究所衰老研究生物样本库获取了26名CR组参与者的血浆样本，这些参与者完成了CALERIE2试验且被认为坚持了干预措施（12个月时约>10%的热量限制）。对基线（BL）、干预中期（12个月）和干预后（24个月）的样本进行了超高效液相色谱（UPLC）或液相色谱-质谱（LC-MS）分析的糖组学研究，并检测了两年CR干预导致的变化。此外，分析了人体测量、临床、代谢、DNA甲基化（表观遗传）和骨骼肌转录组数据，以确定与N-糖组变化同时发生的衰老相关变化。

结果

经过两年的CR干预后，与基线相比，24个月时IgG半乳糖基化更高（p = 0.051），双半乳糖基化和糖龄（基于IgG的生物学年龄替代指标）在基线与12个月或基线与24个月之间无差异，但在12个月至24个月之间增加（分别为p = 0.016、0.027）。糖龄也与肿瘤坏死因子-α（TNF-α）和细胞间黏附分子-1（ICAM-1）呈正相关（分别为p = 0.030、p = 0.017）。两年的干预使血浆高度分支聚糖减少（基线与24个月比较：p = 0.013），但血浆和IgG中的平分型N-乙酰葡糖胺均增加（基线与24个月比较：p<0.001、p = 0.01）。此外，总补体C3蛋白浓度降低（基线与24个月比较：p <0.001），甘露糖9糖型（基线与24个月比较：p<0.001）和甘露糖10（糖基化的）C3糖型（基线与24个月比较：p = 0.046）也降低。