Study Finds Important Role of Gut Microbiome in Aging and Heart Disease

In a recently published study in Nature Medicine, a group of Chinese scientists conducted a prospective analysis of metabolic multimorbidity clusters based on 21 metabolic parameters to explore gut microbiome signatures associated with metabolism and age, and better understand the relationship between metabolism, age and long-term risk of cardiovascular disease.

Cardiovascular disease is a leading cause of global mortality, and metabolic disorders and age, which are also closely related, are thought to significantly increase the risk of cardiovascular disease. Metabolic disorders become more complex and widespread with age, and in older adults, cardiovascular disease typically develops in the context of multimorbidity.

Growing evidence of aging patterns associated with gut microbiome diversity in different populations suggests that the gut microbiome links immunity and metabolism, undergoes age-related changes, and may underlie healthy aging. Research has shown that low Bacteroides diversity and increased diversity of unique taxa in the gut microbiome are associated with healthy aging. However, the patterns of interactions between the gut microbiome, metabolism, and age and the extent to which these interactions influence cardiovascular health remain unclear.

In this study, the researchers began by identifying multimorbidity clusters based on specific metabolic parameters and then examined gut microbiome signatures associated with age and these multimorbidity clusters. Further, based on variation in gut microbiome signatures and 55 microbial species associated with age, they defined the concept of microbial age, which was then used to determine the role of gut microbiome composition and microbial age in specific multimorbidity clusters.

The original cohorts included adults aged 40 to 93 years. Data on demographic characteristics, medical histories, metabolic variables, and lifestyle factors such as alcohol consumption, smoking, and physical activity level were collected in 2010 and 2014. Follow-up data included information on diagnosed cardiovascular diseases. Four fecal metagenomic datasets from Israel, the Netherlands, France, Germany, the USA and the UK were used as validation cohorts.

Metabolic multimorbidity clusters based on 21 metabolic parameters were associated with cardiovascular disease risk. Parameters included body weight, height, waist circumference, high- and low-density cholesterol (HDL-C and LDL-C), apolipoprotein A-1, total cholesterol, fasting insulin levels, apolipoprotein B, γ-glutamyltransferase, aspartate aminotransferase, alanine aminotransferase, tolerance to glucose, uric acid, triglycerides, hemoglobin A1c and fasting plasma glucose.

Based on these parameters, five clusters of metabolic multimorbidity were identified, including a healthy metabolic profile, as well as clusters with low levels of HDL-C and apolipoprotein A1, high levels of LDL-C, apolipoprotein B and total cholesterol, insulin resistance, obesity, elevated enzymes liver and hyperglycemia.

Stool samples were collected from all participants and metagenome sequencing was performed using the extracted DNA. Metagenome data were used for metagenomic profiling of the original cohort.

Participants were divided into two age groups (under or over 60 years of age), and CVD risk ratios were calculated for the four unhealthy multimorbidity clusters compared with the healthy metabolic profile cluster. Risk ratios for cardiovascular disease were also calculated for younger and older age groups.

The influence of environmental and host factors on the gut microbiome was assessed, and the uniqueness and diversity indices of the gut microbiome were calculated. We then examined age- and metabolism-related features of the gut microbiome, identifying associations between metabolism, microbial age, and cardiovascular disease risk.

Results showed that compared with the healthy metabolic profile cluster, the hyperglycemia and obesity clusters had a 117% and 75% higher risk of cardiovascular disease over 11.1 years, respectively. These results were confirmed in the validation cohort.

In addition, fecal metagenome data showed that gut microbiome composition was associated with both age and multimorbidity clusters. Among individuals over 60 years of age, the increased risk of cardiovascular disease associated with hyperglycemia and obesity clusters was greater in those with higher microbial age and decreased in those with lower microbial age, regardless of sex, age, dietary factors, or lifestyle.

Younger microbial age, which was characterized by decreased abundance of Prevotella species, was associated with reduced cardiovascular disease risk in older adults from unhealthy metabolic clusters, independent of medications, dietary factors, education level, sex, age, or lifestyle.

The study revealed distinct age-related signatures of the gut microbiome, such as a significant decrease in Bacteroides species and an increase in the uniqueness and richness of facultative anaerobic bacteria such as Enterobacteriaceae and Streptococcus. These increases in pro-inflammatory pathways and microbial aging patterns appear to be associated with age-related declines in immunity, digestion, and physiological function.

In conclusion, the study examined the interaction between gut microbiome composition and diversity, age, and metabolism and its association with cardiovascular disease risk. Gut microbiome composition has been found to be associated with age and metabolic multimorbidity parameters.

In addition, based on the species composition of the gut microbiome, young microbial age was found to reduce the risk of cardiovascular disease associated with metabolic dysfunction, suggesting that the gut microbiome modulates cardiovascular health in older adults with metabolic dysfunction.