β-Lactolin Reduces Age-Related Inflammation and Cognitive Decline

Abstract

With the rapid increase in aging populations worldwide, there has been an increase in demand for preventive and therapeutic measures for age-related cognitive decline and dementia. Epidemiological studies show that consumption of dairy products reduces the risk for cognitive decline and dementia in the elderly. We have previously demonstrated in randomized trials that the consumption of β-lactolin, a whey-derived Gly-Thr-Trp-Tyr lactotetrapeptide, improves cognitive function in older adults. Orally administered β-lactolin is delivered to the brain and inhibits monoamine oxidase, resulting in alleviation of memory impairment. However, there is currently no evidence of the effects of long-term β-lactolin intake on aging. Here, we found that the discrimination index in the novel object recognition test for object recognition memory was reduced in mice aged 20 months compared with that in young mice, indicating that age-related cognitive decline was induced in the aged mice; in aged mice fed β-lactolin for 3 months, memory impairment was subsequently alleviated. In aged mice, impairment of light/dark activity cycles was found to be induced, which was subsequently alleviated by β-lactolin consumption. Additionally, the number of activated microglia in the hippocampus and cortex and the production of cytokines (tumor necrosis factor-α, macrophage inflammatory protein-1α, and macrophage chemoattractant protein-1) were increased in aged mice compared with those in young mice but were reduced in aged mice fed β-lactolin. The age-related hippocampal atrophy was improved in aged mice fed β-lactolin. Cytochrome c levels in the hippocampus and cortex were increased in aged mice compared with those in young mice but were also reduced by β-lactolin consumption. These results suggest that β-lactolin consumption prevents neural inflammation and alleviates aging-related cognitive decline.

Keywords: aging; cognitive decline; inflammation; memory; whey; β-lactoglobulin; β-lactolin; β-lactopeptide.

Figure 1

Novel object recognition test. The time taken to approach a novel or familiar object was measured (A), and the discrimination index (B) in the novel object recognition test was calculated. Data are represented as mean ± SE and were analyzed by Student t-test (A) and one-way ANOVA, followed by the Tukey–Kramer test (B). ^*p < 0.05 and ^**p < 0.01.

Figure 2

Measurement of activity during light/dark cycles. Distance traveled every 10 min over 72 h. Total distance in the home cage over 72 h (A) and the distance over 10 min during light and dark periods (B). Distance grap every 10 min over 72 h. by young mice (C) and aged control mice (D). Data are represented as mean ± SE and were analyzed by Student t-test (B) and one-way ANOVA, followed by the Tukey–Kramer test (A). ^*p < 0.05 and ^**p < 0.01.

Figure 3

Measurement of glial activation and cytochrome C in aged mice. In the hippocampus and cerebral cortex: percentage of the Iba-1-positive area (A,B, respectively); percentage of the GFAP-positive area (C,D, respectively); percentage of the cytochrome C-positive area (E,F, respectively). Areas were detected by immunohistochemistry. Data are represented as mean ± SE and were analyzed by one-way ANOVA, followed by the Tukey–Kramer test. ^*p < 0.05.

Figure 4

Levels of cytokines and chemokines in the hippocampus of aged mice. The levels of TNF-α, MCP-1, and MIP-1α in the hippocampus (A–C, respectively). Data are represented as mean ± SE and were analyzed by one-way ANOVA, followed by the Tukey–Kramer test. ^*p < 0.05.