A Multidomain Lifestyle Intervention Is Associated With Improved Functional Trajectories and Favorable Changes in Epigenetic Aging Markers in Frail Older Adults: A Randomized Controlled Trial.

The multidomain lifestyle intervention significantly reduced frailty as assessed by the SHARE-FI score compared to the control group.

• Randomized controlled trial with 47 frail, community-dwelling individuals in Spain recruited between October 2019 and July 2022.
• Control group (CG): n=19, mean age 80.2 years (SD 3.1); Intervention group (IG): n=28, mean age 80.5 years (SD 4.3).
• Intervention consisted of a 6-month multidomain lifestyle program including nutritional supplementation and supervised exercise.
• Reduction in frailty (SHARE-FI score) in the IG compared with CG: p<0.0001.

The intervention group showed significant improvements in multiple physical function measures compared to the control group.

• Grip strength improved in the IG compared with CG (p=0.0053).
• Gait speed improved in the IG compared with CG (p=0.0125).
• Tinetti score (balance and gait assessment) improved in the IG compared with CG (p=0.0031).
• Barthel Index (activities of daily living) improved in the IG compared with CG (p=0.0484).

The intervention was associated with a statistically significant reduction in DNAm PhenoAge, an epigenetic clock marker of biological aging.

• DNAm PhenoAge was reduced in the IG compared with CG (p=0.0253).
• Whole-blood methylome analysis included five epigenetic clocks, a DNA methylation-based telomere length estimator, and the Rate of Epigenetic Aging (REA).
• Other epigenetic clocks assessed showed nonsignificant changes.
• The authors identify DNAm PhenoAge as a complementary marker for assessing health span-related changes in frail older adults.

The intervention was associated with preserved DNA methylation-based telomere length, while the control group showed telomere shortening.

• Methylation-based telomere length was preserved in the IG compared with CG (p=0.0246).
• The authors suggest that methylation-based telomere length may serve as a complementary marker for assessing health span-related changes in frail older adults.

The Rate of Epigenetic Aging (REA) using DNAm PhenoAge indicated an acceleration of epigenetic aging in the control group over the 6-month period.

• REA using DNAm PhenoAge showed acceleration of epigenetic aging in the CG (p=0.0300).
• This finding contrasts with the intervention group, where epigenetic aging was not similarly accelerated.
• REA was one of the epigenetic aging metrics derived from the whole-blood methylome analysis.

The intervention was associated with statistically significant improvements in nutritional blood markers.

• Nutritional blood markers improved significantly in the IG compared with the CG.
• Specific nutritional markers were assessed as part of the broader intervention outcomes alongside functional and epigenetic measures.
• The intervention included a nutritional supplement component as part of the multidomain lifestyle approach.

Frailty was identified as an intermediate stage preceding disability, with a recognized gap in molecular signatures for early detection of subclinical cellular changes.

• The study was designed to address the gap in molecular signatures that could help predict frailty onset or the effectiveness of interventions.
• The study population consisted of frail, community-dwelling individuals with mean age approximately 80 years.
• Both phenotypical/functional changes and whole-blood methylome changes were assessed before and after the 6-month intervention.