Preliminary effects of a modified Otago Exercise Program on metabolic, cellular, and epigenetic biomarkers in people living with dementia: A pilot randomized controlled trial

Exercise may be a potential disease-modifying therapy to improve physiological function in people living with dementia (PWD), though further evidence is required. The purpose of this randomized controlled trial (RCT) was to investigate whether a modified Otago Exercise Program (OEP) would improve markers of metabolic aging, cellular aging, and epigenetics relative to usual care alone in PWD. In this 6-month, parallel-group, assessor-blinded RCT (NCT05488951), 42 PWD (mean age 82.1 ± 8.1 years; mean MoCA score 10.0 ± 5.9; 35.7% female) were randomly allocated 1:1 to exercise (n = 21) or usual care (n = 21). The exercise group performed 30 min of physical therapist-supervised strength and balance exercises followed by 30 min of walking, 3×/week for six months, alongside usual care. The usual care group continued routine healthcare and social activities. Primary outcomes were changes in fasted blood biomarkers: kynurenine (metabolic aging), leukocyte telomere length (cellular aging), and global DNA methylation (epigenetics), assessed at baseline and 6 months. The intention-to-treat analysis included all 42 participants, and the per-protocol analysis included only those in the exercise group who completed ≥2×/week exercise (n = 9/21) and all usual care participants (n = 21). Intention-to-treat and per-protocol analyses revealed no statistically significant between-group differences in any biomarker. However, telomere length increased in the usual care group (7.90 ± 0.90 to 8.70 ± 0.90 kb), while there was no change in the exercise group (8.00 ± 0.90 to 7.90 ± 0.90 kb) from baseline to 6 months. While statistically significant group differences were not observed, our trial demonstrates the feasibility of biomarker collection in PWD and reveals trends-particularly in telomere length-that warrant investigation in larger, adequately powered trials.