NiMera Day and Night infant formula based on research of changes to milk due to circadian rhythm
Background
Human milk has been shown to alter its composition, depending on time of day (Hahn-Holbrook, 2019). For mothers who exclusively breast feed, this may not seem so relevant, however for those who pump breast milk, or who utilise infant formula to feed their baby, this information is important, and may influence their feeding regime.
Whilst infant formula can’t replicate human milk, research into improving infant formula leads to breakthroughs to improve its composition and nutritional value to infants. Understanding the circadian rhythm of the feeding of the breast fed infant assisted the latest breakthrough, which will help ensure that nutrition for formula fed infants is optimised. Human milk is a dynamic fluid, changing its formulation based on circadian rhythms, and assisting with baby’s sleep, whereas cows milk, which most infant formulas are based on, is relatively static in nature (Lien, 2003, Hahn-Holbrook, 2019, Cubero, 2007). For this reason, formulation of NiMera, which more closely follows the changes seen in human milk during the day and night will likely result in helping infants receive the right nutrients at the right times, resulting in the right nutrients to support development and improved sleep/wake cycle in bottle fed infants.
Tryptophan
Tryptophan is an essential amino acid. It is a precursor of the neurotransmitter serotonin and of the hormone melatonin (Cubero, 2007). Oral consumption of tryptophan modifies the circulating levels of serotonin and melatonin, with absorption dependent on presence of carbohydrate. Adequate carbohydrate results in easier absorption of tryptophan, and transport into the brain. Numerous papers have shown that formulas designed with these factors in mind improve sleep/wake cycles in infants (Cubero, 2007; Cubero 2006; Lien, 2003).
Tryptophan is regarded as one of the limiting amino acids in low-protein infant formula products (1.3% protein or lower) (Heine, 1995). This means that if the protein level in a standard whey based infant formula is lowered to reach the same level of protein as human milk, this results in low tryptophan levels, amongst other amino acids (Heine, 1994). The amino acid balance within the infant formula must be carefully formulated when working at lower protein levels, as is required of infant formula.
The milk whey fraction, α-lactalbumin, has a relatively high concentration of tryptophan. One study of low-protein infant formulas showed that a tryptophan level of 2.1%, delivered a serum level in infants fed infant formula that did not differ significantly from an exclusively breast-fed control group of infants and has been used to improve the amino acid profile in infant formulas (Heine, 1996).
NIMERA’S QUANTITIES ARE IN LINE WITH RESEARCH WHICH HAS SHOWN THAT PROVIDING NUTRIENTS AT THE CORRECT TIMES CORRELATES WITH IMPROVED SLEEP/WAKE CYCLES IN INFANTS AND SUPPORT THE INFANTS DEVELOPMENT
Tryptophan/Serotonin Pathway
Increasing tryptophan in infant formula will have a significant benefit in providing the right nutrients to support the infants’ development and the sleep/wake cycles. This is due to producing a similar plasma level of tryptophan to that of breast-fed infants (Lien, 2003; Heine, 1996; Cubero, 2007); there is a well-established link between intake of tryptophan in breast milk, and sleep patterns of breast fed infants. This is based upon the synthesis of melatonin from tryptophan through the tryptophan/serotonin pathway (Richard, 2009).
When examining the overall cycle of tryptophan in breast milk, lowest levels are found mid-afternoon. Tryptophan in breast milk peaks at around 3am. This affects 6-sulfatoxymelatonin, a metabolite of melatonin, which subsequently peaks approximately 3 hours later in breast fed infants. The rhythm of this metabolite seems to be influenced by the rhythm of tryptophan found in breast milk (Cubero, 2005). As is expected, the level of melatonin itself is highest overnight, dropping during the day.
From this evidence, an infant formula that is higher in tryptophan for night-time would elicit the most beneficial impact on infant sleep. Two studies have confirmed this, with different formulations; one for day time consumption (6:00 am to 6:00pm) and the other for night time consumption (6:00pm to 6:00am). The use of separate formulations for day and night time consumption was shown to “consolidate the sleep/wake rhythm in bottle-fed infants” (Cubero, 2007).
NiMera’s two separate formulas, for day and night mirror this, with 176mg of tryptophan per 100g in day time formula, and 293mg per 100g in the night time formula, along with 60g and 56g of carbohydrate per 100g in the day and night formula, respectively. These quantities are in line with research which has shown that providing nutrients at the correct times correlates with improved sleep/wake cycles in infants and support the infants development (Cubero 2007, Cubero 2006).
Varying composition of milk
Human milk is a powerful form of chrononutrition, formulated by evolutionary processes to communicate time-of-day information to infants. Human milk contains higher levels of cortisol and activity-promoting amino acids during the day, to promote alertness, feeding behaviour, and catabolic processes in infants. Night milk contains high levels of melatonin and tryptophan to foster sleep, relax digestion, and support cell restoration (Sanchez, 2013, Hahn-Holbrook, 2019). Development of NiMera is formulated around the basis of these changes, and the importance of providing particular nutrients at certain times of day or night, to more closely replicate human breast milk.
Human milk protein has been shown to contain a relatively high concentration of tryptophan, compared with other mammalian milks, such as cows’ milk and goats’ milk. In formula, tryptophan is the limiting amino acid. α-lactalbumin is a protein that is rich in tryptophan. In human milk, the concentrations of α-lactalbumin are much larger than cow milk or whey-dominant formula (Lien, 2003).
As a result, NiMera has been developed with lower protein but higher tryptophan concentrations due to elevated α-lactalbumin.
NIMERA HAS TAKEN ON FINDINGS IN DEVELOPMENT OF THEIR DAY AND NIGHT INFANT FORMULATIONS TO MATCH WHAT HAS SHOWN TO BE EFFICACIOUS IN RESEARCH
Other Nutrients of Note
Other nutrients of interest include a number of nucleotides, due to their varied presence in day and night formulas in research studies (Cubero 2006, Cubero, 2007). Nucleotides are compounds that play a key role in numerous intracellular chemical processes. They are made by the body, though are frequently added to infant formulas due to the important role they play in DNA and RNA; components of co-enzymes NAD, FAD and coenzyme A; as biological regulators and as an energy source. Studies have also shown potential benefits to intestinal flora, immunity, iron absorption, lipid metabolism and gut development (Lerner & Shamir, 2000). Whilst in traditional formulas, levels do not vary due to the presence of a single formulation only. With adenosine 5′-monophosphate and uridine 5′-monophosphate being components of the night time formula, whilst Cytidine 5′-monophosphate, Guanosine 5′-monophosphate and inosine 5′-monophosphate are all found in the day time, or activity promoting formula (Cubero, 2006).
NiMera has taken on these findings in development of their day and night infant formulations to match what has shown to be efficacious in research, and assist with promoting improved sleep/wake cycles in bottle fed infants and support the infants development (refer to table of nutrient levels).
Table A: Summary of Key Nutrients for NiMera Day and NiMera Night infant milk formulas
Nutrient – Stage 1
Amino Acid
Tryptophan mg
Nucleotides
Adenosine 5'-monophosphate mg
Cytidine 5'-monophosphate mg
Guanosine 5'-monophosphate mg
Inosine 5'-monophosphate mg
Uridine 5'-monophosphate mg
Total Nucleotides mg
Nimera Day per 100mL of prepared feed (mg)
0
25.0
0
0.00
1.07
0.19
0.35
0.00
1.61
Nimera Night per 100mL of prepared feed (mg)
0
41.0
0
0.67
0.00
0.00
0.00
0.92
1.59
HELPING INFANTS RECEIVE THE RIGHT NUTRIENTS, AT THE RIGHT TIMES IS IMPERATIVE WHEN IT COMES TO OPTIMISING SLEEP CYCLES, AND ENERGY THROUGH THE DAY. NIMERA DAY AND NIGHT FORMULAS MEET AUSTRALIAN REGULATORY REQUIREMENTS.
Regulatory requirements
The makers of NiMera have worked to ensure that their products meet Australian regulatory requirements, particularly in relation to protein content of infant formula.
In Australia and New Zealand, the level of tryptophan in infant formula products is required to be a minimum of 7mg/100kJ (Schedule 29–6) (FSANZ, 2020). For a formula that is 280kJ/100mL, this translates to 19.6mg/100mL.
The protein content of infant formula is required to be between 0.45g/100kJ and 0.7g/100kJ (FSANZ, 2020b). Again, for a 280kJ/100mL formula, this translates as 1.26g – 1.96g protein/100mL. So the minimum amount of tryptophan within the protein of a 280kJ/100mL formula will range from 1.0% up to 1.6% of the total protein. This contrasts with typical levels of tryptophan within human milk as around 1.9-2.3% of the protein (Heine, 1994).
NiMera’ two separate formulas, for day and night provide 25.0mg of tryptophan per 100mL of prepared feed in day time formula, and 41.0mg of tryptophan per 100mL of prepared feed in the night time formula (refer to table of nutrient levels). This equates to significantly more tryptophan than the required minimum 7mg per 100kJ or 19.6mg per 100mL of prepared feed for a formula that is 280kJ/100mL.
Protein totals 0.5-0.7g in both the day and night formula per 100kJ, with the night time formula being slightly higher protein. This equates to protein of 1.5g and 1.9g per 100mL of prepared feed in day and night formula respectively.
Nutrient – Stage 1
Amino Acid
Tryptophan mg
Regulatory Compliance Range per 280kJ/100mL
≥19.6
NiMera Day per 100mL of prepare feed
25.0
NiMera Night per 100mL of prepare feed
41.0
Why is this important?
Helping infants receive the right nutrients, at the right times is imperative when it comes to optimising sleep cycles, and energy through the day. Ask any new parent, and getting their baby’s sleep ‘right’ is a high priority when it comes to helping adjust to the significant changes that come with becoming a parent. Developing a positive sleep routine is not just essential for the baby, but for the parents as well.
Positive sleep habits start from birth. Babies who do not get enough sleep may have trouble functioning during the day. At night, they may find it hard to settle. Taking steps to help support baby’s circadian rhythms through appropriately timed feeds can help set them up early on for a positive sleep routine, which can significantly impact their long term development and health (Cespedes, 2015).
In adults, inadequate sleep is associated with increased risk of obesity, diabetes and mental health conditions. Conversely, a positive sleep routine can help optimise health across the life.
Background
Tryptophan is an amino acid – one of the building blocks of protein. It is found in varying concentrations in a wide range of food proteins; however the highest concentrations are found in dried egg white and dried milk. Other food sources of tryptophan include turkey meat, oats and canned tuna1. Tryptophan is regarded as one of the Indispensable Amino Acids (IAA), also termed “essential” amino acids as they are amino acids that cannot be synthesised in the human body. There are other amino acids that are regarded as “non-essential” or Dispensable Amino Acids (DAA).
Much has been written regarding tryptophan in the diet of infants, particularly in terms of the levels in human milk. Tryptophan is regarded1,2,3 as a precursor for the synthesis of neurotransmitters (serotonin and tryptamine) and, with its metabolites, has an effect on bodily functions such as appetite, sleeping / waking and also the perception of pain2. Melatonin is a hormone that is produced in the body as part of the “tryptophan/serotonin pathway”1 and regulates the patterns of sleep, among other bodily functions1,2. The highest level of melatonin in the body is associated with darkness at night and in healthy individuals reaches a peak at around 2am4. Sleep quality is associated with peak melatonin secretion and if this is delayed, sleep quality suffers4,5,6,.
The transport of tryptophan through cell membranes in the body can be inhibited by the presence of large neutral amino acids (LNAA)1,3. The LNAA are comprised of: tyrosine, phenylalanine, leucine, isoleucine and valine6. For tryptophan to be optimally available to the body, the ratio of the level of tryptophan to the level of LNAA (TRP/LNAA) must be carefully monitored and maintained at as high a level as possible6.
Levels of Tryptophan in the Diets of Adults
Typically, the level of tryptophan within the protein consumed by adults is low, relative to the level of other amino acids, particularly the other essential (indispensable) amino acids. Despite this, however, it has been estimated that the average intake of tryptophan in USA adults was 826mg/day7. This was in contrast to an Estimated Average Requirement (EAR) for tryptophan for adults in the USA of ~280mg for a 70kg adult7.
The EAR for protein in Australia and New Zealand is 37 – 46g /day (women) and 52 – 65g /day (men)8, with no specified requirements for any individual amino acids. Clearly the intake of protein (and therefore tryptophan) will vary both within a country, but also between countries, depending upon both total protein intake and the types of protein consumed. For the purposes of this discussion and in the absence of specific data for Australia and New Zealand, it has been assumed that the intake of tryptophan by adults in Australia and New Zealand is at similar levels to those in the USA.
The Effects of Supplementary Tryptophan in Adult Diets
The intake of supplementary tryptophan within the diet of an adult has been linked with improvements in sleep duration and depression symptoms7, reduction in cognitive decline, reduced risk of onset of diabetes, mediation of mood disorders9,10, as well as a number of other conditions1,9. The evidence for any specific cause and effect, linked with tryptophan intake, varies to some extent with the type of condition or disease, gender of the individual and the genotype of the individual10. It has been also noted that an intake of pure tryptophan “increases the release of several hormones including growth hormone, cortisol and prolactin”11. Taking this into account, the effects of supplementation of any specific amount of tryptophan for any individual may be difficult to predict. The addition of pure tryptophan to the diet of adults has been the subject of a number of studies, using supplementation levels of between 0.8g to 3.0g per day10. Several studies reported varying effects, depending upon genotype10, however they were regarded as safe9,10.
With regard to the markets of Australian and New Zealand, The consumption of pure tryptophan, in the form of a powder or tablet would be regulated at this time as a therapeutic good, rather than a food. No pure tryptophan therapeutic goods are marketed in Australia at this time.
The Effect of the Consumption of Tryptophan Rich Proteins
With regard to the increased consumption of tryptophan from nutrient rich foods, this has been studied using different proteins that contained relatively high levels of tryptophan9,10,11,13,14. The protein sources included α-lactalbumin, hydrolysed casein, hydrolysed egg white and sodium caseinate7,10,11,12,13. In these studies, specific quantities were added to the diets of adults to study the effects of increased intake of tryptophan and the effect of the TRP/LNAA ratio on the plasma level of tryptophan.
Whilst the intake of tryptophan can be increased by selecting a specific range of foods that have higher levels of tryptophan, there is also the consideration of the TRP/LNAA ratio. The absorption of tryptophan into the bloodstream (measured as ‘plasma tryptophan’10) is affected by the presence and level of LNAA6,10,11,12. The LNAA are preferentially absorbed to tryptophan and at high levels can block the absorption of tryptophan to some extent11,12. To ensure a relatively high level of tryptophan is achieved in the plasma, the ratio of the TRP/LNAA ratio needs to be controlled6,11,13. Studies indicate that a protein source with a TRP/LNAA ratio of 0.10 or higher may be more effective in achieving higher plasma tryptophan levels10,11,12,14,15,16.
In several studies in adults, the ratio of TRP/LNAA of above 0.07 in the protein of food was used, with a ratio of 0.10 being found to make a significant improvement in various aspects of mood (including depression, anger and tension)14,15,16. These studies used α-lactalbumin as a protein source, compared with another type of protein (casein). The TRP/LNAA ratio for α-lactalbumin was measured 0.087, whilst the ratio for casein was 0.04714,15,16. The plasma testing showed a TRP/LNAA ratio in the plasma of 0.104 for the α-lactalbumin and 0.071 for the casein. In a follow-up trial plasma testing showed a TRP/LNAA ratio of 0.104 after an α-lactalbumin diet and 0.073 after the control diet (casein)14,16.
The effect of the differing intakes of tryptophan from food in individuals has been linked to various behaviours and mood disorders16,17,18, particularly with older adults. This has been linked with “enhanced serotonin neurotransmission” that has a “widely acknowledged antidepressant function”11. Studies have indicated that people with mood disorders had a lower intake of tryptophan than those with higher intakes of tryptophan7,18. It has also been proposed that consuming a tryptophan enriched diet may assist with improvement in mood, sleep patterns, cognitive decline and resistance to type 2 diabetes9,10,11,12. Studies have indicated that intakes of as low as 2-4g of pure hydrolysed egg protein11,13 and 15g, 20g and 40g of α-lactalbumin have shown significant increases in plasma tryptophan14,15,16. The effects included improved cognitive performance, improved mood and well-being, including improved coping ability, lower anxiety and better sleep efficiency11,12,14,15,16.
Summary
The effects of increasing the consumption of tryptophan rich foods, such as eggs and milk products, particularly α-lactalbumin, have been studied over the past 20 years or more. The link between a higher level of plasma tryptophan and the higher level of serotonin in the body, have led to evidence of improved mood and well-being, including less anxiety, better cognitive ability and improved sleep. Whilst tryptophan intake can be increased by a simply higher protein diet, the key factor to increasing plasma tryptophan in the body is having protein sources that exhibit a high TRP/LNAA ratio, preferably greater than 0.10.
Austral Foods has taken on these findings in development of their night formulation for adults to match what has shown to be efficacious in research – NiMera’s night drink has been developed to improve cognitive performance, improve mood and well-being and support better sleep efficiency of adults and children.
Based on Science
NiMera Night Sleep Drink Powder is a whey protein concentrate rich in alpha-lactalbumin which naturally contains high amounts of the serotonin precursor tryptophan. Increased dietary intake of tryptophan has documented beneficial effects on brain serotonin synthesis and activity with positive effects on mood, cognitive performance and improved sleep pattern.
NiMera Night Sleep Powder Drink contains:
-Children 6-11 years
-5.6g α-lactalbumin and 180.9mg of tryptophan
-Children 12-17 years
-11.2g of α-lactalbumin and 363.9mg of tryptophan
-Adults 18 and over
-16.8g of α-lactalbumin and 544.8mg of tryptophan.
Refer to the table for all the nutritional information.
Age
Serving size
Average quantity per serve
Total serves per pack
Children
6-11 years
1 spoon
8.3 g
60 serves
Children
12-17 years
2 spoons
16.7 g
30 serves
Adults
18 and over
3 spoons
25 g
20 serves
Nutrient
Energy
Protein
Fat (total)
Saturated
Carbohydrate
Sugars
Sodium
Other
Alpha-lactalbumin
Tryptophan
Units
kJ
Calories
g
g
g
g
g
mg
g
mg
Average Qty per 100g powder
1587
379.3
62.2
0.2
0
30.7
30.7
0.3
67
2179
Average Qty per 8.3 g serve +125 mL of Water
131.7
31.5
5.2
0.0
0.0
2.5
2.5
0.0
5.6
180.9
Average Qty per 16.7 g serve +125 mL of Water
265.0
63.3
10.4
0.0
0.0
5.1
5.1
0.1
11.2
363.9
Average Qty per 25 g serve +125 mL of Water
396.8
94.8
15.6
0.1
0.0
7.7
7.7
0.1
16.8
544.8
NiMera was created with the intent to develop the best milk powder products for infants, toddlers and adults. We combine the best ingredients for our day and night formulations to support development and growth during the day and better sleep during the night.
