The active ingredients on which HAP Body Brain Skin is based

In selecting targets for interventions that seek to assist a healthy aging process for the body, brain, and skin, exclusive synergistic combinations emerge from in-depth research of high-performing ingredients with targeted efficacy verified in the scientific literature.

We design formulations using only the best active ingredients to offer a simple yet targeted response to counteract the Nine Hallmarks of Aging (Body 9:9), support the five major cognitive processes (Brain 5:5), and act transversely on the three key actions essential for skin health over time (Skin 3:3).

All the active ingredients selected for HAP Body Brain Skin® are listed below.


Body 9:9

Magnolia bark is used in traditional Eastern medicine as a remedy for gastrointestinal disorders, anxiety, allergies, and insomnia and is proposed as an antioxidant and antimicrobial agent1. Magnolia bark is reported to have salutary properties related to beneficial gastrointestinal, vascular, pulmonary, and buccal microbial flora rebalancing.2

Magnolia bark’s distinctive phytoconstituents consist of two neolignan isomers with biphenyl structure, magnolol and honokiol. Apart from the numerous references regarding these substances’ action mechanisms and beneficial properties, magnolia symbolizes longevity, strength, and purity in maintaining youth with balance, without excesses.

The literature provides numerous references regarding magnolia extracts’ anti-inflammaging and neuroprotective activity.

In this particular case, magnolol and honokiol are involved in the inhibition of certain specific receptors, transcription factors, and protein kinases such as NF-kB and PPAR active in the production and signaling of cytokines and pro-inflammatory mediators such as COX, PGE2, and iNOS.

Magnolol and honokiol exhibit hypoglycemic action, promoting glucose reuptake and inhibiting alpha-glucosidase, suggesting their usefulness in controlling and preventing metabolic diseases. Not least, the hydroxyl and allyl groups’ characteristic chemical structure  confers antioxidant and antiradical activity.3

Magnolia’s active substances are, therefore, a valuable aid in controlling the inflammatory state and oxidative stress, which, although nonpathological and low-grade, if persistent, can contribute to biochemical changes and imbalances associated with genomic instability, epigenetic alterations, and impaired proteostasis, thereby preventing the action of the four primary hallmarks of damage.

The anti-inflammatory action also helps control excessive inflammatory stress associated with cellular senescence and mitochondrial dysfunction, countering the senescent cells’ toxic communication mechanisms. Furthermore, the hypoglycemic activity stimulates proper nutrient sensing, aiding in metabolic control and the containment of insulin resistance.

Resveratrol is found mainly in the genus Vitis and in Japanese knotweed (Polygonum cuspidatum) and is a classic anti-aging active ingredient with a solid scientific rationale.

Both resveratrol and polydatin are stilbenoids, defense compounds known as “phytoalexins,” naturally produced by plants to protect themselves against attacks by pathogenic microorganisms and which exert a variety of biological properties, from cardioprotection to neuroprotection, including hypoglycemic, depigmenting, anti-inflammatory, and antioxidant activity.

In support of magnolia’s anti-inflammatory action, resveratrol positively modulates gene stability, acting on the ARF/p53 (alternative reading frame) pathway involved in tumor suppression, stabilizes histone deacetylase expression and the proper functioning thereof, promoting a suitable chromatin structure.4 Directly or indirectly, resveratrol activates several factors, such as sirtuins, AMPK, and ATM, with multiple positive effects at the metabolic and epigenetic levels.5 Through the upregulation of SIRT1, Resveratrol facilitates the action of epithelial and endothelial stem cell telomerase6 and stimulates mitochondrial biogenesis.7,8

Besides being found in Japanese knotweed, Polydatin is also obtained from the bark of Picea sitchensis and is the glycosylated form of resveratrol (resveratrol glucoside).

Following oral administration, resveratrol is rapidly absorbed and conjugated into more hydrophilic forms (glucuronide/sulfate) and then excreted in the urine. Polydatin, because of its glycosylated form, is more resistant to enzymatic oxidation and has better solubility in aqueous environments.9,10

In-vivo studies have shown that the serum concentration of polydatin is about 3 to 5 times higher than that of resveratrol at the same dosages and that these two substances coexist following reciprocal interconversion after oral administration. Polydatin is, therefore, a more bioavailable, more metabolically stable, and technically advantageous source of resveratrol.11

Quercetin is a flavonoid found in many botanical species and, along with resveratrol, is considered, along with resveratrol, an active ingredient with senolytic properties. In vitro and in vivo studies have confirmed that quercetin can reduce the state of senescence by promoting cell reproduction and restoring the proper chromatin state. Its administration correlates with a reduction of aging-related biological markers such as pro-inflammatory and pro-oxidant substances, cytokines, and mediators produced due to DNA damage.12,13

Quercetin positively modulates gene regulation related to the cell cycle, cell division, and cell proliferation and has immunomodulatory and anti-inflammatory activity. Quercetin reduces cytokine and chemokine production, inhibiting the migration of dendritic cells induced by LPS and the activation of T cells, enhancing immune response that may be deficient due to age-induced stem cell depletion.14

An essential element for human nutrition, zinc plays a key role in the catalysis, structure, and regulation of numerous enzymes, including those involved in metabolizing nucleic acids and proteins. Zinc is a component of zinc fingers, specific protein domains used by transcription factors; it is involved in the regulation of gene activity, maintains the proper structure of biological membranes, and protects against pro-oxidant agents.15

Niacin, or vitamin B3, a collective term for nicotinamide and nicotinic acid, is involved in numerous biological processes, including energy production, the regulation of gene expression, and the maintenance of genomic integrity. Niacin’s metabolite, nicotinamide adenine dinucleotide or NAD+, along with its reduced form NADH, acts as the major acceptor or donor of hydrogen, respectively, in many biochemical redox reactions, thereby mediating Niacin’s biochemical effects.” NAD+ is used in metabolic reactions to transfer the free energy stored in macronutrients to NADH, which is used in the synthesis of ATP, essential for cellular energy. NAD+ has been shown to play a key role in extending lifespan induced by caloric restriction in the yeast Saccharomyces cerevisiae, as it serves as a cofactor for a specific NAD+-dependent histone deacetylase, favoring gene silencing, which in turn is critical for longevity as it favors the suppression of gene expression alterations that lead to cellular aging.15

Vitamin B6, or pyridoxine, is involved in the metabolism of amino acids and glycogen in the synthesis of nucleic acids, sphingolipids, and neurotransmitters. A vitamin B6 deficiency impairs the immune system’s cellular and humoral responses as it causes an alteration in lymphocyte differentiation and maturation, in the production of antibody response, and interleukins.15

Folic acid, or vitamin B9, is a folate used in dietary supplements and specialty medicines. Folates participate in DNA, RNA, and protein synthesis; they are necessary for DNA replication and repair, maintaining genome integrity, and regulating gene expression. Together with vitamin B12, folates play a role in the conversion of homocysteine to methionine, which participates in protein synthesis and is a source for the synthesis of S-adenosyl methionine (SAMe), which regulates many reactions involving nucleic acids, phospholipids, and proteins, such as the synthesis of certain neurotransmitters. Folates also provide a carbon atom to form thymidylic acid, a DNA precursor and are involved in the synthesis of purine nucleotides.15

Cyanocobalamin, the form of vitamin B12 most commonly used in food fortification, consists of a nucleotide linked to a corrin group with a central cobalt atom and is part of the so-called “pigments of life.” Vitamin B12, together with folic acid, promotes the synthesis of DNA, RNA, and other molecules important for genome integrity. A vitamin B12 deficiency reduces the formation of thymidylic acid and purine nucleotides, precursors to DNA synthesis.15

Brain 5:5

Due to its high lipophilicity, the active ingredients in magnolia bark (magnolol and honokiol)

can cross the blood-brain barrier and enter the central nervous system.

Because of their anti-inflammatory and antioxidant activity, they promote neuroprotection, countering in vitro neuronal damage induced by toxic stimuli such as glucose deprivation or stimulation with excitatory amino acids such as aspartate. Concomitant treatment with magnolol and honokiol stimulates the hippocampal release of acetylcholine, positively impacting memory and preventing aging-related learning impairments. Magnolia’s active ingredients inhibit the inflammatory state following ischemia-induced damage and reduce the rate of neuronal death caused by beta-amyloid, preventing neurodegeneration.

Magnolol and honokiol exhibit agonistic activity on GABA receptors, promoting anxiolytic activity.16,17

Nervonic acid is a long-chain fatty acid essential for neuronal development found in breast milk. Nervonic acid promotes the biosynthesis and maintenance of the myelin sheath, which alters the brain, spinal cord, and optic nerve and can cause neurological deficits such as vision problems, weakness, impaired sensitivity, and behavioral or cognitive problems. In vivo tests demonstrate that nervonic acid supplementation favors the improvement of cognitive functions and memory. High serum levels of nervonic acid have been correlated with a lower risk of developing Alzheimer’s disease; thus, nervonic acid is associated, albeit preliminarily, with neurodegeneration-preventing action. 18

Sialic acid, or N-acetylneuraminic acid, is a sugar found in breast milk oligosaccharides and is essential for neurological development. Sialic acid is a component of gangliosides, glycolipids found in the brain, specifically in the receptors of many neurotransmitters and hormones. An altered metabolism of gangliosides is associated with cognitive problems and neurodegeneration and is implicated in the pathogenesis of Alzheimer’s disease. Sialic acid also promotes the inclusion of beta-amyloid protein complexes in microglial cells and their subsequent phagocytosis, promoting their elimination.19

Ginkgo is one of the most studied botanical species as a natural remedy for cognitive disorders; it improves cerebral circulation, strengthens capillary walls, protects neuronal cells from oxygen depletion, and prevents clot formation. Ginkgo extracts are used to improve concentration and memory, enhance neuronal plasticity, and preserve brain receptors that regulate nerve signal transmission from aging-induced damage.20

Citicoline, or Cytidine 5′-diphosphocholinene or CDP-Choline, is an intermediate metabolite that serves as a precursor in the endogenous synthesis of nerve cell membrane phospholipids, ensuring their integrity and fluidity and of the neurotransmitter acetylcholine. Cognizin® is a patented form of citicoline and has been clinically tested on humans across various age groups. It has been shown that 250-500 mg daily promotes brain membrane turnover and energy utilization by the brain, in addition to improved attention capacity, physical performance, and memory.21-23 

Finally, longer-term trials have been conducted with lower dosages, including in combination with drug therapies.

Cognizin® is a registered trademark of KYOWA HAKKO BIO CO., LTD.”

Skin 3:3

The key active ingredients of the HAP Body Brain Skin® line, Magnolol and Honokiol, boast of antioxidant, anti-inflammatory, and antibacterial properties for the skin. They offer a transversal mechanism underlying the aging process of all skin layers, helping to counter inflammaging. 24-27

Pullulan is a complex, water-soluble sugar produced by the fungus Aureobasidium pullulans under aerobic conditions.

Structurally, it is a polysaccharide composed of alpha-glucopyranosyl units linked together through branched glycosidic bonds.

It binds water and leaves a film on the skin with a protective, moisturizing action, with a potentially lifting and tightening effect. Well recognized and valued in the pharmaceutical field as a scaffold for tissue engineering and treating wounds, this polysaccharide is still not widely used in skin care despite its film-forming properties and high biocompatibility.28

A polyhydroxy acid capable of binding large amounts of water, it acts as a powerful antioxidant by inhibiting metalloproteinases and having a strong chelating power.

The application of lactobionic acid maintains the integrity of the epidermal barrier, thus allowing its use on sensitive skin.29

Betaine or trimethylglycine, named after the sugar beet (Beta vulgaris), is a small trimethylated amino acid. Because of its structure, betaine can easily form hydrogen bonds with water and other molecules, giving it moisturizing properties. It is highly soluble in water and chemically stable. It is an osmolyte, meaning it can maintain the water balance of cells, protecting them from dehydration.

It affects Tight Junctions, which are literally tight or sealed junctions, protein structures that act as a junction between cells to seal the intercellular space. The TJ system comprises a second-level barrier helping to prevent the penetration of external antigens and is crucial for properly structuring the Stratum Corneum itself and maintaining hydration. The transport of organic osmolytes that regulate intracellular water homeostasis by keratinocytes is largely unexplored, and little is known about how cellular and extracellular water conservation mechanisms might interact.

A 2021 study reported in the British Journal of Dermatology found that treating the skin with organic osmolytes, such as betaine, modulates the structure and function of Tight Junctions, contributing to the function of the epidermal barrier. This underscores a role for organic osmolytes that goes beyond maintaining intracellular osmolarity to improving skin barrier dysfunctions.30

A natural alternative to retinol, effective but better tolerated by the skin, bakuchiol is an active ingredient supported by numerous studies in the literature.

One of aged and prematurely aged skin’s main characteristics is a high degree of fragmentation in the dermal collagen matrix. Metalloproteinases (MMPs) play an important role in protein and collagen degradation, affecting the structural integrity of the dermis. In normal skin, MMP production is in balance with natural metalloproteinase inhibitors (TIMPs), but aging and sun exposure lead to an imbalance between active enzymes, resulting in accelerated connective tissue destruction and (photo-)aging. Therefore, protecting extracellular matrix proteins, such as collagen, in aged or photo-aged human skin and reducing MMPs should delay the clinical manifestations of skin aging.

A 2014 study comparing the performance of bacuchiol and retinol on two key matrix metalloproteinases, MMP-1 and MMP-12, found that bacuchiol had a significant inhibitory effect on MMP-1 and a very marked inhibitory effect on MMP-12, far exceeding retinol’s effect.31

Collagen fragmentation is responsible for the loss of structural integrity and impaired fibroblast function in aging, with less collagen production and high levels of degradative enzymes. This imbalance furthers the aging process in a deleterious, self-perpetuating cycle.

Chaudhuri and Bojanowski demonstrated the effects of bakuchiol on collagen stimulation, showing a significant improvement in collagen stimulation compared with retinol.

A biotechnological extract derived from a Bacillus sp. isolated in the Florida Keys, USA. It strengthens and protects skin telocytes and proliferating epidermal stem cells from psychological stress, as demonstrated in vitro, to preserve skin organization and restore facial harmony.

The architecture of the skin is based on a three-dimensional network of cells kept in equilibrium by telocytes, whose role in tissue repair and regeneration has recently been discovered, providing a fresh perspective on the skin’s inherent ability to self-repair..32

Telocytes communicate with stem cells through exosomes, but psychological stress can damage both telocytes and epidermal stem cells, deteriorating the skin architecture and compromising its proportional harmony.

Bacillus Ferment’s protective properties help restore the skin’s internal organization, aligning it more closely with the harmony and symmetry of the Golden Ratio.


        Body 9:9
  1. Sarrica A, Kirika N, Romeo M, Salmona M, Diomede L. Safety and Toxicology of Magnolol and Honokiol. Planta Med. 2018 Nov;84(16):1151-1164.
  2. Allegato 1, DM 10 agosto 2018 “Disciplina dell’impiego negli integratori alimentari di Sostanze e preparati vegetali”
  3. Zhang J, Chen Z, Huang X, Shi W, Zhang R, Chen M, Huang H, Wu L. Insights on the Multifunctional Activities of Magnolol. Biomed Res Int. 2019 May 23;2019:1847130.
  4. Matsuno Y, Atsumi Y, Alauddin M, Rana MM, Fujimori H, Hyodo M, Shimizu A, Ikuta T, Tani H, Torigoe H, Nakatsu Y, Tsuzuki T, Komai M, Shirakawa H, Yoshioka KI. Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability. Sci Rep. 2020 Mar 25;10(1):5388.
  5. Pyo IS, Yun S, Yoon YE, Choi JW, Lee SJ. Mechanisms of Aging and the Preventive Effects of Resveratrol on Age-Related Diseases. Molecules. 2020 Oct 12;25(20):4649.
  6. Jacczak, B.; Rubiś, B.; Totoń, E. Potential of Naturally Derived Compounds in Telomerase and Telomere Modulation in Skin Senescence and Aging. Int. J. Mol. Sci. 2021, 22, 6381.
  7. Uriho, A., Tang, X., Le, G. et al. Effects of resveratrol on mitochondrial biogenesis and physiological diseases. ADV TRADIT MED (ADTM) 21, 1–14 (2021).
  8. Ungvari Z, Sonntag WE, de Cabo R, Baur JA, Csiszar A. Mitochondrial protection by resveratrol. Exerc Sport Sci Rev. 2011 Jul;39(3):128-32.
  9. Henry, C.; Vitrac, X.; Decendit, A.; Ennamany, R.; Krisa, S.; Mérillon, J.-M. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem. 2005, 53, 798–803
  10. Henry-Vitrac, C.; Desmoulière, A.; Girard, D.; Mérillon, J.-M.; Krisa, S. Transport, deglycosylation, and metabolism of trans-piceid by small intestinal epithelial cells. Eur. J. Nutr. 2006, 45, 376–382
  11. Wang HL, Gao JP, Han YL, Xu X, Wu R, Gao Y, Cui XH. Comparative studies of polydatin and resveratrol on mutual transformation and antioxidative effect in vivo. Phytomedicine. 2015 May 15;22(5):553-9.
  12. Russo GL, Spagnuolo C, Russo M, Tedesco I, Moccia S, Cervellera C. Mechanisms of aging and potential role of selected polyphenols in extending healthspan. Biochem Pharmacol. 2020 Mar;173:113719.
  13. Melo Pereira S, Ribeiro R, Logarinho E. Approaches towards Longevity: Reprogramming, Senolysis, and Improved Mitotic Competence as Anti-Aging Therapies. Int J Mol Sci. 2019 Feb 21;20(4):938
  14. Hosseinzade A, Sadeghi O, Naghdipour Biregani A, Soukhtehzari S, Brandt GS, Esmaillzadeh A. Immunomodulatory Effects of Flavonoids: Possible Induction of T CD4+ Regulatory Cells Through Suppression of mTOR Pathway Signaling Activity. Front Immunol. 2019 Jan 31;10:51.
  15. PDR Integratori nutrizionali, edizione 2017 CEC editore
    Brain 5:5
  16. Lee YJ, Choi DY, Han SB, Kim YH, Kim KH, Seong YH, Oh KW, Hong JT. A Comparison between Extract Products of Magnolia officinalis on Memory Impairment and Amyloidogenesis in a Transgenic Mouse Model of Alzheimer’s Disease. Biomol Ther (Seoul). 2012 May;20(3):332-9.
  17. Woodbury A, Yu SP, Wei L, García P. Neuro-modulating effects of honokiol: a review. Front Neurol. 2013 Sep 11;4:130.
  18. Liu F, Wang P, Xiong X, Zeng X, Zhang X, Wu G. A Review of Nervonic Acid Production in Plants: Prospects for the Genetic Engineering of High Nervonic Acid Cultivars Plants. Front Plant Sci. 2021 Mar 5;12:626625.
  19. Li Q, Chen J, Yu X, Gao JM. A mini review of nervonic acid: Source, production, and biological functions. Food Chem. 2019 Dec 15;301:125286.
  20. Singh SK, Srivastav S, Castellani RJ, Plascencia-Villa G, Perry G. Neuroprotective and Antioxidant Effect of Ginkgo biloba Extract Against AD and Other Neurological Disorders. Neurotherapeutics. 2019 Jul;16(3):666-674.
  21. McGlade, Erin et al. “Improved Attentional Performance Following Citicoline Administration in Healthy Adult Women.” Food and Nutrition Sciences 3 (2012): 769-773.
  22. McGlade E, Agoston AM, DiMuzio J, Kizaki M, Nakazaki E, Kamiya T, Yurgelun-Todd D. The Effect of Citicoline Supplementation on Motor Speed and Attention in Adolescent Males. J Atten Disord. 2019 Jan;23(2):121-134.
  23. Nakazaki E, Mah E, Sanoshy K, Citrolo D, Watanabe F. Citicoline and Memory Function in Healthy Older Adults: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. J Nutr. 2021 Aug 7;151(8):2153-2160.
    Skin 3:3
  24. Zhang J, Chen Z, Huang X, Shi W, Zhang R, Chen M, Huang H, Wu L. Insights on the Multifunctional Activities of Magnolol. Biomed Res Int. 2019;2019. doi:10.1155/2019/1847130
  25. Jui-Lung Shen et al. Honokiol and Magnolol as Multifunctional Antioxidative Molecules for Dermatologic Disorders Molecules 2010, 15, 6452-6465; doi:10.3390/molecules15096452
  26. Riccardo Amorati et al. Antioxidant Activity of Magnolol and Honokiol: Kinetic and Mechanistic Investigations of Their Reaction with Peroxyl RadicalsJ. Org. Chem. 2015, 80, 21, 10651–10659, October 8, 2015
  27. Kun-Yen Ho et al. Antimicrobial Activity of Honokiol and Magnolol Isolated from Magnolia officinalis Phytother. Res. 15, 139–141 (2001) DOI: 10.1002/ptr.736 
  28. Engineered pullulan-collagen composite dermal hydrogels improve early cutaneous wound healing. Wong VW, Rustad KC, Galvez MG, Neofytou E, Glotzbach JP, Januszyk M, Major MR, Sorkin M, Longaker MT, Rajadas J, Gurtner GC. Tissue Eng Part A. 2011 Mar;17(5-6):631-44
  29. B. Algiert-Zielińska MSc, Lactic and lactobionic acids as typically moisturizing compounds, International journal of dermatology
  30. C. El-Chami et al Organic osmolytes increase expression of specific tight junction proteins in skin and alter barrier function in keratinocytes. British Journal of Dermatology (2021) 184, 482-494
  31. R. K. Chaudhuri* and K. Bojanowski Bakuchiol: a retinol-like functional compound revealed by gene expression profiling and clinically proven to have anti-aging effects International Journal of Cosmetic Science, 2014, 36, 221–230
  32. Catalin G. Manole et al, Dermal Telocytes: A Different Viewpoint of Skin Repairing and Regeneration Cells 2022, 11, 3903


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