Anti-Aging Skin Care Tips

Updated: Apr 30, 2019

Wrinkles, bags under the eyes – the signs of aging all of us ladies want to avoid as we get older.

What if I told you there are powerhouse nutrients in certain plants and foods that you can use to slow your skins aging process, and in some cases, even reverse these effects?


It sounds like a gimmick...but of course…I have research to back it up! ;)


Let’s talk antioxidants.


In this post I will share how applying antioxidants topically to the skin can slow the effects of aging, what types of ingredients to look for in skin care products, steps to prevent oxidative damage to the skin, product suggestions and nutritional strategies on eating antioxidant rich foods to help maintain youthful, glowing skin.


Let us start with the basics.


A N T I O X I D A N T S 1 0 1

Most people are familiar with the term antioxidants, but why are they so good for us and what do they actually do?


Basically, antioxidants are substances that prevent, limit, or delay some types of cell damage[i]. This cell damage is typically caused by free radicals. Free radicals are unstable and highly reactive molecules that lead to damage of cell proteins, DNA, cell membranes, and more. This damage is called oxidative stress, and occurs when free radicals cause more damage than the antioxidants are able to defend[ii].

A N T I O X I D A N T S & T H E S K I N

Skin molecules are constantly bombarded by these free radicals. We are continually exposed to things like environmental pollution and ultra violet radiation (UVR) from the sun, which are capable of causing generation of free radicals[iii].


It is estimated that UVR contributes to up to 80% of the skins visual signs of aging, such as wrinkling, fine lines, and dehydrated skin[iv]. There are many protective antioxidants present in the skin, such as carotenoids, lutein, beta carotene, Vitamin A, and Vitamin C (which I’ll share about more in depth later)[v]. UVR can damage and destroy the skins antioxidant defenses, even at low doses[vi],[vii],[viii],[ix].

So this oxidative stress (typically from UVR) can lead to tissue damage, which means wrinkles and fine lines.


Now aging and wrinkling as you get older is natural, and you are still beautiful even with some wrinkles or lines under your eyes!


You won’t be able to protect yourself from all the sources of free radical damage and oxidative stress, but there are some steps you can take to prevent and slow the process and limit/reverse the amount of damage done to your skin.


P R E V E N T I O N

As UVR can cause significant decreases in the skin’s level of antioxidants, and therefore its ability to fight off free radicals, prevention is the best way to limit these effects over the long term.


The main preventative strategies are avoiding sun exposure, using sunscreens to block or reduce skin exposure to UVR, and using a combination of antioxidants, both topically and through nutrition to re-supply antioxidants to the body to help reduce and limit the effects of free radicals[x].


Completely avoiding sun exposure is almost impossible, and if you are like me, you LOVE spending time outdoors in the sun! So this means sunscreen is important. I will save the specifics of that for another day, but just remember:


When it comes to UVR protection, limit time exposed to sun, use sunscreen and replenish antioxidants.

In this post, I want to focus on how we replenish our skins antioxidants to slow our skin cell damage.


T O P I C A L A N T I O X I D A N T S

Antioxidants are typically found in fruits and vegetables. This means, using products that are derived from plants will typically have some sort of antioxidant component to them.


Below I will share some great sources of antioxidants and what ingredients to look for. This will not cover the full span of sources of antioxidants, but it will give you a thorough starting point for what to look for in products!


Vitamin A

Also referred to as Retinol, which is a component of vitamin A, and is often used as an anti-aging compound in many cosmetic products.

Topical retinal has been shown to improve fine lines that are associated with natural aging and increases collagen production, which helps maintain elasticity in the skin[xi],[xii],[xiii].

Tretinoin, a Vitamin A derivative, can also help restore the skin to a pre-sun-damaged state and stimulate collagen synthesis as well[xiv].


Vitamin A also stimulates collagen synthesis, which is responsible for helping the skin maintain its elasticity[xv].


Some ingredients to look for: Rosehip Oil, Avocado Oil, Argan Oil, berries[xvi],[xvii] .


Vitamin E

Vitamin E (Tocopheral) is the major naturally occurring antioxidant in the skin[xviii]. After being applied topically, it’s levels in the skin greatly increase and it can penetrate into all layers of the skin[xix],[xx].

Animal studies show that UVR destroys vitamin e in the skin, but when it is applied topically, the levels are higher[xxi],[xxii],[xxiii],[xxiv],[xxv].


Ingredients to look for: Vitamin E Oil, Almond Oil, Safflower Oil, Sunflower Oil, and most berry seed oils, such as Blueberry Seed Oil[xxvi],[xxvii],[xxviii].


Carotenoids

Carotenoids are responsible for the red, orange and yellow colors in many fruits and veggies. Some examples of these foods are carrots, watermelon, spinach, tomatoes, bell peppers, and oranges[xxix]. Some carotenoids can be converted to vitamin A in the body. These plant pigments are great sources of free-radical fighting antioxidants[xxx]!


Surprise, surprise, but UVR can reduce levels of carotenoids in skin[xxxi],[xxxii]! Betchya didn’t see that coming…Some common carotenoids are beta-carotene, lycopene and leutine[xxxiii].


One study showed that topical use of lycopene, a common phytonutrient in tomatoes, increased antioxidant activity of skin 10 times greater than untreated skin[xxxiv]. It has been shown to have protective affects against UVR damage[xxxv].


Ingredients to look for: Plant extracts or essential oils from red, yellow and orange plant foods. Rosehip oil[xxxvi].


Vitamin C

Also commonly called Ascorbic Acid, vitamin C protects the skin by neutralizing free radicals[xxxvii]. It also improves sun-damaged skin and helps prevent and reduce wrinkles by stimulating collagen synthesis[xxxviii],[xxxix],[xl],[xli]. It not only prevents damage and future signs of aging, but actually REVERSES many of these outward signs! Vitamin C and E are extremely effective when used together, more so than by themselves[xlii],[xliii],[xliv].


Ingredients to look for: Ascorbic Acid, Vitamin C, Papaya Extract or Enzymes[xlv].


Polyphenols

Polyphenols are plant compounds found in teas, wine, citrus fruits, cacao, and berries[xlvi]. The most common polyphenol used in skin care products is Green Tea[xlvii]. It provides protective effects against UVR in both human and animal studies[xlviii],[xlix],[l]. This is the star of one of my favorite anti-aging products, which I will share about later!


Ingredients to look for: Coffeeberry Extract[li], Green Tea, White Tea, Resveratrol, Argan Oil [lii],[liii],[liv],[lv].


A N T I O X I D A N T P R O D U C T S U G G E S T I O N S

As a general rule of thumb, look for products with ingredients that come from colorful plants, such as berries and fruits. Here are some more specific products I have used whose ingredients are high in anti-oxidants, giving you the anti-aging benefits.




1. Lilian Organics Superfood Smoothie – This water-based serum has a variety of plant extracts, vitamin e oil!


2. 100% Pure Luminous Primer – This is my go to primer and it is filled with antioxidants and vitamins, including red wine resveratrol, vitamin E, vitamin C, and green tea.


3. Ultra-Hydration Moisturizer by Rejuva Minerals – This moisturizer is made with green tea, cocoa, and their multi-fruit antioxidant complex, which includes a variety of fruit enzymes.


4. 100% Coffee Bean Caffeine Eye Cream – This is my go to eye cream, not just because it moisturizes and smells heavenly, but because of the green coffee and green tea extract, rosehip oil, vitamin E and Vitamin C that prevent and combat those fine under-eye lines!


5. Joylin Naturals Blueberry Oil – We all know blueberries are a great source of anti-oxidants, and this oil is so light, it sinks quickly into your skin and provides SO MUCH HYDRATION!


A N T I O XI D A N T S & N U T R I T I O N

It turns out that a diet high in anti-oxidants helps improve skin health as well[lvi],[lvii]. To make it easy, try to include colorful veggies, berries, fruits high in vitamin c (citrus fruits), and other foods like cocoa and green tea! You’ll be set!


Phew. I know that was a lot of info, but you are now an expert on antioxidants and skin health! You should feel like an anti-aging guru! Message me if you have any questions about the products I mentioned, further info on how to pick antioxidant-rich products, if products you currently have are high in antioxidants, or anything else!


Comment below your favorite antioxidant! Mine is green tea :)




[i] “Antioxidants: In Depth.” National Center for Complementary and Integrative Health, U.S. Department of Health and Human Services, 4 May 2016, nccih.nih.gov/health/antioxidants/introduction.htm.


[ii] Lobo, V., et al. “Free Radicals, Antioxidants and Functional Foods: Impact on Human Health.” Pharmacognosy Reviews, Medknow Publications & Media Pvt Ltd, 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC3249911/.


[iii] Poljšak, Borut, and Raja Dahmane. “Free Radicals and Extrinsic Skin Aging.” Dermatology Research and Practice, Hindawi Publishing Corporation, 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3299230/.


[iv] Amaro-Ortiz, Alexandra, et al. “Ultraviolet Radiation, Aging and the Skin: Prevention of Damage by Topical CAMP Manipulation.” Molecules (Basel, Switzerland), U.S. National Library of Medicine, 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC4344124/#R15.


[v] Poljšak, Borut, and Raja Dahmane. “Free Radicals and Extrinsic Skin Aging.” Dermatology Research and Practice, Hindawi Publishing Corporation, 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3299230/.


[vi] Shindo, Y, et al. “Dose-Response Effects of Acute Ultraviolet Irradiation on Antioxidants and Molecular Markers of Oxidation in Murine Epidermis and Dermis.” National Center for Biotechnology Information, U.S. National Library of Medicine, 1994, www.ncbi.nlm.nih.gov/pubmed.


[vii] Shindo, Y, et al. “Antioxidant Defense Mechanisms in Murine Epidermis and Dermis and Their Responses to Ultraviolet Light.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Mar. 1993, www.ncbi.nlm.nih.gov/pubmed/8440901.


[viii] Weber, S U, et al. “Vitamin C, Uric Acid, and Glutathione Gradients in Murine Stratum Corneum and Their Susceptibility to Ozone Exposure.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Dec. 1999, www.ncbi.nlm.nih.gov/pubmed/10594762.


[ix] Thiele, J J, et al. “Depletion of Human Stratum Corneum Vitamin E: an Early and Sensitive in Vivo Marker of UV Induced Photo-Oxidation.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, May 1998, www.ncbi.nlm.nih.gov/pubmed/9579541.


[x] Baumann, L. “Skin Ageing and Its Treatment.” The Journal of Pathology., U.S. National Library of Medicine, Jan. 2007, www.ncbi.nlm.nih.gov/pubmed/17200942.


[xi] Kafi, R, et al. “Improvement of Naturally Aged Skin with Vitamin A (Retinol).” Archives of Dermatology., U.S. National Library of Medicine, May 2007, www.ncbi.nlm.nih.gov/pubmed/17515510.


[xii] Varani, J, et al. “Vitamin A Antagonizes Decreased Cell Growth and Elevated Collagen-Degrading Matrix Metalloproteinases and Stimulates Collagen Accumulation in Naturally Aged Human Skin.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Mar. 2000, www.ncbi.nlm.nih.gov/pubmed/10692106.


[xiii] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699641/


[xiv] Bhawan, J. “Short- and Long-Term Histologic Effects of Topical Tretinoin on Photodamaged Skin.” International Journal of Dermatology., U.S. National Library of Medicine, Apr. 1998, www.ncbi.nlm.nih.gov/pubmed/9585903.


[xv] Varani, J, et al. “Vitamin A Antagonizes Decreased Cell Growth and Elevated Collagen-Degrading Matrix Metalloproteinases and Stimulates Collagen Accumulation in Naturally Aged Human Skin.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Mar. 2000, www.ncbi.nlm.nih.gov/pubmed/10692106.


[xvi] Nayak, B S, et al. “Wound Healing Activity of Persea Americana (Avocado) Fruit: a Preclinical Study on Rats.” Journal of Wound Care., U.S. National Library of Medicine, Mar. 2008, www.ncbi.nlm.nih.gov/pubmed/18376654.


[xvii] Marfil, Rocío, et al. “Determination of Polyphenols, Tocopherols, and Antioxidant Capacity in Virgin Argan Oil (Argania Spinosa, Skeels).” European Journal of Lipid Science and Technology, Wiley-Blackwell, 24 May 2011, onlinelibrary.wiley.com/doi/abs/10.1002/ejlt.201000503.


[xviii] Nachbar, F, and H C Korting. “The Role of Vitamin E in Normal and Damaged Skin.” Journal of Molecular Medicine (Berlin, Germany)., U.S. National Library of Medicine, Jan. 1995, www.ncbi.nlm.nih.gov/pubmed/7633944.


[xix] Thiele, J J, et al. “Sebaceous Gland Secretion Is a Major Physiologic Route of Vitamin E Delivery to Skin.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Dec. 1999, www.ncbi.nlm.nih.gov/pubmed/10594744?dopt=Citation.


[xx] Traber, M G, et al. “Penetration and Distribution of Alpha-Tocopherol, Alpha- or Gamma-Tocotrienols Applied Individually onto Murine Skin.” Lipids., U.S. National Library of Medicine, Jan. 1998, www.ncbi.nlm.nih.gov/pubmed/9470177?dopt=Citation%2B-.


[xxi] Weber, C, et al. “Efficacy of Topically Applied Tocopherols and Tocotrienols in Protection of Murine Skin from Oxidative Damage Induced by UV-Irradiation.” Free Radical Biology & Medicine., U.S. National Library of Medicine, 1997, www.ncbi.nlm.nih.gov/pubmed/9119243?dopt=Citation.


[xxii] Valacchi, G, et al. “Ozone Potentiates Vitamin E Depletion by Ultraviolet Radiation in the Murine Stratum Corneum.” FEBS Letters., U.S. National Library of Medicine, 21 Jan. 2000, www.ncbi.nlm.nih.gov/pubmed/10648834?dopt=Citation.


[xxiii] Shindo, Y, et al. “Dose-Response Effects of Acute Ultraviolet Irradiation on Antioxidants and Molecular Markers of Oxidation in Murine Epidermis and Dermis.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, Apr. 1994, www.ncbi.nlm.nih.gov/pubmed/8151122?dopt=Citation.


[xxiv] Thiele, J J, et al. “Depletion of Human Stratum Corneum Vitamin E: an Early and Sensitive in Vivo Marker of UV Induced Photo-Oxidation.” The Journal of Investigative Dermatology., U.S. National Library of Medicine, May 1998, www.ncbi.nlm.nih.gov/pubmed/9579541?dopt=Citation.


[xxv] Evans, Julie A., and Elizabeth J. Johnson. “The Role of Phytonutrients in Skin Health.” Nutrients, MDPI, Aug. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC3257702/.


[xxvi] Sultana, Y, et al. “Effect of Pre-Treatment of Almond Oil on Ultraviolet B-Induced Cutaneous Photoaging in Mice.” Journal of Cosmetic Dermatology., U.S. National Library of Medicine, Mar. 2007, www.ncbi.nlm.nih.gov/pubmed/17348990.


[xxvii] Shahidi, Fereidoon, and Adriano Costa de Camargo. “Tocopherols and Tocotrienols in Common and Emerging Dietary Sources: Occurrence, Applications, and Health Benefits.” MDPI, Multidisciplinary Digital Publishing Institute, 20 Oct. 2016, www.mdpi.com/1422-0067/17/10/1745.


[xxviii] Parry, J, et al. “Fatty Acid Composition and Antioxidant Properties of Cold-Pressed Marionberry, Boysenberry, Red Raspberry, and Blueberry Seed Oils.” Journal of Agricultural and Food Chemistry., U.S. National Library of Medicine, 9 Feb. 2005, www.ncbi.nlm.nih.gov/pubmed/15686403.


[xxix] Szalay, Jessie. “What Are Carotenoids?” LiveScience, Purch, 15 Oct. 2015, www.livescience.com/52487-carotenoids.html.


[xxx] Cantrell, A, et al. “Singlet Oxygen Quenching by Dietary Carotenoids in a Model Membrane Environment.” Archives of Biochemistry and Biophysics., U.S. National Library of Medicine, 1 Apr. 2003, www.ncbi.nlm.nih.gov/pubmed/12646267.


[xxxi] White, W S, et al. “Ultraviolet Light-Induced Reductions in Plasma Carotenoid Levels.” The American Journal of Clinical Nutrition., U.S. National Library of Medicine, May 1988, www.ncbi.nlm.nih.gov/pubmed/3364402.


[xxxii] Ribaya-Mercado, J D, et al. “Skin Lycopene Is Destroyed Preferentially over Beta-Carotene during Ultraviolet Irradiation in Humans.” The Journal of Nutrition., U.S. National Library of Medicine, July 1995, www.ncbi.nlm.nih.gov/pubmed/7616301.


[xxxiii] Evans, Julie A., and Elizabeth J. Johnson. “The Role of Phytonutrients in Skin Health.” Nutrients, MDPI, Aug. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC3257702/.


[xxxiv] Lopes, L B, et al. “Topical Delivery of Lycopene Using Microemulsions: Enhanced Skin Penetration and Tissue Antioxidant Activity.” Journal of Pharmaceutical Sciences., U.S. National Library of Medicine, Mar. 2010, www.ncbi.nlm.nih.gov/pubmed/19798758.


[xxxv] Lebwhol, Mark, and et.al. Protective Effects of Lycopene Against Ultraviolet B-Induced Photodamage. Journal of Nutrition and Cancer., 18 Nov. 2009, www.tandfonline.com/doi/abs/10.1207/s15327914nc4702_11.


[xxxvi] Frohlich, Kati, and et.al. “Rosehip –– a ‘New’ Source of Lycopene?” Molecular Aspects of Medicine, Pergamon, 15 July 2003, www.sciencedirect.com/science/article/pii/S0098299703000347.


[xxxvii] Telang, Pumori Saokar. “Vitamin C in Dermatology.” Indian Dermatology Online Journal, Medknow Publications & Media Pvt Ltd, 2013, www.ncbi.nlm.nih.gov/pmc/articles/PMC3673383/.


[xxxviii] Traikovich, S S. “Use of Topical Ascorbic Acid and Its Effects on Photodamaged Skin Topography.” Archives of Otolaryngology--Head & Neck Surgery., U.S. National Library of Medicine, Oct. 1999, www.ncbi.nlm.nih.gov/pubmed/10522500.


[xxxix] Burke, K E. “Interaction of Vitamins C and E as Better Cosmeceuticals.” Dermatologic Therapy., U.S. National Library of Medicine, 2007, www.ncbi.nlm.nih.gov/pubmed/18045356.


[xl] Kishimoto, Y, et al. “Ascorbic Acid Enhances the Expression of Type 1 and Type 4 Collagen and SVCT2 in Cultured Human Skin Fibroblasts.” Biochemical and Biophysical Research Communications., U.S. National Library of Medicine, 11 Jan. 2013, www.ncbi.nlm.nih.gov/pubmed/23228664.


[xli] Michaels, Alexander J. Vitamin C and Skin Health. Linus Pauling Institute, 1 Jan. 2018, lpi.oregonstate.edu/mic/health-disease/skin-health/vitamin-C.


[xlii] Lin, J Y, et al. “UV Photoprotection by Combination Topical Antioxidants Vitamin C and Vitamin E.” Journal of the American Academy of Dermatology., U.S. National Library of Medicine, June 2003, www.ncbi.nlm.nih.gov/pubmed/12789176.


[xliii] Dreher, F, et al. “Topical Melatonin in Combination with Vitamins E and C Protects Skin from Ultraviolet-Induced Erythema: a Human Study in Vivo.” The British Journal of Dermatology., U.S. National Library of Medicine, Aug. 1998, www.ncbi.nlm.nih.gov/pubmed/9767255.


[xliv] Darr, D, et al. “Effectiveness of Antioxidants (Vitamin C and E) with and without Sunscreens as Topical Photoprotectants.” Acta Dermato-Venereologica., U.S. National Library of Medicine, July 1996, www.ncbi.nlm.nih.gov/pubmed/8869680.


[xlv] Mármol, Inés, et al. “Administration Dependent Antioxidant Effect of Carica Papaya Seeds Water Extract.” International Journal of Molecular Sciences, MDPI, June 2017, www.ncbi.nlm.nih.gov/pmc/articles/PMC5485961/.


[xlvi] Nichols, Joi A., and Santosh K. Katiyar. “Skin Photoprotection by Natural Polyphenols: Anti-Inflammatory, Anti-Oxidant and DNA Repair Mechanisms.” Archives of Dermatological Research, U.S. National Library of Medicine, Mar. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC2813915/.


[xlvii] Thasleema , S Aafrin. “Green Tea as an Antioxidant- A Short Review .” Journal of Pharmaceutical Sciences and Rsearch, vol. 5, no. 9, pp. 171–173., www.jpsr.pharmainfo.in/Documents/Volumes/vol5issue09/jpsr05091301.pdf.


[xlviii] Camouse, M M, et al. “Topical Application of Green and White Tea Extracts Provides Protection from Solar-Simulated Ultraviolet Light in Human Skin.” Experimental Dermatology., U.S. National Library of Medicine, June 2009, www.ncbi.nlm.nih.gov/pubmed/19492999.


[xlix] Katiyar, S K, et al. “Green Tea Polyphenol Treatment to Human Skin Prevents Formation of Ultraviolet Light B-Induced Pyrimidine Dimers in DNA.” Clinical Cancer Research : an Official Journal of the American Association for Cancer Research., U.S. National Library of Medicine, Oct. 2000, www.ncbi.nlm.nih.gov/pubmed/11051231.


[l] Elmets, C A, et al. “Cutaneous Photoprotection from Ultraviolet Injury by Green Tea Polyphenols.” Journal of the American Academy of Dermatology., U.S. National Library of Medicine, Mar. 2001, www.ncbi.nlm.nih.gov/pubmed/11209110.


[li] Stallings, Alison F., and Mary P. Lupo. “Practical Uses of Botanicals in Skin Care.” The Journal of Clinical and Aesthetic Dermatology, Matrix Medical Communications, Jan. 2009, www.ncbi.nlm.nih.gov/pmc/articles/PMC2958188/.


[lii] Stallings, Alison F., and Mary P. Lupo. “Practical Uses of Botanicals in Skin Care.” The Journal of Clinical and Aesthetic Dermatology, Matrix Medical Communications, Jan. 2009, www.ncbi.nlm.nih.gov/pmc/articles/PMC2958188/.


[liii] Afaq, F, et al. “Prevention of Short-Term Ultraviolet B Radiation-Mediated Damages by Resveratrol in SKH-1 Hairless Mice.” Toxicology and Applied Pharmacology., U.S. National Library of Medicine, 1 Jan. 2003, www.ncbi.nlm.nih.gov/pubmed/12583990.


[liv] Farris, P, and et. al. Resveratrol: A Unique Antioxidant Offering a Multi-Mechanistic Approach for Treating Aging Skin. Journal of Drugs in Dermatology, Dec. 2013, www.researchgate.net/profile/Yevgeniy_Krol/publication/259154437_Resveratrol_A_Unique_Antioxidant_Offering_a_Multi-Mechanistic_Approach_for_Treating_Aging_Skin/links/53f777e60cf24a9236d06c71.pdf+.


[lv] Giménez, Rafael, et al. “Determination of Polyphenols, Tocopherols, and Antioxidant Capacity in Virgin Argan Oil (Argania Spinosa, Skeels).” European Journal of Lipid Science and Technology, Wiley-Blackwell, 24 May 2011, onlinelibrary.wiley.com/doi/abs/10.1002/ejlt.201000503.


[lvi] Evans, Julie A., and Elizabeth J. Johnson. “The Role of Phytonutrients in Skin Health.” Nutrients, MDPI, Aug. 2010, www.ncbi.nlm.nih.gov/pmc/articles/PMC3257702/.


[lvii] Schagen, Silke K., et al. “Discovering the Link between Nutrition and Skin Aging.” Dermato-Endocrinology, Landes Bioscience, 1 July 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3583891/.