The Women’s Health Initiative (WHI) Dietary Modification (DM) randomized trial tested a low-fat dietary pattern in 48,835 postmenopausal women. The intervention reduced fat intake and increased fruits, vegetables, and grains, and prior analyses reported reductions in specific breast cancer subtypes and a lower breast cancer mortality (hazard ratio 0.79, 95% CI 0.64–0.97, P = 0.02). Because metabolic health pathways have been hypothesized to mediate some of these benefits, and because dietary advanced glycation end-products (dAGE) are linked to metabolic dysfunction, obesity, chronic inflammation, and cancer in observational and experimental studies, the investigators examined whether the WHI dietary intervention influenced estimated dAGE consumption over time.
Foods of animal origin, particularly red and processed meats, high-fat spreads, and baked or fried foods prepared with dry heat are among the highest contributors to dAGE intake, whereas fruits, vegetables, whole grains and legumes tend to be lower in AGE content. Given the WHI intervention’s emphasis on reducing high-fat foods and increasing plant foods, the trial provided an opportunity to evaluate effects on estimated dAGE intake in a randomized setting.
The WHI DM trial enrolled 48,835 postmenopausal women aged 50–79 years at 40 U.S. clinical centers between 1993 and 1998. Participants were randomized in a 40:60 ratio to a low-fat dietary pattern intervention (n = 19,541) or to a usual diet comparison group (n = 29,294). The trial was conducted with institutional approvals and written informed consent from participants. The randomization algorithm and trial processes were implemented centrally by the WHI Clinical Coordinating Center.
The dietary intervention sought to reduce fat to 20% of total energy and to increase intake of fruits, vegetables, and grains. The program did not set caloric restriction or weight loss as goals. The intervention included 18 group sessions led by centrally trained registered dietitians and nutritionists during year one and quarterly maintenance sessions throughout the intervention period. Comparison-group participants received written health-related materials only.
Dietary intake was measured using the WHI food frequency questionnaire (FFQ) at baseline, at 1 year, and then annually in a rotating subgroup of roughly one-third of participants across the 7-year intervention. Annual measurements of weight and height were obtained by trained clinical staff, and BMI was calculated.
To estimate dietary AGE intake, the analysis matched FFQ items to Nε-carboxymethyl-lysine (CML)-AGE values reported in a previously published database that measured CML-AGE content of 540 selected foods using an enzyme-linked immunosorbent assay (ELISA) with a monoclonal anti-CML antibody. The CML-AGE values from Uribarri et al. were used as a dAGE measure, expressed as kilo Units per 1000 kilocalories (kU/1000 kcal), and have been applied in multiple prior studies assessing dAGE intake.
The analysis included 40,209 women who had FFQ data at baseline and serially through 5–7 years. Multivariable regressions with repeated dAGE measures were used to compare trajectories of estimated dAGE intake between the randomized intervention and comparison groups. The repeated-measures approach allowed examination of dAGE over time by randomization assignment.
At baseline, mean estimated dAGE scores were similar between groups: intervention 7542 kU/1000 kcal (standard deviation 912) and comparison 7514 kU/1000 kcal (standard deviation 917). Over the 5–7 year period, dAGE scores were persistently lower in the intervention group compared with the comparison group. Mean dAGE values in the intervention group ranged approximately from 5361 to 6236 kU/1000 kcal, whereas mean scores in the comparison group ranged approximately from 7159 to 7669 kU/1000 kcal. The between-group difference in dAGE across follow-up was statistically significant (P < 0.0001).
In this large randomized trial, the WHI low-fat dietary pattern intervention substantially reduced estimated dAGE consumption compared with a usual diet. The observed reductions are consistent with the intervention’s goals to lower intake of foods that tend to be high in AGEs (for example, foods of animal origin and high-fat prepared foods) and to increase consumption of fruits, vegetables and grains, which are generally lower in AGE content.
These findings align with prior WHI reports showing improvements in components of the metabolic syndrome within the intervention group, and with observational literature linking higher dAGE intake to metabolic dysfunction and cancer risk. The randomized design strengthens inference that a behavioral dietary intervention focused on fat reduction and plant food increases can meaningfully lower estimated dietary AGE exposure.
Details regarding additional covariate adjustments, subgroup analyses, or potential mediation of breast cancer outcomes by dAGE were not reported here and would require reference to the full article for further information.
The Women’s Health Initiative low-fat dietary pattern intervention led to substantial and sustained reductions in estimated dietary AGE (dAGE) intake over 5–7 years compared with usual diet. This change in estimated AGE exposure is consistent with the intervention’s targeted food changes and may be relevant to hypothesized metabolic pathways linking diet to long-term cancer outcomes.
ClinicalTrials.gov NCT00000611; registration date reported as 10/28/1999.