No organ is an island: Genetic study reveals unique but interrelated markers of aging

In a recent study published in the journal The aging of naturea team of researchers used a large dataset of participants of European descent from the United Kingdom (UK) Biobank to explore the genetic underpinnings of the biological age gap, or BAG, a comprehensive marker of human aging, in nine organ systems .

Study: Genetic architecture of biological age in nine human organ systems. Image credit: Orawan Pattarawimonchai / Shutterstock

Background

A multitude of environmental, genetic, and lifestyle factors contribute to and influence the complex process of biological aging. Understanding the genetic architecture and phenotypic patterns of biological aging across organ systems in the human body is essential for identifying resilience factors and vulnerabilities in human health, as well as for assessing age-related diseases and developing personalized therapeutic interventions. .

Studies have reported the involvement and connection of multiple organ systems in human health and disease, such as the heart-brain-liver axis and the biological pathways shared by the three organs. Other studies have reported the role of central nervous system and intercellular peptide and lipid-mediated signaling in metabolic health.

Advances in artificial intelligence technology have also led to the adoption of the concept of the biological age gap (BAG) as a biomarker of human aging in organ systems. BAG is defined as the difference between an individual’s age predicted through machine learning and their chronological age.

About the study

In the current study, researchers aimed to investigate the genetic architecture of BAG in nine organ systems using a multimodal UK Biobank dataset of over 377,000 participants of European descent.

Previously, the same team of researchers had used a genome-wide association study and magnetic resonance imaging to determine the genetic architecture of BAG in the brain. Here, they extended that work by examining the underlying genetic architecture of BAG in nine organ systems: the cardiovascular, optic, immune, hepatic, metabolic, renal, pulmonary, and musculoskeletal systems.

The researchers hypothesized that the underlying genetic architecture of BAGs would be specific to each organ system, but interconnected across organ systems. To explore this hypothesis, they first performed a genome-wide association study and a genetic correlation and heritability analysis at the gene level for 154,774 from the UK.

The multimodal data used for the study also included physiological and physical measurements and phenotypes derived from magnetic resonance imaging data and various other measurements such as blood pressure, pulse rate, liver-related blood biomarkers, hematological variables , C-reactive protein levels, Lung function measurements, vitamin D levels and electrolyte regulation, and glomerular filtration biomarkers.

The genome-wide association study also included a cognitive variable and six lifestyle factors. Lifestyle factors included coffee, tea and fresh fruit consumption, sleep duration, body weight and time spent outside, while the cognitive variable included in the analysis was reaction time.

Single nucleotide polymorphism (SNP)-based inheritance was assessed, followed by annotation of mapped genes and BAG-associated genomic loci for each organ system. These SNPs were further analyzed for inter-organ associations across the phenomenon and organ-specific associations.

For the remaining 222,254 participants, a Mendelian randomization analysis was also performed to explore potential causality between BAGs, modifiable lifestyle factors, and chronic diseases such as diabetes and Alzheimer’s.

Results

The results showed that the genetic architecture of BAGs for the nine organ systems was organ-specific but also exerted cross-organ cross-talk through pleiotropic connections with other organ systems. Moreover, the genetic and phenotypic correlations among the BAGs of the nine organ systems mirrored each other.

Results from the Mendelian randomization also revealed possible causal links between the nine BAGs, lifestyle factors such as sleep duration and body weight, and chronic diseases such as diabetes and Alzheimer’s disease.

Given that the brain regulates numerous physiological processes and is involved in maintaining homeostasis, the researchers believe that the correlation between the brain and clinical features of other organ systems was not surprising. It was also not found that other organ systems showed enrichment of metabolic traits.

Musculoskeletal and hepatic BAGs exhibited a bidirectional relationship, which was supported by findings from previous research on the influence of metabolic health and liver function on musculoskeletal health. Moreover, this inter-organ connection may also explain the role of musculoskeletal disorders such as muscle wasting, sarcopenia, and osteoporosis in derangement of liver metabolism and causation of non-alcoholic fatty liver disease.

conclusions

To summarize, the study analyzed the genetic basis of biological age gaps for nine organ systems and found that each organ system had specific genetic variants associated with BAGs, but were also linked through pleiotropic mechanisms. The findings revealed that examining people through a multi-organ perspective and considering the impact of lifestyle factors on these inter-organ connections can help to better understand complex diseases and design more holistic treatment approaches.