Table 1.

Summary of human studies on the effect of caloric restriction or its mimetics on Alzheimer’s disease outcomes.

Study	Intervention	Study type and participants	AD biomarker outcome	Mechanisms of aging outcome	Cognitive outcomes	Conclusion
Waziry et al. (20)	25% calorie reduction for 2 years	Post-hoc analysis of the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, phase II, multicenter, randomized controlled trial; n = 220 healthy adults (men 21–50 years old, women 21–47 years old)	—	Based on serum DNA methylation levels, significantly decreased the pace of aging (DunedinPACE algorithm; p = <0.003) but no significant difference in biological age estimation (PhenoAge and GrimAge)	—	25% calorie reduction decreased the rate of aging, however, did not lead to changes in biological age estimation
Horie et al. (21)	Nutritional counseling on weight loss via CR in group meetings for 12 months	Single-center prospective randomized controlled trial; n = 80 older adults (>60 years old) with obesity and MCI	—	Reduced HOMA-IR and CRP were associated with improved global cognition and an increase in delayed memory, respectively; increased leptin correlated with improved attention	Decreased BMI was associated with improved verbal memory, fluency, executive function, and global cognition via RAVLT and TMT	Intentional weight loss through CR correlated with improved cognition in older adults with MCI, and the strongest association was with younger seniors and APOE e4 carriers
Turner et al. (18), Sawda et al. (19)	Resveratrol (final dose of 1,000 mg BID) - caloric restriction mimic via SIRT1 activation	52-week randomized, double-blind, placebo-controlled phase II trial; n = 104 adults >49 years old with mild-to-moderate AD	Significantly higher Aβ40 levels in CSF and plasma in the resveratrol-treated group (p = 0.002)	—	Reduced decline in ADCS-ADL scores in the resveratrol-treated group, although not significant (underpowered)	Resveratrol stabilizes plasma and CSF Aβ40 levels
Moussa et al. (22)	Resveratrol (final dose of 1,000 mg BID)	Retrospective subgroup study of Turner et al. (18); analyzed CSF and plasma samples from a subset of participants with CSF biomarker-proven AD at baseline (CSF Aβ42 < 600 ng/mL); n = 19 resveratrol-treated, n = 19 placebo-treated	Greater decline of CSF Aβ42 in the placebo group than resveratrol group (p = 0.0618)	In CSF, ~50% decline in CSF MMP-9 and increased MDC, IL-4, FGF-2 in resveratrol group after 52 weeks; in plasma, increased levels of MMP-10 and decreased IL-12P40, IL12P70, and RANTES with resveratrol treatment	Reduced decline in MMSE and ADCS-ADL scores in the resveratrol group	Resveratrol slows the progression of AD via its effects on regulating neuroinflammation and inducing adaptive immunity
Ooi et al. (23)	Intermittent fasting (IF) practiced regularly or irregularly (control: not fasting)	Longitudinal study of n = 99 older adults (>60 years old) with mild cognitive impairment (MCI) and otherwise healthy; maximum follow-up 36 months	—	Increased superoxide dismutase activity, decreased body weight, insulin levels, CRP, and DNA damage with regular IF	Increase in mean scores for Digit Span Test, RAVLT, MMSE, and MOCA in fasting groups	Regularly practiced IF led to improved cognitive scores and cognitive function in older adults with MCI