News | Karolinska team discovers new genes that may help prevent frailty in the elderly
A new study from the Karolinska Institutet in Sweden, published in the journal Nature Aging, has for the first time revealed multiple genetic variants associated with frailty in the elderly by integrating large-scale genomic analysis with proteomics. This finding offers new hope for early prediction and intervention in age-related functional decline.
Frailty: A key clinical phenotype of aging
Aging is a complex process accompanied by the gradual decline of multiple physiological functions. Frailty is a key clinical phenotype of this process, characterized by reduced resilience, making individuals more susceptible to falls, infections, hospitalization, and even death.
Currently, there is no unified gold standard for measuring frailty. In recent years, the "Hospital Frailty Risk Score" (HFRS) has been developed to assess at-risk populations. It overlaps to some extent with the traditional "frailty index" and "frailty phenotype" models but places greater emphasis on the clinical value of medical diagnostic records.
Study design: Large-scale multinational population genetic analysis
The research team first conducted a genome-wide association study in FinnGen, Finland's national genetic database (with over 500,000 genetic and health data records), to identify genetic variants associated with frailty. They then validated the findings in the UK Biobank (with over 400,000 genetic samples) and integrated the results using polygenic risk scores (PRS) and meta-analysis. Additionally, the study incorporated protein-level expression and colocalization analyses to screen for potential causal genes.
Key findings: 53 genetic variants associated with frailty
Fifty-three significant variants were found to be associated with frailty, 45 of which were reported for the first time; these variants mapped to 41 genes, 6 of which had no prior related reports.
Colocalization analysis identified multiple candidate causal genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1, and PPP6C.
CHST9: encodes a key enzyme in intercellular signal transduction
C6orf106 (ILRUN): regulates inflammation and lipid metabolism
CGREF1: associated with cell cycle and adhesion
APOE: an important gene in Alzheimer's disease
PPP6C: involved in the regulation of the NF-kappa-B pathway
Despite their diverse functions, the polygenic evidence collectively points to the central role of immune-inflammatory regulation, cell interaction, and adhesion mechanisms in the development of frailty.
Protein expression analysis showed that elevated levels of CGREF1 and NECTIN2, as well as decreased levels of MET and APOC1, were associated with an increased risk of frailty.
Cell-type enrichment analysis found that these genes are highly expressed in multiple brain regions (limbic system, cerebrum, cerebellum, etc.), further highlighting the role of the central nervous system in the development of frailty.
Clinical significance: New opportunities for early prediction and intervention
The study showed that polygenic risk scores based on the HFRS can effectively predict frailty risk, early-onset frailty, mortality, and hospitalization risk. The researchers estimated that the heritability of frailty is approximately 6%, similar to results from other assessment methods.
This implies that if high-risk individuals could be identified early through genetic risk scores during midlife, targeted lifestyle adjustments or interventions might delay or even prevent the onset of frailty.
Limitations and outlook
The research team noted that the validation results from the UK Biobank were weaker than those from the Finnish database, possibly due to differences in sample sources: FinnGen involves nationwide cohorts and hospitalized patients, whereas the UK Biobank primarily consists of voluntary participants with a generally lower overall incidence of frailty.
Future research needs to further explore the role of immune-inflammatory responses and the nervous system in the development of "cognitive frailty" and promote the application of genetic risk prediction in clinical practice.
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Author LinkedIVF TeamPublished 2025-09-02
This article used AI assistance; LinkedIVF has not recorded an editorial review for this item. It is not medical advice.
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News | Karolinska Team Identifies New Genes That May Help Prevent Frailty in Older Adults
News | Karolinska team discovers new genes that may help prevent frailty in the elderly
A new study from the Karolinska Institutet in Sweden, published in the journal Nature Aging, has for the first time revealed multiple genetic variants associated with frailty in the elderly by integrating large-scale genomic analysis with proteomics. This finding offers new hope for early prediction and intervention in age-related functional decline.
Frailty: A key clinical phenotype of aging
Aging is a complex process accompanied by the gradual decline of multiple physiological functions. Frailty is a key clinical phenotype of this process, characterized by reduced resilience, making individuals more susceptible to falls, infections, hospitalization, and even death.
Currently, there is no unified gold standard for measuring frailty. In recent years, the "Hospital Frailty Risk Score" (HFRS) has been developed to assess at-risk populations. It overlaps to some extent with the traditional "frailty index" and "frailty phenotype" models but places greater emphasis on the clinical value of medical diagnostic records.
Study design: Large-scale multinational population genetic analysis
The research team first conducted a genome-wide association study in FinnGen, Finland's national genetic database (with over 500,000 genetic and health data records), to identify genetic variants associated with frailty. They then validated the findings in the UK Biobank (with over 400,000 genetic samples) and integrated the results using polygenic risk scores (PRS) and meta-analysis. Additionally, the study incorporated protein-level expression and colocalization analyses to screen for potential causal genes.
Key findings: 53 genetic variants associated with frailty
Fifty-three significant variants were found to be associated with frailty, 45 of which were reported for the first time; these variants mapped to 41 genes, 6 of which had no prior related reports.
Colocalization analysis identified multiple candidate causal genes, including CHST9, C6orf106 (ILRUN), KHK, MET, APOE, CGREF1, and PPP6C.
CHST9: encodes a key enzyme in intercellular signal transduction
C6orf106 (ILRUN): regulates inflammation and lipid metabolism
CGREF1: associated with cell cycle and adhesion
APOE: an important gene in Alzheimer's disease
PPP6C: involved in the regulation of the NF-kappa-B pathway
Despite their diverse functions, the polygenic evidence collectively points to the central role of immune-inflammatory regulation, cell interaction, and adhesion mechanisms in the development of frailty.
Protein expression analysis showed that elevated levels of CGREF1 and NECTIN2, as well as decreased levels of MET and APOC1, were associated with an increased risk of frailty.
Cell-type enrichment analysis found that these genes are highly expressed in multiple brain regions (limbic system, cerebrum, cerebellum, etc.), further highlighting the role of the central nervous system in the development of frailty.
Clinical significance: New opportunities for early prediction and intervention
The study showed that polygenic risk scores based on the HFRS can effectively predict frailty risk, early-onset frailty, mortality, and hospitalization risk. The researchers estimated that the heritability of frailty is approximately 6%, similar to results from other assessment methods.
This implies that if high-risk individuals could be identified early through genetic risk scores during midlife, targeted lifestyle adjustments or interventions might delay or even prevent the onset of frailty.
Limitations and outlook
The research team noted that the validation results from the UK Biobank were weaker than those from the Finnish database, possibly due to differences in sample sources: FinnGen involves nationwide cohorts and hospitalized patients, whereas the UK Biobank primarily consists of voluntary participants with a generally lower overall incidence of frailty.
Future research needs to further explore the role of immune-inflammatory responses and the nervous system in the development of "cognitive frailty" and promote the application of genetic risk prediction in clinical practice.
Story source:
Collected from the internet