Combined physical and cognitive training enhances telomere length in mild cognitive impairment patients

Background: Environmental enrichment training may delay cognitive decline in mild cognitive impairment (MCI) by reducing telomere shortening, a cellular marker of aging. We investigated whether combined physical/cognitive training affects leukocyte telomere length (LTL) in the randomized trial “Train the Brain”. Methods: LTL was assessed in 94 MCI (75.1 ± 5.1 years) subjects and 37 non-MCI subjects (73.2 ± 4.6 years). MCI patients were assigned to receive either 7 months of training or standard care. After 7 months, both groups were reassessed for changes in LTL and the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog). Telomerase reverse transcriptase (hTERT) mRNA and telomeric repeat-containing RNA (TERRA) were also tested in 24 patients. Results: MCI patients had shorter LTL than controls (p = 0.02), and short LTL was associated with a higher risk of MCI (ORadjusted = 2.6; 95%CI, 1.1–6.0; p = 0.03). Training improved ADAS-cog scores (T0 = 15.1 ± 4.8 to T7 = 13.4 ± 5.0, p = 0.01) and increased LTL (T0 = 0.97 ± 0.21 to T7 = 1.04 ± 0.23, p = 0.04). hTERT mRNA levels were negligible in MCI patients at T0 and T7, indicating inactive telomerase. TERRA expression increased in untrained MCI (p = 0.02), which may reflect impaired telomere homeostasis. Conclusions: MCI patients have shorter telomeres, and combined training lengthens them, suggesting modifiable telomere homeostasis through non-pharmacological intervention. Telomere shortening may underlie increased telomeric transcription in untrained individuals, highlighting telomeric non-coding RNAs as potential therapeutic targets in age-related disease.