Study reveals 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 investigate gut microbiome signatures associated with metabolism and age and better understand the relationship between metabolism, age, and long-term cardiovascular disease risk.

Cardiovascular diseases are the 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 prevalent with age, and in older people, cardiovascular disease usually develops in the context of multimorbidity.

Growing evidence on patterns of aging 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. Studies have 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 defining multimorbidity clusters based on specific metabolic parameters and then examined gut microbiome signatures associated with age and these multimorbidity clusters. They then defined the concept of microbial age based on variations in gut microbiome signatures and 55 microbial species associated with age, which they then used to determine the role of gut microbiome composition and microbial age in specific multimorbidity clusters.

The initial 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 were collected in 2010 and 2014. Follow-up data included information on incident cardiovascular disease. Four faecal metagenomic datasets from Israel, the Netherlands, France, Germany, the United States, and the United Kingdom were used as validation cohorts.

Metabolic multimorbidity clusters constructed from 21 metabolic parameters were associated with the risk of incident cardiovascular disease. The parameters included body weight, height, waist circumference, high-density lipoprotein (HDL-C) and low-density lipoprotein (LDL-C), apolipoprotein A-1, total cholesterol, fasting insulin levels, apolipoprotein B, γ-glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, glucose tolerance, 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 HDL-C and apolipoprotein A1, high LDL-C, apolipoprotein B and total cholesterol, insulin resistance, obesity, elevated liver enzymes 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), and CVD risk ratios were calculated for the four unhealthy multimorbidity clusters compared with the healthy metabolic profile cluster. CVD risk ratios were also calculated for the 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. Age- and metabolism-related features of the gut microbiome were then examined, and associations between metabolism, microbial age, and cardiovascular disease risk were determined.

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.

Furthermore, faecal 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 higher in individuals with higher microbial ages and lower in individuals with lower microbial ages, independent of sex, age, dietary factors, or lifestyle.

Young microbial age, which was characterized by reduced abundance of Prevotella species, was associated with reduced CVD risk in older adults from unhealthy metabolic clusters, independent of medication use, dietary factors, education level, gender, age, or lifestyle.

The study found distinct age-related gut microbiome signatures, 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. This increase 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. It was found that gut microbiome composition was associated with age and metabolic multimorbidity parameters.

Furthermore, based on the composition of gut microbiome species, 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.