THE SCIENCE OF AGING
Oh aging! As much as we try to fight it, it’s inevitable.
Aging can be understood as the decline in physiological activity that occurs over the lifespan. It involves the breakdown of important structures and cellular processes. Stress, damage, and inflammation contribute to this process of deterioration with age. The rate and onset of this breakdown is highly determined by our genetics. While there isn’t much to be done about these intrinsic factors, some extrinsic aging can be controlled. Photoaging is one type of extrinsic aging that occurs as a result of prolonged and repeated exposure to solar radiation.
A very special class of enzymes orchestrate the breakdown process.
Matrix metalloprotinases (MMPs) are a special type of digestive enzyme. This is a class of proteins that breaks down other proteins into their smaller peptide building blocks. In living systems, the space that exist between cells is highly important. This space, known as the extracellular matrix (ECM) is a dynamic mesh of structural proteins and sticky glycoproteins. MMPs break down the components of the extracellular space [1].
The extracellular matrix contains 3 classes of molecules.
Structural proteins like collagens and elastins
Anchoring proteins which embed the sutural proteins to cells (proteoglycans)
Sticky glycoproteins that attach cells to matrix (fibronectins and laminins)
Maintaining tight control over these proteinases is crucial. Disturbed activity or regulation is associated with neurodegenerative, cardiovascular, digestive and lung diseases [2] [3]. In the context of skin, studies have linked the activity of MMPs to aging. It involves the breakdown of collagen (one of the major structural proteins of our skin). Under normal conditions, collagen and elastin fibers provide our skin firmness and bounce. Cross linkages between collagen molecules keep the protein strong— preventing skin sagging and wrinkles.
UV Radiation activates MMPs and in turn accelerates the aging process
UV radiation generates reactive oxygens species (ROS). These are unstable molecules that cause damage to DNA, RNA, and proteins. We call the damage oxidative stress. If a cell accumulates too much oxidative stress, it will die. The presence of these molecules activates a signaling pathway, called the mitogen-activated protein kinase (MAPK) signaling pathway [4]. How a cell responds to a certain stimulus (like UV radiation) will vary depending on the type of stimulus it receives. Cells utilize signal transduction pathways to communicate what is happening in the internal and external environments. It’s like a game of telephone. Proteins whisper updates to each other, and pass the message along to the nucleus. In the nucleus is where the cell integrates all the information before responding.
MMPs are activated via the MAPK signaling pathway
The MAPK pathway ultimately results in one of three outcomes:
the cell dividing
a cell becoming a new cell type or
the cell dies (sad!) [4].
On the left you can see a depiction of this process. Unstable molecules generated by UV irradiation activate three signaling molecules in this MAPK pathway— ERK, p38, or JNK (not pictured).
These molecules then trigger another round of signaling molecules— c-Fos and c-Jun. The interaction of these proteins in the signaling cascade culminates with a new protein, AP-1 crossing the nucleus and fliping the ‘on switch’ for MMP-1,-3,and -9 [5].
Keratinocytes and fibroblasts secrete MMP-1,-3 and -9. Once these proteins make their way into the ECM they eat away at collagen and other important structures [6]. It’s this advanced degradation that contributes to aging.
But I want to be young forever!
I hate to break it to you, but that’s impossible (for now). Fortunately there are many things you can do to relieve the burden of MMPs on your skin. There are some promising studies that show glycolic acid mitigates damage to extracellular collagen and elastin [7].
In an animal study researchers found that glycolic acid reduced the production of UV induced inflammatory mediators (like Il-6, IL-8). [8]
Others have shown that niacinamide, (a personal favorite of mine) can help maintain a youthful appearance by stimulating elastin production and inhibit MMP activity [9]. Niacinamide is easily the most well studied and best understood of all skincare ingredients. This makes it a popular choice amongst cosmetic formulators! It’s generally well tolerated and can be used in combination with other active ingredients.
Another skincare favorite, vitamin c, is praised by beauty brands and skincare influencers alike for it’s antioxidant activity. Vitamin C neutralizes harmful reactive oxygen species that are generated by UV radiation (discussed above), and therefore prevents activation of MMPs. Cooler still, other studies have demonstrated Vitamin C’s ability to produce collagens I and III [10]. These are important components of your ski, bones, tendons and even blood vessels!
Above all, wear your sunscreen!
Thanks to decades of research cosmetic formulators have been able to conjure some amazing cosmetic products. It feels almost like cheating to resist the biologically inevitable. And while it’s impossible to stop aging altogether, it’s a wonder that we can have this degree of control. But of course, all these efforts would be useless without wearing sunscreen and practicing other sun protection measures. By some estimates, UV exposure is responsible for 80% of skin aging [11]. So please, do yourself a favor and remember to apply sunscreen! Your skin will thank you ;)
References
1. Sarah A. Hibbert, Rachel E.B. Watson, Christopher E.M. Griffiths, Neil K. Gibbs, Michael J. Sherratt, Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins, Cellular Signalling, Volume 54, 2019,Pages 191-199.
2. Marjana Brkic, Sriram Balusu, Claude Libert, Roosmarijn E. Vandenbroucke, "Friends or Foes: Matrix Metalloproteinases and Their Multifaceted Roles in Neurodegenerative Diseases", Mediators of Inflammation, vol. 2015, Article ID 620581, 27 pages, 2015. https://doi.org/10.1155/2015/620581
3. Tokito A, Jougasaki M. Matrix Metalloproteinases in Non-Neoplastic Disorders. Int J Mol Sci. 2016 Jul 21;17(7):1178. doi: 10.3390/ijms17071178. PMID: 27455234; PMCID: PMC4964549.
4. Morrison DK. MAP kinase pathways. Cold Spring Harb Perspect Biol. 2012 Nov 1;4(11):a011254. doi: 10.1101/cshperspect.a011254. PMID: 23125017; PMCID: PMC3536342.
5. Sandra Freitas-Rodríguez, Alicia R. Folgueras, Carlos López-Otín, The role of matrix metalloproteinases in aging: Tissue remodeling and beyond, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1864, Issue 11, Part A, 2017, Pages 2015-2025, ISSN 0167-4889, https://doi.org/10.1016/j.bbamcr.2017.05.007.
6. Ågren MS, Schnabel R, Christensen LH, Mirastschijski U. Tumor necrosis factor-α-accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase (MMP)-1 and MMP-3 ex vivo. Eur J Cell Biol. 2015 Jan;94(1):12-21. doi: 10.1016/j.ejcb.2014.10.001. Epub 2014 Oct 23. PMID: 25457675; PMCID: PMC4300401.
7. Tang SC, Tang LC, Liu CH, Liao PY, Lai JC, Yang JH. Glycolic acid attenuates UVB-induced aquaporin-3, matrix metalloproteinase-9 expression, and collagen degradation in keratinocytes and mouse skin. Biochem J. 2019 May 21;476(10):1387-1400. doi: 10.1042/BCJ20180974. PMID: 31036716.
8. Tang SC, Liao PY, Hung SJ, Ge JS, Chen SM, Lai JC, Hsiao YP, Yang JH. Topical application of glycolic acid suppresses the UVB induced IL-6, IL-8, MCP-1 and COX-2 inflammation by modulating NF-κB signaling pathway in keratinocytes and mice skin. J Dermatol Sci. 2017 Jun;86(3):238-248. doi: 10.1016/j.jdermsci.2017.03.004. Epub 2017 Mar 11. PMID: 28330776.
9 Philips N, Chalensouk-Khaosaat J, Gonzalez S. Simulation of the Elastin and Fibrillin in Non-Irradiated or UVA Radiated Fibroblasts, and Direct Inhibition of Elastase or Matrix Metalloptoteinases Activity by Nicotinamide or Its Derivatives. J Cosmet Sci. 2018 Jan/Feb;69(1):47-56. PMID: 29658877.
10. Nusgens BV, Humbert P, Rougier A, Colige AC, Haftek M, Lambert CA, Richard A, Creidi P, Lapière CM. Topically applied vitamin C enhances the mRNA level of collagens I and III, their processing enzymes and tissue inhibitor of matrix metalloproteinase 1 in the human dermis. J Invest Dermatol. 2001 Jun;116(6):853-9. doi: 10.1046/j.0022-202x.2001.01362.x. PMID: 11407971.
11. Flament F, Bazin R, Laquieze S, Rubert V, Simonpietri E, Piot B. Effect of the sun on visible clinical signs of aging in Caucasian skin. Clin Cosmet Investig Dermatol. 2013 Sep 27;6:221-32. doi: 10.2147/CCID.S44686. PMID: 24101874; PMCID: PMC3790843.