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Researchers Develop 'Proteomic Healthy Aging Score' Using Longitudinal Blood Serum Data

NEW YORK – New research suggests that a score derived from 22 blood serum proteins — and the gut microbes associated with that score — may serve as biomarkers for healthy aging and age-related cardiovascular or metabolic conditions.

"Our data constitute a valuable resource and offer useful insights into the roles of serum proteins in aging and age-associated cardiometabolic diseases, providing potential targets for intervention with therapeutics to promote healthy aging," co-senior and co-corresponding authors Ju-Sheng Zheng and Tiannan Guo from Westlake University in China and Yu-ming Chen, an epidemiology researcher at Sun Yat-sen University, and their colleagues wrote in a paper published in Nature Metabolism on Monday.

For their study, the researchers used data-independent acquisition mass spectrometry-based proteomics to quantify proteins in 7,565 blood serum samples collected at three time points over nine years from 3,796 middle-aged and elderly participants in the Guangzhou Nutrition and Health Study.

"Although aptamer-based proteomics (SOMAscan) and antibody-based proteomics (Olink) have the advantage of high sensitivity and the ability to detect thousands of proteins, MS-based proteomics offers an unbiased and hypothesis-free way of analyzing the serum proteome," the authors explained.

Starting with serum proteomic data for a subset of 1,939 participants placed in the discovery cohort, the team tracked down 86 proteins with ties to aging, including 38 age-related proteins not found in past studies, that were subsequently tested using serum protein data for 1,857 GNHS participants in the validation cohort.

The proteins also appeared to coincide with 14 age-related chronic diseases and 32 clinical traits in the investigators' follow-up pathway and protein-protein interaction network analyses, prompting them to use machine learning to focus in on a serum protein signature for aging — known as the "proteomic healthy aging score" or PHAS — that included 22 of the 86 original proteins.

"Our findings suggest that aging-related proteins are closely associated with health status and disease risk during aging, especially for cardiometabolic health," the authors wrote. "Based on these aging-related proteins, we created a PHAS that was associated with long-term risk of several cardiometabolic diseases."

After validating the PHAS with targeted liquid chromatography and mass spectrometry-based proteomic testing in 179 serum samples collected at two time points from 115 participants in an independent cohort, the investigators used proportion of variances analyses to search for physical or lifestyle factors associated with the PHAS — from diet, alcohol consumption, physical activity, or smoking behavior to host genetics, age, sex, body mass index, or gut microbial community features.

While host genetics appeared to explain nearly 8 percent of variance in the serum representation of the 22 proteins in the PHAS collection, some 3.8 percent of variance tracked with potentially modifiable gut microbiome features. Another 4 percent of PHAS protein variance was linked to intrinsic factors such as age, while diet appeared to explain just 0.4 percent of the PHAS variance.

When the team dug into the metagenomic sequence data used to find gut microbial ties to PHAS variance, it identified 18 gut microbial species linked to that variance, which together made up a gut microbial score associated with PHAS in data from both the discovery and independent validation cohort.

"A microbial score derived from variance-contributing microbial species for PHAS showed a robust positive association with PHAS," the authors reported, "aligning with previous evidence suggesting that gut microbiome patterns can reflect healthy aging and predict survival in older age."

Based on these and other data, they suggested that "aging-related proteomic biomarkers hold great clinical relevance, promising intervention and therapeutic targets for addressing aging-related morbidities."