Not Just Vitamin A: What Is A5 and Why Do We Need 9-cis-β-Carotene

Nutrients has published a review that could shake up our understanding of “vitamin A.” The authors propose a separate subpopulation, vitamin A5. This is an “umbrella” term for the dietary precursors from which the body produces the endogenous activator of the nuclear receptor RXR: we are talking about 9-cis-β-carotene (provitamin A5) and 9-cis-13,14-dihydroretinol, leading to the active acid 9-cis-13,14-dihydroretinoic acid. The new concept is intended to explain why leafy greens and other vegetables are so consistently associated with better neurocognitive outcomes and lower risks of “Western lifestyle diseases.”

To understand, let's start with the term itself. Classic "vitamin A" is retinol/retinyl esters from animal products and provitamin carotenoids from plants. A5 is a "parallel branch": not about the RAR receptor (like retinoic acid "class A1"), but about RXR, the "master switch" that assembles heterodimers with VDR, PPAR, LXR, TR, RAR and NR4A2 and thus regulates immunity, lipids, vitamin D signaling and much more. The authors' idea is simple: without a sufficient flow of provitamin A5 from the diet, RXR signaling does not work at full capacity.

Background

The classic "vitamin A" in nutrition is retinol and retinyl esters from animal products plus provitamin carotenoids from plants, which are converted in the body to retinoic acid and work through RAR receptors. In recent years, it has become clear that in a parallel branch, signals go through another nuclear receptor - RXR. It forms heterodimers with VDR, PPAR, LXR, TR and RAR, thereby affecting lipid metabolism, sensitivity to vitamin D, immune response, neuroplasticity and myelination. The question of "which food stream feeds RXR" remained open for a long time: synthetic agonists (like bexarotene) have proven the principle, but are clinically inconvenient due to side effects.

This led to the idea of isolating “vitamin A5,” a group of food precursors whose final RXR activator may be 9-cis-13,14-dihydroretinoic acid. The key candidate is 9-cis-β-carotene (provitamin A5), which is found in higher amounts in leafy greens and some root vegetables. Unlike “regular” all-trans-β-carotene and retinol, this isomeric branch theoretically mediates RXR signaling. The first human data are emerging (e.g., HDL shifts via the RXR-LXR axis), and preclinical studies link RXR activation to improved neurocognitive function and metabolic profiles—but the evidence is still fragmentary and requires systematization.

The nutritional context adds motivation: the recommendation of “5 portions of fruit and vegetables per day” is met by a minority of adults, especially in northern and central Europe; greens are chronically lacking in the diet. If 9-cis-β-carotene is indeed critical for “fueling” RXR, then a massive shortage of green vegetables may mean not only a deficiency of fiber and potassium, but also a functional deficiency of A5 - with possible consequences for the brain, psychoemotional status and lipid metabolism.

The scientific bottlenecks are also clear. It is technically difficult to accurately measure the isomeric composition of carotenoids, track their conversion in tissues, and isolate the contribution of A5 from the classical retinoic branch. There are no unified biomarkers of A5 status, thresholds for “sufficiency” have not been described, and data on the content of 9-cis-β-carotene in foods are widely scattered between laboratories and seasons. Therefore, the next logical step is to carefully describe the evidence, propose working definitions, and outline a research agenda: standardization of analytics, dose-response for food/supplements, RCTs with cognitive and metabolic endpoints, and consideration of interindividual variability in need. This is precisely the groundwork that the work under discussion creates.

What is Vitamin A5 - in three accents

• Source: In food, this is primarily 9-cis-β-carotene (provitamin A5), which is more common in leafy and root greens/vegetables. Small traces of 9-cis-13,14-dihydroretinol have been described, for example, in the liver, but the nutritional value of this form is still modest.
• Active form. In the body, provitamin A5 is converted into 9-cis-13,14-dihydroretinoic acid, an endogenous ligand of RXR. This is what distinguishes the A5 branch from the "classic" retinoic acid (A1), which works through RAR. An important detail: all-trans-retinol and regular β-carotene do not make a noticeable contribution to this branch.
• Why the body cares. RXR is a hub where vitamin D, lipid metabolism, and inflammation pathways converge; it may explain signals related to cognition, anxiety/depression, myelination, and remyelination. So far, these are mostly animal models and indirect evidence in humans — but the biology is plausible.

At the nutritional level, the authors made an important calculation for practice: 1.1 mg of 9-cis-β-carotene per day - this is how much, according to their estimates, is needed to "feed" the RXR branch. The "how it looks on a plate" option: ≈30 g of raw spinach (an order of magnitude!) will give such a dose; theoretically, the same amount can be "gained" from 1.8 kg of peaches, but it is clear that greens are the real way. If you follow the rule of "5 servings of vegetables and fruits per day", the average European diet just gains ≈1.1 mg of provitamin A5. The problem is that only 10-30% of people really follow the "5-a-day", and according to the authors, about two thirds of Europeans remain below the optimum for A5, especially in northern and central Europe, where they eat less greens.

Key points to take away from the review

• A5 is not a "synonym" for A1. It is a different functional branch of vitamin A, tailored for RXR; confusing it with retinol and considering it "the same thing" is a methodological error.
• Food → ligand → receptor. This is a rare case where a whole cascade chain can be traced from a specific molecule in food to the activation of a specific nuclear receptor and physiology.
• There is human data, but it is spotty. In small studies, provitamin A5 supplements increased HDL cholesterol via the RXR-LXR axis - a direct hint at the mechanism at work in humans. But large RCTs on the brain/behavior are yet to come.
• Synthetic RXR agonists ≠ food precursors. Drugs like bexarotene can turn on RXR, but they cause hypertriglyceridemia and other "side effects". Provitamin A5 does not have such toxicity - it works as a "prodrug" with tissue activation.

The issue of deficiency is also treated in a special way here. The authors distinguish between a general deficiency of "vitamin A" and a specific deficiency of A5, in which the RXR partner pathways (VDR/PPAR/LXR, etc.) suffer - with an emphasis on the nervous system and mental health. They list the conditions where such a "sag in RXR" is biologically plausible, but emphasize that clinical trials are needed to establish causality and thresholds.

What to Put in Your Cart (and What to Expect Next)

• Leafy and root vegetables are the main food source of 9-cis-β-carotene; the "5 servings a day" rule almost guarantees the "A5 norm". For Europeans, this is also a way to get out of the "risk zone" of deficiency.
• Supplements? It is too early to talk about an “A5 pill”: the necessary status biomarkers, thresholds and recommended norms are only being formed; the authors honestly call this the “first version” of dietary guidelines (1.1 mg/d) and plan to expand the databases on A5 content in products.
• Research agenda: Priorities are to standardize 9-cis-β-carotene/metabolite assays, calculate kinetics (absorption/transport/activation), conduct RCTs with targets in cognitive and affective domains, and clarify interpersonal variability in needs.

Conclusion

The review doesn't "rebrand carrots as medicine," but rather offers a careful rethinking of the vitamin A family. If the RXR branch (A5) is really that important, then the vegetable portion of the plate is not only fiber and potassium, but also fuel for the "master switch" of genes. This means that the simple recommendation of "more greens every day" may have a much more specific molecular basis than we thought.

Source: Bohn T. et al. Vitamin A5: Evidence, Definitions, Gaps, and Future Directions. Nutrients 17(14):2317, July 14, 2025. Open access. https://doi.org/10.3390/nu17142317