Skin Laxity

Macrene Alexiades

BACKGROUND

Skin laxity is a primary finding in skin aging and manifests as sagging of the skin. The survey by the American Society for Dermatologic Surgery reported that 67% of the population seeks treatment to sagging skin on jawline and neck.¹ From 1900 to 1990, plastic surgery, including rhytidectomy or the surgical face lift, was the primary cosmetic treatment option for skin laxity. In the 1990s, ablative resurfacing lasers were introduced and applied to achieve facial skin tightening.² Despite high efficacy for rhytid reduction, ablative devices required significant recovery time, prolonged wound healing, and an increased risk of side effects and complications. Nonablative and minimally invasive technologies with little to no recovery time and a more favorable risk-reward profile without epidermal vaporization were subsequently developed. In the early 2000s, skin tightening energy-based technologies were developed, including radiofrequency (RF) and infrared wavelengths. Although the gold standard of skin tightening remains surgical rhytidectomy or redraping, patients continue to demand for treatment alternatives in light of the anesthesia risks, morbidity, and the potential for unwanted cosmetic outcomes associated with plastic surgery. Nonsurgical skin tightening technologies are not yet a replacement for those with advanced to severe skin laxity but provide alternative for mild to moderate skin laxity candidates willing to accept less efficacy in exchange for facile recovery and rare risk of side effects or complications (see Table 4.5.1).

PRESENTATION

Patients with skin laxity present with a complaint of sagging or lax skin. They describe the skin in the undereyes and cheeks as sunken, complain of folds in the perioral regions, note the worsening of jowls, and/or report looseness to the skin. Similar complaints regarding body skin laxity refer to folding in the abdominal skin, linear undulations, and crepiness or irregularity to the skin of the thighs or arms.

TABLE 4.5.1 Quantitative Comprehensive Grading Scale of Rhytids, Laxity, and Photoaging^a

Grade	Descriptive Parameter	Alexiades Classification and Grading Scale of Skin Aging
Grade	Descriptive Parameter	Rhytids	Laxity	Elastosis	Dyschromia	Erythema-Telangiectasia (E-T)	Keratoses	Texture
0	None	None	None	None	None	None	None	None
1	Mild	Wrinkles in motion, few, superficial	Localized to nasolabial (nL) folds	Early, minimal yellow hue	Few (1-3) discrete small (<5 mm) lentigines	Pink E or few T, localized to single site	Few	Subtle irregularity
1.5	Mild	Wrinkles in motion, multiple, superficial	Localized, nL and early melolabial (mL) folds	Yellow hue or early, localized periorbital (po) elastotic beads (eb)	Several (3-6), discrete small lentigines	Pink E or several T localized 2 sites	Several	Mild irregularity in few areas
2	Moderate	Wrinkles at rest, few, localized, superficial	Localized, nL/mL folds, early jowls, early submental/submandibular (sm)	Yellow hue, localized po eb	Multiple (7-10), small lentigines	Red E or multiple T localized to 2 sites	Multiple, small	Rough in few, localized sites
2.5	Moderate	Wrinkles at rest, multiple, localized, superficial	Localized, prominent nL/mL folds, jowls, and sm	Yellow hue, po and malar eb	Multiple small and few large lentigines	Red E or multiple T, localized to 3 sites	Multiple, large	Rough in several, localized areas
3	Advanced	Wrinkles at rest, multiple, forehead, periorbital and perioral sites, superficial	Prominent nL/mL folds, jowls and sm, early neck strands	Yellow hue, eb involving po, malar and other sites	Many (10-20) small and large lentigines	Violaceous E or many T, multiple sites	Many	Rough in multiple, localized sites
3.5	Advanced	Wrinkles at rest, multiple, generalized, superficial; few, deep	Deep nL/mL folds, prominent jowls and sm, prominent neck strands	Deep yellow hue, extensive eb with little uninvolved skin	Numerous (>20) or multiple large with little uninvolved skin	Violaceous E, numerous T little uninvolved skin	Little uninvolved skin	Mostly rough, little uninvolved skin
4	Severe	Wrinkles throughout, numerous, extensively distributed, deep	Marked nL/mL folds, jowls and sm, neck redundancy and strands	Deep yellow hue, eb throughout, comedones	Numerous, extensive, no uninvolved skin	Deep, violaceous E, numerous T throughout	No uninvolved skin	Rough throughout
^aThis 4-point grading scale has been extensively tested and employed for evaluating laser and energy-based cosmetic treatments.¹,²,³

DIAGNOSIS

Clinical Diagnosis

The clinical signs of skin aging are classified into rhytids, laxity, and the subcategories of photoaging, including dyspigmentation, erythema/telangiectasia, solar elastosis, keratosis, and textural changes (Table 4.5.1).¹,²,³ In assessing for facial and neck skin laxity, the clinical signs include nasolabial folds, melolabial folds, jowls, submental and submandibular redundancy, and neck strands. Loose, redundant skin with loss of elasticity and recoil are clinical hallmarks of skin laxity. The following grading scale classifies facial and neck skin severity according to the absence or progressive presence of clinical signs.

Skin laxity on the body has not been validated with an objective grading scale. The relative degree of tightness or firmness has been assessed in clinical studies alongside the presence or absence of surface irregularities.⁴ The diagnosis of skin laxity on the body is therefore a clinical one based on the relative presence of rhytids, lack of recoil, folds upon flexion, linear undulations, and poor texture.

Histopathology

The elastic fiber network in the dermis is composed of horizontally oriented fibers in the reticular dermis that interconnect with more perpendicularly oriented fibers in the papillary dermis and are cross-linked. This network allows the skin to maintain its overall structure by affording elasticity. Elastic fibers can be stained with Verhoeff von Gieson, which is a silver stain. Other elastic stains that may be used include Weigert resorcin-fuchsin and Pinkus acid orcein.⁵,⁶

In intrinsic aging, elastin density decreases over time, whereas in photoaging, elastic fibers increase in density in the dermis and take on an abnormal morphology. One study compared the changes in elastin staining intensity from the first decade to the ninth decade between intrinsically aged skin versus photoaged skin and found that elastin in sun-protected skin decreased from 49.2% to 30.4% but increased from 56.5% in to 75.2% in sun-exposed skin.⁷

Subtypes

Skin laxity may be categorized as acquired, namely, due to skin aging, and genetic, including genetic mutation-related elastic fiber system defects. In some instances, patients may exhibit a combination of the two.

Acquired

In skin laxity due to aging and photodamage, a progressive appearance of laxity is the rule over time, with associated findings of rhytids and photoaging accompanying the progression of clinical signs (Table 4.5.1).

Genetic

Hereditary forms of skin laxity manifest early in age and may be associated with elastic fiber defects of other organs besides the skin, such as the heart or blood vessels (Table 4.5.2).

PATHOGENESIS

The properties of elasticity and resilience of the skin are conferred by the elastic fiber system in the connective tissue. These major insoluble extracellular matrix assemblies allow for the deformability and passive recoil of tissue. The elastic fibers complement the collagen fibers, which confer tensile strength. The elastic fiber system comprises roughly 2% to 4% of the dermis (dry weight) in sun-protected adult skin. Each elastic fiber is formed from an amorphous elastin core and a surrounding mantle of elastic microfibrils, comprising fibrillin, fibulin, microfibrillar-associated glycoproteins, and elastin receptors.⁸ In diseases characterized by alterations in elastic fibers, the skin is loose and sagging with a loss of recoil, elasticity, and resilience⁹,¹⁰ (Table 4.5.2). Elastic fiber mutations, deficiency, degradation, or alteration result in reduced skin elasticity and increased skin laxity, which may be reversed through stimulation of neoelastogenesis.¹¹

TABLE 4.5.2 Elastic Fiber System Genes, Functions in Skin Elasticity, and Associated Skin Laxity Syndromes

Protein	Gene	Function	Syndrome
Elastin	ELN	Structural core of elastin fiber complex
Fibrillins	FBN1	Structural proteins of microfibrils, extracellular matrix; components and structural support of elastin fibers	Marfan
	FBN2		Congenital contractural arachnodactyly
	FBN3		Marfan
Fibulins	FBLN1	Endothelial development
	FBLN2 FBLN3 FBLN4 FBLN5	Elastin-microfibril interface Binds tissue inhibitor of metalloproteases 3 (TIMP3) (EFEMP2) Binds LOX and FBN1 Binds ELN, FBN1, LTBP2, LOXL1, and integrins	Autosomal recessive cutis laxa, type 1
ATP7a	ATP7a	Transmembrane Cu²⁺ transport protein; required for function of Cu containing enzymes such as lysyl oxidase	Meinke’s
ATP-binding cassette subfamily C member 6	ABCC6	Transmembrane transporter protein	Pseudoxanthoma elasticum
LEMD3	LEMD3	Inner nuclear membrane protein	Buschke-Ollendorf

TREATMENT

The treatment algorithm of skin laxity is determined by the anatomical location of the laxity and the properties of the target tissue (Algorithm 4.5.1). All approaches may include topical therapy with anticipated minimal results, cosmetic treatments that primarily include RF, infrared light, and ultrasound, followed by surgical options as the most aggressive approach.

Medical

Medical treatment of skin laxity is primarily aimed at prevention, and topical treatments have been efficacious.

Cosmetic

A large variety of lasers, light, and energy-based technologies have been developed to treat skin aging.¹,¹² With increasing specialization, devices have been developed that target skin laxity (Table 4.5.4). Among the devices targeting skin laxity and resulting in skin tightening, RF, broadband light, and ultrasound are the best known.

RF, infrared light, and ultrasound technologies work by delivering energy to the skin or underlying structures. This creates thermal, mechanical, and biochemical effects that lead to collagen denaturation and dermal remodeling that increases volume and improves the elastic properties of the skin.¹³ Starting in the third decade of life, collagen and elastin synthesis decrease and elastin fibers are degraded owing to sun exposure. Collagen fibers are composed of a triple helix of protein chains linked with interchain bonds into a crystalline
structure. When collagen fibers are heated to specific temperatures, they contract as a result of breakage of intramolecular hydrogen bonds. It had been thought that contraction causes the crystalline triple helix structure to fold, creating thicker and shorter collagen fibers resulting in tissue tightening. However, recent findings have demonstrated that partially denatured collagen is superior to fully denatured collagen in inducing histologic dermal remodeling and clinical laxity reduction.⁹ Fully denatured collagen >70°C resulted in charring of collagen and lower clinical efficacy; maximal volumes of partial collagen denaturation and optimal clinical efficacy were found at intradermal temperatures of 62°C to 67°C. The author theorized that exposure of arginyl-glycinyl-aspartic acid (RGD) sequences on partially heat-denatured collagen are required for induction of neocollagenesis and neoelastinogenesis.⁹ The process of neocollagenesis has been demonstrated to take up to 12 months following treatment to complete and this correlates with continued clinical improvement.

ALGORITHM 4.5.1 Treatment for skin laxity. (Courtesy of Macrene Alexiades, MD, PhD.)

Radiofrequency

Mechanism of Action. RF delivers volumetric heating to the dermis, the controlled thermal injury inducing neocollagenesis and neoelastogenesis. These histologic changes correlate clinically with rhytid and laxity reduction. RF is in the 3-kHz to 24-GHz frequency range and employs an oscillating electric current, which induces collisions between charged atoms and molecules in tissue generating heat. Penetration depth is inversely proportional to frequency; lower RF frequencies penetrate

more deeply when applied to skin surface. Heat is generated from the resistance of tissue components to the movement of electrons within the oscillating RF field as governed by Ohm law. This resistance, termed impedance, generates heat relative to the amount of current and time, converting electric current to thermal energy.

TABLE 4.5.3 Topical Peptides to Treat Skin Aging and Laxity

Oligopeptides	Derivation	Mechanism of Action	Reference
Dermal remodeling regulators
Amino acid derivatives
Dipalmitoyl hydroxyproline Sepilift DPHP and it is marketed by SEPPIC	Plant-derived single amino acid	Prevention of collagen degradation; production of tissue inhibitors of metalloproteinases	Bode W, Fernandez-Catalan C, Grams F, et al. Insights into MMP-TIMP Interactions. Ann N Y Acad Sci. 1999;878:73-91.
Dipeptide
β-Ala-His Carnosine N-Acetyl-Ala-His N-Acetylcarnosine palmitoyl β-Ala-His	Synthetic dipeptide	Antioxidant; wrinkle reduction	Lintner K, Peschard O. Biologically active peptides: from a laboratory bench curiosity to a functional skin care product. Int J Cosmet Sci. 2000;22:207-218.
Tripeptides
TFA-Val-Try-Val-OH Trifluoroacetyl-Tripeptide-2 Progeline^®	Synthetic tripeptide	Matrix metalloproteinase and elastase inhibitor; wrinkles, firmness, elasticity and sagging	Loing E. Unipex Innovations, Québec, Canada; Thiery Suere and Elisabeth Lamarque, Unipex Innovations, Ramonville St. Agne, France, Trifluoroacetyl-Tripeptide-2 to Target Senescence for Anti-aging Benefits. Available at http://www. cosmeticsandtoiletries.com/formulating/category/skincare/premium-Trifluoroacetyl-Tripept. Accessed April 22, 2017.
Lys-α-Asp-Ile-Citrulline; Tripeptide-10 citrulline Decorinyl	Synthetic tripeptide mimicking decorin that binds to collagen fibrils; a decorin-like tripeptide	Collagen fiber cohesion	Puig A, Antón JM, Mangues M. A new decorin-like tetrapeptide for optimal organization of collagen fibres. Int J Cosmet Sci. 2008;30:97-104.
Gly-His-Lys -Cu Cu-GHK lamin	Synthetic tripeptide fragment of alpha chain of collagen	Upregulates MMP-2, TIMP-1, and TIMP-2; induces collagen remodeling and elastin production; stimulates hair growth	Maquart FX, Pickart L, Laurent M, et al. FEBS Lett. 1988;238:343-346. Mazurowska L, Mojski M. J Cosmet Sci. 2008;59:59-69. Siméon A, Emonard H, Hornebeck W, et al. Life Sci. 2000;67:2257-2265. Leyden J, Stephens T, Finkey MB, et al. Presented at the American Academy Dermatology Meeting 2002: Abstract P68. Leyden J, Stephens T, Finkey MB, et al. Presented at the American Academy Dermatology Meeting 2002: Abstract P69.
Manganese tripeptide-1 GHK-Mn²⁺	Synthetic tripeptide	Clinical improvement in rhytids and dyspigmentation	Hussain M, Goldberg DJ. Topical manganese peptide in the treatment of photodamaged skin. J Cosmet Laser Ther. 2007;9:232-236.
Pal-Gly-His-Lys pal-GHK Palmitoyl oligopeptide Palmitoyl tripeptide-1 Matrixyl 2999 BIOPEPTIDE CL Matrixyl 3000 (with Palmitoyl tetrapeptide-7)	Synthetic tripeptide fragment of type I collagen	Collagen and glycosaminoglycan syntheses are stimulated, the epidermis is reinforced, and wrinkles are diminished. This peptide is suggested to act on TGFβ to stimulate fibrillogenesis; stimulates fibroblasts	Lintner K, Peschard O. Biologically active peptides: from a laboratory bench curiosity to a functional skin care product. Int J Cosmet Sci. 2000;22:207-218.
Pal-Lys-Val-Lys bistrifluoroacetate salt Palmitoyl Tripeptide-3/5 SYN-COLL	Synthetic tripeptide mimics thrombospondin I tripeptide sequence activates TGFb	Mimics the effects of an extracellular matrix protein, thrombospondin-1 (TSP-1), a naturally occurring molecule that increases TGFβ activity; Stimulates collagen production in in vitro and in vivo studies through the growth factor TGFβ	Rahnamaeian M, Vilcinskas A. Short antimicrobial peptides as cosmetic ingredients to deter dermatological pathogens. Appl Microbiol Biotechnol. 2015;99:8847-8855. Murphy-Ullrich JE, Poczatek M. Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 2000;11:59-69.
Pal-Lys-Met(O₂)-Lys-OH Palmitoyl-Lysyl-Dioxymethiony-Lysine Palmitoyl Tripeptide-38 Matrixyl Synthe-6 Volulip	Synthetic tripeptide	Stimulating constituents of skin matrix and dermal-epidermal junction (ie, collagen I, II, IV, fibronectin, hyaluronic acid, and laminin 5)	Sanz MT, Campos C, Milani M, et al. Biorevitalizing effect of a novel facial serum containing apple stem cell extract, pro-collagen lipopeptide, creatine, and urea on skin aging signs. J Cosmet Dermatol. 2016;15:24-30. Herndon JH Jr, Jiang L, Kononov T, Fox T. An open label clinical trial of a multi-ingredient anti-aging moisturizer designed to improve the appearance of facial skin. J Drugs Dermatol. 2015;14:699-704.
Tetrapeptides
Pal-Gly-Gln-Pro-Arg or pal-GQPR Palmitoyl tetrapeptide-7 (previously -3) Rigin Matrixyl 3000 (with palmitoyl oligopeptide)	Fragment of immunoglobulin G	Decreases IL-6 Anti-inflammatory after exposure to UVB radiation; fibrillin-rich microfibrils	Mondon P, Hillion M, Peschard O, et al. Evaluation of dermal extracellular matrix and epidermal-dermal junction modifications using matrix-assisted laser desorption/ionization mass spectrometric imaging, in vivo reflectance confocal microscopy, echography, and histology: effect of age and peptide applications. J Cosmet Dermatol. 2015;14:152-160. Watson RE, Ogden S, Cotterell LF, et al. Effects of a cosmetic “anti-ageing” product improves photoaged skin. Br J Dermatol. 2009;161:419-426.
Acetyl tetrapeptide-9 (Dermican) (Sequence: N-Acetyl-Gln-Asp-Val-His)	Synthetic tetrapeptide	Stimulate collagen Type I and lumican synthesis	Rodrigues AL, Benoit I, Clarius T, Pauly G. Counter acting ageing phenomena by new pure tetrapeptides with targeted efficacy. Cosmet Sci Technol. 2009;27:63-71.
Acetyl tetrapeptide-11 (Sequence: N-Acetyl-Pro-Pro-Tyr-Leu) (Syniorage)	Synthetic tetrapeptide	Stimulates keratinocyte cell growth and syndecan-1 synthesis	Rodrigues AL, Benoit I, Clarius T, Pauly G. Counter acting ageing phenomena by new pure tetrapeptides with targeted efficacy. Cosmet Sci Technol. 2009;27:63-71.
Tetrapeptide PKEK (Sequence: Pro-Lys-Glu-Lys)	Synthetic tetrapeptide	Reduces interleukin-6, interleukin-8, and tumor necrosis factor-α, as well as cyclooxygenase gene expression in UV light-stressed keratinocytes	Farwick M, Maczkiewitz U, Lersch P, Summers B, Rawlings AV. Facial skin-lightening benefits of the tetrapeptide Pro-Lys-Glu-Lys on subjects with skin types V-VI living in South Africa. J Cosmet Dermatol. 2011;10:217-223.
Gly-Glu-Lys-Gly (GEKG)		Induces collagen	Farwick M, Grether-Beck S, Marini A, et al. Exp Dermatol. 2011;20:602-604.
Pentapeptides
Pentapeptide-3 (Vialox) (Sequence: Gly-Pro-Arg-Pro-Ala)	Snake venom derived	Ach receptor antagonist, muscle relaxation; wrinkle reduction	Zhmak MN, Utkin YN, Andreeva TV, et al. Peptide inhibitors of nicotinic acetylcholine receptor. US Patent US 20,¹⁵⁰,³⁶¹,¹³⁷ A1, 17 December 2015.
Palmitoyl pentapeptide-4 Matrixyl Sequence: Lys-Thr-Thr-Lys-Ser (KTTKS); Conjugated to 16C fatty acid palmitate (pal-KTTKS)	Synthetic; fragment of carboxyl-terminus of type I procollagen	Stimulates ECM synthesis; upregulates synthesis of collagen types I & III and fibronectin	Katayama K, Armendariz-Borunda J, Raghow R, et al. J Biol Chem. 1993;268:9941-9944. Robinson LR, Fitzgerald NC, Doughty DG, Dawes NC, Berge CA, Bissett DL. Topical palmitoyl pentapeptide provides improvement in photoaged human facial skin. Int J Cosmet Sci. 2005;27:155-160.
Pentapeptide-18 (Leuphasyl) (Sequence: Tyr-D-Ala-Gly-Phe-Leu)		Enkephalin mimic; inhibits catecholamine release; wrinkle reduction	Leuphasyl a New Pentapeptide for Expression Wrinkles. Available at http://docplayer.net/15401907-Leuphasyl-a-new-pentapeptide-for-expression-wrinkles-code-pd080-date-june-2005-revision-1-a-gmp-peptide-for-cosmetic-applications.html. Accessed December 19, 2016. Dragomirescu AO, Andoni M, Ionescu D, Andrei F. The efficiency and safety of leuphasyl—A Botox-like peptide. Cosmetics. 2014;1:75-81. Rull M, Davi C, Cañadas E, Almiñana N, Delgado R. Peptide approach to enhance anti-wrinkle efficacy between injections. Available at http://www.cosmeticsandtoiletries.com/formulating/category/antiaging/Peptide-Approach-to-Enhance-Anti-wrinkle-Efficacy-Between-Injections-premium-273052431.html. Accessed May 15, 2017.
Hexapeptides
Pal-Val-Gly-Val-Ala-Pro-Gly Palmitoyl hexapeptide-12 Biopeptide EL	Synthetic hexapeptide	Reducing the production of interleukin-6 (IL-6) by key skin cells, keratinocytes, and fibroblasts	Biopeptide ELTM. Available at http://www.webareal.com.ua/fotky27371/BIOPEPTIDE_EL_.pdf. Accessed April 22, 2017.
Hexapeptide-11 (Pentamide-6, Sequence: Phe-Val-Ala-Pro-Phe-Pro)	Originally isolated from S. cerevisiae; now synthetic	Regulates cell senescence	Gruber JV, Ludwig P, Holtz R. Modulation of cellular senescence in fibroblasts and dermal papillae cells in vitro. J Cosmet Sci. 2013;64:79-87.
Hexapeptide-14 (palmitoyl hexapeptide-14)		Stimulate cell migration, collagen synthesis, and fibroblast proliferation and scaffolding	Fields K, Falla TJ, Rodan K, Bush L. Bioactive peptides: signaling the future. J Cosmet Dermatol. 2009;8:8-13.
Tyr-Tyr-Arg-Ala-Asp-Ala		Induces dermatan sulfate and chondroitin sulfate synthesis. Inhibits procollagen C-proteinase	Njieha FK, Morikawa T, Tuderman L, et al. Bio-chemistry. 1982;21:757-764.
Val-Gly-Val-Ala-Pro-Gly (VGVAPG)	Fragment of tropoelastin, binding site to a G protein-and phospholipase C-coupled recep tor on human fibroblasts	Stimulates human skin fibroblasts, angiogenesis, endothelial cell migration; downregulates elastin	Kamoun A, Landeau JM, Godeau G, et al. Cell Adhes Commun. 1995;3:273-281.
Phe-Val-Ala-Pro-Phe-Pro, peptamide-6		Upregulates growth factors, MMPs, and HSPs	Gorouhi F, Maibach HI. Int J Cosmet Sci. 2009;31:327-345. Epub 2009 Jun 30.
Pigment Regulators
His-D-Phe-Arg-Trp	Fragment of a-MSH	Binds to a specific receptor on the surface of melanocytes and stimulates melanin synthesis and secretion	Abdel-Malek ZA, Kadekaro AL, Kavanagh RJ, et al. FASEB J. 2006;20:1561-1563.
Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val, also known as Melano-Tan-I	Synthetic 13-amino acid a-MSH fragment	Tanning	Hadley ME, Sharma SD, Hruby VJ, et al. Ann N Y Acad Sci. 1993;680:424-439.
Tyr-Arg-Ser-Arg-Lys-Tyr-Ser-Ser-Trp-Tyr also known as decapeptide-12, Lumixyl	Synthetic fragment of basic FGF	Inhibiting tyrosinase	Schubert D, Ling N, Baird A. J Cell Biol. 1987;104:635-643; Hantash BM, Jimenez F. J Drugs Dermatol. 2009;8:732-735.
Neurotransmitters
Acetyl hexapeptide-3 (or -8) (Argireline) (Sequence: Acetyl-Glu-Glu-Met-Gln-Arg-Arg-NH₂)	Synthetic sequence of synaptosomal-associated protein 25, which competes for a position in the SNARE complex	Inhibition of muscle contraction	Ruiz MA, Clares B, Morales ME, Cazalla S, Gallardo V. Preparation and stability of cosmetic formulations with an anti-aging peptide. J Cosmet Sci. 2007;58:157-171. Krishnan G, Roberts MS, Grice J, Anissimov YG, Moghimi HR, Benson HA. Iontophoretic skin permeation of peptides: an investigation into the influence of molecular properties, iontophoretic conditions and formulation parameters. Drug Deliv Transl Res. 2014;4:222-232. Blanes-Mira C, Clemente J, Jodas G, et al. A synthetic hexapeptide (Argireline) with antiwrinkle activity. Int J Cosmet Sci. 2002;24:303-310. Wang Y, Wang M, Xiao S, Pan P, Li P, Huo J. The anti-wrinkle efficacy of argireline, a synthetic hexapeptide, in Chinese subjects: a randomized, placebo-controlled study. Am J Clin Dermatol. 2013;14:147-153.
Pentapeptide-3 (Vialox) (Sequence: Gly-Pro-Arg-Pro-Ala)	Derived from snake venom Antagonist of the acetylcholine receptor	Blocks nerves at the postsynaptic membrane, leading to muscle relaxation	Zhmak MN, Utkin YN, Andreeva TV, et al. Peptide inhibitors of nicotinic acetylcholine receptor. US Patent US 20,¹⁵⁰,³⁶¹,¹³⁷ A1, 17 December 2015.
Pentapeptide-18 (Leuphasyl) (Sequence: Tyr-D-Ala-Gly-Phe-Leu)	Synthetic encephalin fragment	Mimics the natural mechanism of enkephalins and inhibits neuronal activity and catecholamine release; decrease on glutamate release	Dragomirescu AO, Andoni M, Ionescu D, Andrei F. The Efficiency and safety of leuphasyl—A Botox-like peptide. Cosmetics. 2014;1:75-81. Rull M, Davi C, Cañadas E, Almiñana N, Delgado R. Peptide Approach to Enhance Anti-wrinkle Efficacy Between Injections. Available at http://www.cosmeticsandtoiletries.com/formulating/category/antiaging/Peptide-Approach-to-Enhance-Anti-wrinkle-Efficacy-Between-Injections-premium-273052431.html.
Tripeptide-3 (Sequence: β-Ala-Pro-Dab-NHBn-2-Acetate), also named dipeptide diamino-butyroyl benzylamide diacetate or SYN-AKE	Synthetic mimic of waglerin-1 originally isolated from viper venom	Mimics the effect of waglerin-1, a peptide that is found in the venom of the viper Tropidolaemus wagleri. Tripeptide-3 acts at the postsynaptic membrane and is a reversible antagonist of the acetylcholine receptor	Trookman NS, Rizer RL, Ford R, Ho E, Gotz V. Immediate and long-term clinical benefits of a topical treatment for facial lines and wrinkles. J Clin Aesthet Dermatol. 2009;2:38-43. Zhou BR, Ma LW, Liu J, et al. Protective effects of soy oligopeptides in ultraviolet B-induced acute photodamage of human skin. Oxid Med Cell Longev. 2016;2016.
Miscellaneous Regulators
Soy oligopeptides	Obtained from soybean proteins, consisting of 3-6 amino acids, mainly in the size range of 300-700 kDa	Increased Bcl-2 protein expression and decreased cyclobutane pyrimidine dimers-positive cells, sunburn cells, apoptotic cells, p⁵³ protein expression, and Bax protein expressions in the epidermis of UVB-irradiated foreskin	Zhou BR, Ma LW, Liu J, et al. Protective effects of soy oligopeptides in ultraviolet B-induced acute photodamage of human skin. Oxid Med Cell Longev. 2016;2016.
Silk fibroin peptide	Derived from the silkworm Bombyx mori	Enhance the anti-inflammatory activity of tTAT-superoxide dismutase	Kim DW, Hwang HS, Kim DS, et al. Effect of silk fibroin peptide derived from silkworm Bombyx mori on the anti-inflammatory effect of Tat-SOD in a mice edema model. BMB Rep. 2011;44:787-792.
Black rice oligopeptides	Processing rice bran protein; low-molecular-weight peptides (<3000 Da) obtained	Inhibiting MMP (matrix metalloproteinase) activity and stimulated hyaluronan synthase 2 gene expression in human keratinocytes; inhibited melanogenesis	Sim GS, Lee DH, Kim JH, et al. Black rice (Oryza sativa L. var. japonica) hydrolyzed peptides induce expression of hyaluronan synthase 2 gene in HaCaT keratinocytes. J Microbiol Biotechnol. 2007;17:271-279. Ochiai A, Tanaka S, Tanaka T, Taniguchi M. Rice bran protein as a potent source of Antimelanogenic peptides with tyrosinase inhibitory activity. J Nat Prod. 2016;79:2545-2551. Manosroi A, Chutoprapat R, Abe M, Manosroi W, Manosroi J. Anti-aging efficacy of topical formulations containing niosomes entrapped with rice bran bioactive compounds. Pharm Biol. 2012;50:208-224.