Distinct epigenetic ageing patterns are associated with heterogeneity in kidney function decline in type 2 diabetes

Area of Science:

• Gerontology
• Endocrinology
• Epigenetics

Background:

• Biological ageing is heterogeneous and influences chronic disease susceptibility.
• Type 2 diabetes (T2D) presents diverse clinical phenotypes, but their distinct ageing patterns and impact on kidney health are not well understood.

Purpose of the Study:

• To investigate differences in epigenetic age acceleration (EAA) across T2D subgroups.
• To determine if these EAA patterns correlate with longitudinal kidney function decline.

Main Methods:

• Utilized epigenetic clocks to quantify EAA in 607 multi-ethnic Asians with recent-onset T2D, classified into mild obesity-related diabetes (MOD), mild age-related diabetes with insulin insufficiency (MARD-II), and severe insulin-resistant diabetes with relative insulin insufficiency (SIRD-RII) subgroups.
• Assessed kidney function longitudinally via estimated glomerular filtration rate (eGFR) slope over a median of 7.3 years.
• Performed epigenome-wide analyses to identify subgroup-specific, glucose-responsive ageing loci.

Main Results:

• The SIRD-RII subgroup exhibited accelerated ageing across multiple epigenetic clocks, despite being chronologically younger, while MARD-II showed lower EAA despite being older.
• GrimAge2logA1c was highest in SIRD-RII and significantly associated with kidney function decline (eGFR slope).
• Hypomethylation at TXNIP (cg19693031) characterized SIRD-RII, correlating with faster ageing and kidney function decline; longitudinal glucose-linked epigenetic ageing changes were linked to TXNIP methylation.

Conclusions:

• T2D subgroups represent distinct epigenetic ageing phenotypes associated with varying renal vulnerability.
• Integrating epigenetic ageing metrics into clinical T2D stratification may identify individuals at risk for accelerated ageing, enabling early geroscience-guided interventions.