Aging is associated to cognitive decline, which can lead to loss of life quality, personal suffering, and ultimately neurodegenerative diseases. Neuroinflammation is one of the mechanisms explaining the loss of cognitive functions. Indeed, aging is associated to the activation of inflammatory signaling pathways, which can be targeted by specific nutrients with anti-inflammatory effects. Dietary n-3 polyunsaturated fatty acids (PUFAs) are particularly attractive as they are present in the brain, possess immunomodulatory properties, and are precursors of lipid derivates named specialized pro-resolving mediators (SPM). SPMs are crucially involved in the resolution of inflammation that is modified during aging, resulting in chronic inflammation. In this review, we first examine the effect of aging on neuroinflammation and then evaluate the potential beneficial effect of n-3 PUFA as precursors of bioactive derivates, particularly during aging, on the resolution of inflammation. Lastly, we highlight evidence supporting a role of n-3 PUFA during aging.

Neuroinflammation constitutes a normal part of the brain immune response orchestrated by microglial cells. However, a sustained and uncontrolled production of proinflammatory factors together with microglial activation contribute to the onset of a chronic low-grade inflammation, leading to neuronal damage and cognitive as well as behavioral impairments. Hence, limiting brain inflammatory response and improving the resolution of inflammation could be particularly of interest to prevent these alterations. Dietary n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides are good candidates because of their immunomodulatory and proresolutive properties. These compounds are present in a fish hydrolysate derived from marine-derived byproducts. In this study, we compared the effect of an 18-day supplementation with this fish hydrolysate to a supplementation with docosahexaenoic acid (DHA) on lipopolysaccharide (LPS)-induced inflammation in mice. In response to peripherally injected LPS, the fish hydrolysate supplementation decreased the hippocampal mRNA expression of the proinflammatory cytokines IL-6 (p < 0.001), IL-1β (p = 0.0008) and TNF-α (p < 0.0001), whereas the DHA supplementation reduced only the expression of IL-6 (p = 0.004). This decline in proinflammatory cytokine expressions was associated with an increase in the protein expression of IκB (p = 0.014 and p = 0.0054 as compared to the DHA supplementation and control groups, respectively) and to a modulation of microglial activation markers in the hippocampus. The beneficial effects of the fish hydrolysate could be due in part to the switch of the hippocampal oxylipin profile towards a more anti-inflammatory profile as compared to the DHA supplementation. Thus, the valorization of fish byproducts seems very attractive to prevent and counteract neuroinflammation.

Aging is characterized by a decline in social behavior and cognitive functions leading to a decrease in life quality. In a previous study, we show that a fish hydrolysate supplementation prevents age-related decline in spatial short-term memory and long-term memory and anxiety-like behavior and improves the stress response in aged mice. The aim of this study was to determine the effects of a fish hydrolysate enriched with EPA/DHA or not on the cognitive ability and social interaction during aging and the biological mechanisms involved. We showed for the first time that a fish hydrolysate enriched with EPA/DHA or not improved memory performance and preference for social novelty that were diminished by aging. These changes were associated with the modulation of the gut microbiota, normalization of corticosterone, and modulation of the expression of genes involved in the mitochondrial respiratory chain, circadian clock, neuroprotection, and antioxidant activity. Thus, these changes may contribute to the observed improvements in social behavior and memory and reinforced the innovative character of fish hydrolysate in the prevention of age-related impairments.

Aging is characterized by cognitive decline, including episodic and working memory impairments, which can lead to loss of autonomy. Among older adults, one quarter, referred to here as "decliners," show greater-than-average cognitive decline for their age group without reporting memory complaints. To prevent or slow this accelerated decline and maintain a good quality of life in seniors, nutrition represents a promising approach. This study evaluates the effect of a 3-mo fish hydrolysate (FH) supplementation on memory performance in healthy older adults identified as decliners. The primary outcome of this study was the Paired Associates Learning Total Error Adjusted (PALTEA) score, assessing episodic memory. In this double-blind, randomized, placebo-controlled trial, 53 healthy older adults (60-73 y; Mini-Mental State Examination >27; PALTEA ≥41) received either FH [1 g of low-molecular-weight peptides and 30 mg n-3 (ω-3) long-chain polyunsaturated fatty acids (PUFAs)] or placebo daily for 3 mo. Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery. Statistical analyses were performed using analysis of covariance, adjusting for baseline values, age, and education level, with significance set at P < 0.05. FH supplementation significantly improved PALTEA scores compared with placebo [P = 0.003; β = -11.75; confidence interval (CI): -19.30, -4.19], with more patterns completed (P < 0.001; β = 1.34; CI: 0.58, 2.09) and fewer errors at higher levels (6 and 8 patterns; P = 0.040; β = -3.66; CI: -7.15, -0.17, and P = 0.004; β = -5.74; CI: -9.60, -1.89). Working memory showed partial improvement, notably the spatial working memory strategy score (P = 0.018; β = -1.26; CI: -2.31, -0.22). Verbal recognition did not differ between groups. FH supplementation increased erythrocyte n-3 PUFA levels (P = 0.036; β = 0.80; CI: 0.05, 1.54), and reduced serum C-reactive protein levels (P = 0.038; β = -0.33; CI: -0.63, -0.02) and inflammation status score (P = 0.046; β = -0.35; CI: -0.69, -0.01). Three months of FH supplementation improved episodic memory and working memory in older adults with accelerated cognitive decline, alongside a better n-3 PUFA profile and reduced inflammation, supporting FH as a promising strategy to promote healthy cognitive aging. This trial was registered at clinicaltrials.gov as NCT04910399.