Elderly person climbing a DNA staircase representing frailty and healthy aging.

Unlocking the Secrets of Frailty: How Genes and Lifestyle Impact Healthy Aging

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Jordan Keane in Health & Wellness July 2025 • 4 min read.

"New research identifies a key genetic link to frailty, opening doors for personalized approaches to healthy aging and improved quality of life."


Frailty, a state of increased vulnerability to stressors, affects millions worldwide, particularly as populations age. Characterized by a decline in physiological reserves, frailty increases the risk of falls, disability, and other adverse health outcomes. Understanding the underlying factors that contribute to frailty is crucial for developing effective prevention and treatment strategies.

While aging and certain chronic conditions are known risk factors, the specific mechanisms that drive frailty are still being unraveled. Recent research has begun to explore the role of genetics, alongside lifestyle and environmental factors, in determining an individual's susceptibility to frailty.

A new study published in PLOS ONE sheds light on a potential genetic link to frailty. Researchers analyzed data from two large, representative samples of older adults in the United States and the United Kingdom, identifying a gene called GRIN2B as a key player in the frailty process. This discovery could pave the way for personalized interventions that target specific genetic vulnerabilities and promote healthier aging.

Decoding the Genetics of Frailty: What the Study Revealed

Elderly person climbing a DNA staircase representing frailty and healthy aging.

The study, led by Krisztina Mekli and colleagues, employed a genome-wide association scan (GWAS) approach, examining the entire genome of participants to identify genetic variants associated with frailty. Frailty was measured using a Frailty Index (FI), which assesses the accumulation of health deficits across various domains, including physical function, cognitive ability, and chronic diseases.

The researchers discovered a significant association between a specific variant in the GRIN2B gene and frailty. Specifically, the rs7134291 A allele was linked to a decrease in the square-root transformed Frailty Index score. This finding suggests that this particular genetic variant may offer some protection against the development of frailty. The GRIN2B gene is responsible for production of N-methyl-D-aspartate receptors (NMDARs)

  • Discovery Sample: The rs6765037 A allele was significantly associated with a decrease in the square-root transformed FI score (beta = -0.01958, p = 2.14E-08).
  • Replication Sample: Nominal replication: the rs7134291 A allele was significantly associated with a decrease in the square-root transformed FI score (Discovery sample: beta = -0.01021, p = 1.85E-06, Replication sample: beta = -0.005013, p = 0.03433).
Furthermore, the study explored the biological pathways associated with frailty. Gene ontology analysis revealed that pathways related to "Neuropathic pain signaling in dorsal horn neurons" and "GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells" were significantly enriched in individuals with higher frailty scores. These findings highlight the complex interplay between genetic factors, pain pathways, and nutrient sensing in the development of frailty.

The Future of Frailty Research: Personalization and Prevention

This study provides valuable insights into the genetic underpinnings of frailty. While further research is needed to confirm these findings and explore the precise mechanisms by which GRIN2B influences frailty, the results suggest that genetic testing could one day be used to identify individuals at higher risk. This would allow for the implementation of personalized interventions, such as targeted exercise programs, nutritional guidance, and cognitive training, to delay or prevent the onset of frailty and promote healthy aging.

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This article is based on research published under:

DOI-LINK: 10.1371/journal.pone.0207824, Alternate LINK

Title: Frailty Index Associates With Grin2B In Two Representative Samples From The United States And The United Kingdom

Subject: Multidisciplinary

Journal: PLOS ONE

Publisher: Public Library of Science (PLoS)

Authors: Krisztina Mekli, Adam Stevens, Alan D. Marshall, Thalida E. Arpawong, Drystan F. Phillips, Gindo Tampubolon, Jinkook Lee, Carol A. Prescott, James Y. Nazroo, Neil Pendleton

Published: 2018-11-26

Everything You Need To Know

1

What is frailty, and why is it important to study its causes?

Frailty is a state of increased vulnerability to stressors, characterized by a decline in physiological reserves. It's important to study because it affects millions worldwide, particularly as populations age, increasing the risk of falls, disability, and other adverse health outcomes. Understanding the factors that contribute to frailty is crucial for developing effective prevention and treatment strategies, ultimately promoting healthier aging and improved quality of life.

2

How does the *GRIN2B* gene relate to frailty, according to recent research?

Recent research has identified a link between the *GRIN2B* gene and frailty. A specific variant in the *GRIN2B* gene, the rs7134291 A allele, was associated with a decrease in the square-root transformed Frailty Index score, suggesting that this particular genetic variant may offer some protection against the development of frailty. The *GRIN2B* gene is responsible for producing *N*-methyl-D-aspartate receptors (NMDARs).

3

What methods were used to determine the genetic link between the *GRIN2B* gene and frailty?

Researchers employed a genome-wide association scan (GWAS) approach, examining the entire genome of participants to identify genetic variants associated with frailty. Frailty was measured using a Frailty Index (FI), which assesses the accumulation of health deficits across various domains, including physical function, cognitive ability, and chronic diseases. The GWAS approach allowed them to pinpoint the *GRIN2B* gene as a key player.

4

Besides genetics, what other biological pathways are associated with frailty, and how might they contribute to the condition?

Gene ontology analysis revealed that pathways related to "Neuropathic pain signaling in dorsal horn neurons" and "GPCR-Mediated Nutrient Sensing in Enteroendocrine Cells" were significantly enriched in individuals with higher frailty scores. This suggests a complex interplay between genetic factors, pain pathways, and nutrient sensing in the development of frailty. The involvement of neuropathic pain signaling suggests that chronic pain may contribute to frailty, while altered nutrient sensing could affect energy metabolism and overall physiological function, further exacerbating frailty.

5

Considering the discovery of the *GRIN2B* gene's role in frailty, what potential future interventions could be developed to promote healthy aging?

The discovery suggests that genetic testing could potentially be used to identify individuals at higher risk of developing frailty. This would allow for the implementation of personalized interventions, such as targeted exercise programs, nutritional guidance, and cognitive training, to delay or prevent the onset of frailty and promote healthy aging. Further research is needed to confirm these findings and explore the precise mechanisms by which *GRIN2B* influences frailty, but the results offer a promising avenue for personalized prevention strategies. It does not mean genetic modification will happen, but personalized life interventions can begin sooner.

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