I recently wrote this as a paper for school! Hope you learn something useful and feel free to share more resources. I literally could have written 25 pages with all of my research, but I had to keep it to 5-6 pages double spaced. The mTORC1 pathway research is REALLY interesting.
DISCLAIMER: This is not to be used as medical advice. I am not a doctor so please consult your doctor or dermatologist before trying anything mentioned below.
Creating a Comprehensive Dietary Solution for Acne
Beyond providing a semipermeable barrier between humans and the environment, the skin serves as a mirror reflecting the internal balance of many biological processes, especially hormonal regulation. Physiological events that disrupt hormones and/or regulation of the pilosebaceous unit can result in acne vulgaris and other skin disorders. Pilosebaceous units are found throughout the skin except in the palms and soles of the feet and they consist of a hair follicle, sebaceous gland, and an arrector pili muscle. The sebaceous glands allow the skin to function as an endocrine organ by synthesizing local hormones with systemic effects, expressing diverse hormone receptors, and serving as a hormone target for other endocrine organs (Chen & Zouboulis, 2009). The sebaceous glands produce sebum, which is a complex mixture of triglycerides and fatty acid degradation byproducts, wax esters, squalene, cholesterol esters and cholesterol that lubricate the skin and protect against friction and moisture (Makrantonaki, Ganceviciene, & Zouboulis, 2011). The sebaceous glands also transport antioxidants in and on the skin, exhibit a natural light protectant, possess antimicrobial activity, and pro- and anti-inflammatory functions (Makrantonaki et al, 2011).
Acne vulgaris, the most common form of acne affecting upwards of 85% of adolescents in Western countries (Melnik, 2012), has four fundamental physiological components: 1.) hyperproliferation of keratinocytes obstructing the hair follicle canal, 2.) sebaceous hyperproduction leading to excess sebum production, 3.) proliferation and colonization of Propionibacterium acnes contributing to pore blockage and provoking an immune inflammatory response, and 4.) significant dermal inflammation and oxidative stress due to follicular wall rupture and the presence of macrophage- and neutrophil-secreted cytokines and mediators to clear out infection (Costa, Lage, & Moisés, 2010). Anything that contributes to further clogging of the pores, exacerbates inflammation, and promotes infection will complicate acne.
The four fundamental physiological components of acne manifest from a complex interaction between hormones, diet, nutrient deficiencies, gut microbiome balance, stress, genetics and inflammation. There are a number of hypotheses aimed at identifying the proverbial match that ignites the acne cascade at the cellular level. Most recently, Melnik and Zouboulis (2013) suggest that increased plasma glucose levels from the standard Western diet perpetuate a low-grade hyperinsulinemia that persuades the transcription factor FoxO1 to leave the cell nucleus thus exposing androgen receptors to circulating androgens from endogenous and exogenous sources. Milk consumption pushes insulin levels higher and contains insulin-like growth factor-1 (IGF-1), which triggers elevation of the body’s internal IGF-1 further exposing the androgen receptors to hormonal sources from ovaries, testes, adrenals, progestins from contraceptives, and diet. This hormone cocktail acts through the master growth regulator, the mTORC1 signaling pathway, which provokes hyperproliferation of keratinocytes and increases sebum production (Danby, 2013). Like dairy, high glycemic load diets also have implications in acne etiology because of their insulinogenic properties that subsequently increase androgen production and decrease a binding protein to IGF-1 facilitating its hyperproliferative effects (Smith, Mann, Braue, & Varigos, 2007). Several other hormones besides androgens and insulin have been linked to acne and may regulate sebaceous secretion including: estrogens, growth hormone, corticotropin-releasing hormone (CRF), adrenocorticotopicc hormone (ACTH), melanocortins, and glucocorticoids (Lolis, Bowe, & Shalita, 2009).
Other hypotheses focus less on androgens and IGF-1 as the central players and more on the connection between the brain and skin and the brain-skin-gut-axis. Bowe & Logan (2010) found subclinical inflammatory events, such as increased IL-1 around the pilosebaceous unit, occurring in acne-prone skin even prior to the hyperproliferation of keratinocytes (Bowe & Logan, 2010). Due to this cutaneous and systemic oxidative stress, there are noted changes in mitochondrial function, membrane fluidity, enzymes, and ion channel functioning in the nervous system priming acne-prone individuals to an increased susceptibility to anxiety and depression via the brain-skin axis (Bowe & Logan, 2010). Anxiety and depression lead to increased CRH, cortisol, and oxidative stress perpetuating the acne cycle. The increased levels of oxidative stress simultaneously increase insulin levels, which reflect back to the aforementioned mTORC1 signaling hypothesis. The gut-brain-skin axis takes the brain-skin connection a step further by bringing GI dysfunction into the acne equation. Approximately 40% of people with acne have hypochlorhydria leading to small intestine bacterial overgrowth and an alteration in normal intestinal microflora (Bowe & Logan, 2011). Bowe and Logan (2011) believe the imbalanced gut microbiome leads to intestinal permeability causing systemic and localized cutaneous inflammation as evidenced by a high reactivity to lipopolysaccharide endotoxins in the blood of those with acne.
Other researchers have found vitamin and mineral deficiencies and differences in sebum lipid composition in acne-prone individuals. Vitamins A and D act as skin hormones and have receptor sites all throughout the skin (Pappas, 2009). Vitamin A and its metabolites have been used in the treatment of acne and Vitamin D has been shown to regulate growth and differentiation of keratinocytes. Lower levels of essential fatty acids, such as linoleic and α-linoleic acid were found in the wax esters of individuals with acne (Makrantonaki et al, 2011). The presence of lipoperoxides in the sebum of acne-prone skin indicates the peroxidation of squalene and a decrease in the levels of vitamin E, the major sebum antioxidant, both of which contribute to keratinocyte proliferation and pro-inflammatory cytokines. Zinc, copper, and iron also influence pro- and anti-inflammatory enzymes and pathways thus playing a role in the regulation of acne. Finally, a properly balanced omega-6 to omega-3 ratio has been shown to reduce inflammation and help acne heal as evidenced by the absence of acne in primitive diets, which tend to have a low glycemic load and more omega-3 fatty acids (Pappas, 2009).
Due to the relationship between acne and hormones, a number of other endocrine disorders share similar pathophysiologies or have acne as a major presenting symptom. Approximately 23 – 35% of women with polycystic ovarian syndrome (PCOS) have acne and the majority of women with severe acne have PCOS (83.33%) likely related to the elevated androgen and insulin levels associated with the syndrome (Lolis et al, 2009). Cushing syndrome may cause acne due to disruptions to CRH, ACTH, and cortisol whereas androgen-secreting tumors cause acne due to the direct elevation of androgen levels. Acne, breast cancer, and prostate cancer have all been linked epidemiologically to dairy intake (Danby, 2009). The link involves IGF-1 as a stimulating factor that is synergized in conjunction with the steroid hormones present in milk which sensitizes certain cells to estrogens and other hormones. Acne shares an over-activation of the mTORC1 signaling pathway along with other diseases of modern civilization like obesity, type II diabetes, metabolic syndrome, cancer, and neurodegenerative disease (Melnik, 2012). The nutrient-mediated over-activation of this pathway leads to cellular growth, cell proliferation, tumorigenic stimulation, endoplasmic reticulum stress, and disruptions to cell protein homeostasis.
Current medical treatments address acne by interfering with one or several of the following: colonization by P. acnes, FoxO1 nuclear translocation and mTORC1 signaling, hyperproliferation of keratinocytes, androgen receptors and production, and inflammation. Benzoyl peroxide, a common topical treatment for acne, mainly works as a bactericidal in the extinction of P. acnes; however, it may also stimulate FoxO1 nuclear transcription factor which attenuates mTORC1 signaling causing antiproliferative effects in keratinocytes (Melnik & Schmitz, 2013). Tetracyclines and other systemic antiobiotics mainly suppress the growth of P. acnes and help to reduce inflammation (Lolis et al, 2009). Isotretinoin (Accutane) and all-trans retinoic acid increase nuclear FoxO1 levels (Melnik & Schmitz, 2013), which block the previously exposed androgen receptor. Hormonal agents such as some oral contraceptives and Spironolactone serve as anti-androgens. Physical treatments like intralesional steroids, acne surgery, laser and light source treatments, and photodynamic therapy mainly work by reducing inflammation and hyperpigmentation associated with acne (Lolis et al, 2009). These medical treatments for acne are not without their negative side effects: benzoyl peroxide can lower vitamin E levels in the already vitamin E deficient acne-prone skin, systemic antibiotics interfere with the gut microbiome which may already be compromised in individuals with acne, and isotretinoin (Accutane) may cause mood disorders, hepatotoxicity, and elevated triglycerides among other serious health consequences (Lolis et al, 2009).
Especially with the discovery of the relationship between the Western diet and the mTORC1 pathway, dietary treatments for acne have garnered more support in recent years from the scientific and dermatological communities. Mounting evidence suggests that a low glycemic load dairy-free diet – similar to a Paleolithic diet – with ample fruits, vegetables, and fish for a balanced omega-6:omega-3 ratio would reduce acne. Higher consumptions of vegetables, fruits and green teas increase plant-derived mTORC1 inhibitors that reduce the hyperproliferation of keratinocytes (Melnik & Zouboulis, 2013). Consuming additional plant-derived m-TORC1 inhibitors like resveratrol, EGCG, curcumin, genestein, and indole-3-carbonil monomers (precursors to DIM, a natural anti-androgen) will further mitigate the androgenic response (Melnik, 2012). By reducing both dairy and excessive meat consumption, those with acne can help diminish the insulin/IGF-1 response that excessively stimulates androgen receptors (Melnik, 2012).
While dairy induces acne, research has shown that fermented dairy products containing Lactobacilli may actually improve acne. In the fermenting process, Lactobacilli utilize IGF-1 and lower the levels in diary by fourfold (Ismail, Manaf, & Azizan, 2012). In a 12-week trial, Lactobacillus fermented dairy beverages improved clinical aspects of acne (Bowe & Logan, 2011). In lieu of fermented dairy products, a probiotic with Lactobacilli strains could be included in the regimen, especially if systemic antibiotics are being used as part of the treatment plan. Contrary to popular belief, no significant relationship was found between chocolate and nuts (Ismail et al, 2012); although, high glycemic milk chocolate should be avoided as part of the low glycemic load and dairy-free diet.
In terms of supplements, adequate levels of vitamins A, D, E and zinc should be considered as well as an omega-3 supplement if adequate intake cannot be met through diet. Designs for Health sells a formula called AcnutrolTM that contains all of the above plus more in an effort to help reduce oxidative stress, prevent or balance insulin resistance, and to help balance hormones (“Acnutrol long-term support for acne control”, n.d.). It contains pantothenic acid and carnitine for healthy lipid metabolism to reduce inflammation and prevent lipid peroxidation. Zinc helps with wound healing, immune system response, and reducing inflammation. Chromium helps prevent the insulin resistance that is associated with acne. In addition to AcnutrolTM, there are several natural anti-androgenic herbs that provide an androgen-blocking alternative to hormonal therapies. Red reishi, licorice, white peony, green tea, spearmint, black cohosh, chaste tree, and saw palmetto can assist the acne client in reducing the stimulation of androgen receptors (Grant & Ramasamy, 2012).
“Acnutrol long-term support for acne.” (n.d.). Retrieved March 22, 2014 from
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