DRIs for bioactives? Start with lutein, set the template, and work out the kinks, says academic

09-Jun-2014 - Last updated on 19-Oct-2023 at 14:32 GMT

Efforts to establish a framework for dietary reference intakes for bioactives should start with lutein, says a leading researcher, with ‘different kinds of data saying the same thing’.

For our recent Eye Health Special Edition, we discussed the pursuit of a DRI for lutein with leading industry figures, all of whom agreed that achieving this would be “a long and arduous process”, which could require more than five years to complete.

Dietary Reference Intakes (DRIs) are a set of four nutrient reference values for healthy populations. They include the Recommended Daily Allowance (RDA), Adequate Intake (AI), Estimated Average Requirement (EAR), and Tolerable Upper Intake Level (UL).

“I think academia and industry is enthused about DRIs for lutein, but we’re a long way away,” said Elizabeth Johnson, PhD, Scientist I in the Antioxidants Laboratory in the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University.

Dr Johnson, who works at the cutting edge of lutein research, said that any progress on a DRI would require someone from the FDA getting on board, or as she puts it, “a cheerleader on the inside. Someone to push it internally and we don’t have that”.

“But I think it’s important that it happens. Lutein is out there and people know about it. I think it would be a nice case scenario for bioactives because of the science behind lutein.”

All eyes on lutein

The link between lutein and eye health was first reported in 1994 by Dr Johanna Seddon and her co-workers at Harvard University, who found a link between the intake of carotenoid-rich food, particularly dark green leafy vegetables like spinach, and a significant reduction in age-related macular degeneration (AMD) (

The macula is a yellow spot of about five millimeters diameter on the retina. As we age, levels of the pigments in the macula decrease naturally, thereby increasing the risk of AMD. The yellow color is due to the content of the carotenoids lutein and zeaxanthin.

JAMA, Vol. 272, pp. 1413-1420). The burden of AMD falls on 25 to 30 million people worldwide, according to AMD Alliance International.

Research dollars have flowed into research (both public and private) exploring lutein and zeaxanthin for eye health, with many positive studies boosting the lutein/zeaxanthin market, worth approximately $145 million globally. In the US it is estimated to be between $90 and 100 million.

“Lutein is not an essential nutrient,” said Dr Johnson, “meaning you don’t see a specific disease when it’s removed from the diet, and so for this bioactive we need a different framework for DRIs.

“Ideally we need to do something,” she added, “because most everyone is getting less than two milligrams per day. The level to give a protective reduction in the risk of AMD is about six milligrams per day, so there’s a gap. People really need to have the recommendation to meet those needs. And this has implications for meals on wheels, for school lunch programs, and so on.”

New criteria for DRIs for bioactives

At Experimental Biology earlier this year Dr Johnson discussed the criteria needed for bioactives to get recommendations, based on the nine criteria presented by Joanne Lupton et al. in the European Journal of Nutrition (Vol. 53 Suppl 1, pp. 1-9, doi: 10.1007/s00394-014-0666-3), which are listed as:

1. A deﬁnition of the substance which is commonly accepted
2. Preferably backed up by a multi-center analysis such as an AOAC method
3. Database of the amount of the bioactive in foods
4. Prospective cohort studies
5. Clinical trials on digestion, absorption, activation, transport, excretion of the substance
6. Clinical trials on efﬁcacy and dose–response data
7. Safety data at the level of intake that might be anticipated
8. Systematic Reviews and/or meta analyses showing efﬁcacy
9. A plausible biological explanation for efﬁcacy

Eye — "There are about 600 carotenoids in nature, but only lutein and zeaxanthin get to the retina" - Dr Liz Johnson

So how does lutein compare with these nine? “It does really well,” said Dr Johnson. The only criteria lacking, she said, was on the limited number of meta-analyses for the compound (PubMed shows three for lutein related to eye health: One for AMD (Ma at al. British Journal of Nutrition, 2012, Vol. 107, pp. 350-9), and two for cataracts (Ma et al. Graefes Arch Clin Exp Ophthalmol. 2014, Vol. 252, pp. 63-70, and Liu et al. Nutrients, 2014, Vol. 6, pp. 452-65).

“As far as having a test case for a bioactive, lutein would be a good one to start with,” she said. “We could do a dry run with lutein to set the template, and work out the kinks.”

Despite missing out on meta-analyses, Dr Johnson said that the strongest case for lutein is the biological explanation for its efficacy. “There is a binding protein for lutein in the retina, which means your body really wants it.”

Data from monkey studies (because primates have maculas, unlike guinea pigs and white rats) indicate that animals who were devoid of carotenoids all their lives (and the mothers were deficient) had no macula pigment, there was no lutein or zeaxanthin present. Monkeys exposed to blue light displayed damage to their maculas, but when they were fed lutein and zeaxanthin and then exposed to blue light the damage was reduced or prevented.

Other studies with monkeys have shown that lutein is distributed in retina pigment epithelial cells, which traffic nutrients into the retina and waste out, explained Dr Johnson. In monkeys without lutein and zeaxanthin these retina pigment epithelial cells are distorted. In monkeys supplemented with lutein and zeaxathin, these cells look more normal.

The brain issue

There is also compelling evidence linking lutein and cognitive function, she said. Data from pediatric brain tissue studies have shown that about 60% of the total carotenoids in the pediatric brain tissue is lutein, and yet NHANES data show that lutein is only about 12% of the carotenoids in the diets, so there is a preference for lutein in the brain, she noted.

“There’s no link between beta-carotene or lycopene and cognitive measures,” she added. “It was only lutein.”

The mechanism of action for lutein is probably more than its action as an antioxidant, she said, since there is a lot more alpha-tocopherol (vitamin E) in the brain than lutein, but no link between alpha-tocopherol and cognitive function.

There’s also a closing of the circle between eye and cognitive health, she said, with the macular acting as a biomarker of lutein in the brain. Lutein levels in the macula are associated with cognitive function, and this relationship, she said, has been reported by both the group at Tufts and John Nolan’s group in Ireland (the Macular Pigment Research Group at the Waterford Institute of Technology). For this lutein would have to go from the diet to the circulation to the brain, and past the blood brain barrier. “It makes sense that lutein is linked to passing the blood brain barrier because it’s the same for the eye.”

Optimal nutrition

Taking all the evidence together Dr Johnson said we’re seeing different kinds of data saying the same thing.

“We think lutein should get more attention because it’s needed for optimal nutrition,” she said. “I think we’re at a turning point and we’re starting to talk about optimal nutrition.”