Epidemiological studies and basic research suggest a protective effect of long-chain omega-3 polyunsaturated fatty acids, antioxidants and B vitamins against brain aging. However, most randomized controlled trial (RCTs) with nutritional supplements have yielded disappointing effects on cognition so far. This paper suggests some original directions for future research to better support a role of nutrition in brain aging. The role of other nutrients such as docosapentaenoic acid and fat-soluble vitamins D and K should be investigated. A more holistic approach of nutrition is necessary, encompassing potential synergies between nutrients as found in a balanced diet. Potential beneficiaries of a nutritional supplementation should be better targeted, according to their dietary, cognitive and maybe genetic characteristics. Innovative RCTs should be implemented to assess the impact of nutrition for the prevention or treatment of cognitive decline in older persons, using intermediate biomarkers of disease progression and mechanisms of action of nutrients as outcomes.