Sagging skin. What could be more a more pathognomonic sign of aging? What causes skin to sag, or not? How come I used to be able to stretch my skin and it would snap right back? And why can I no longer do that?
While it is true that all living things are made of cells, it is the extracellular matrix (ECM) that provides structure to tissues. In some cases the ECM accounts for more of the organism’s bulk than its cells. Collagen comprises the majority of fibrous tissue support within the ECM of mammals. This is especially true of the skin, but that is only part of the story, especially when it comes to skin changes seen with aging.
Soft, supple, resilient skin requires healthy elastin, despite it being considerably lesser a constituent of skin (by total volume) than collagen. While collagen has great tensile strength and provides robust mechanical and structural support, it is elastin that enables tissues to be stretched and pulled out of shape and then rebound back again. Without elastin, even young skin would hang and sag in places, simply to provide the slack necessary to enable changes in body angles, geometry and distance associated with movement and locomotion. Older people “hang and sag” for a different reason. Elastin and collagen both undergo considerable degeneration and reduction in mass over the decades.
Thinning, wrinkling, and laxity of skin is due to changes in collagen and elastin, and for both, the major culprit is repetitive and cumulative UV radiation. (Have you ever noticed that older sunbathers who have deep brown, year-round, all-over tans are the ones who also have deep, year-round, all-over wrinkles?) The UV radiation that induces melanocytes to reactively produce melanin also induces reactive oxygen species that damage proteins, lipids, and DNA (as well as damage DNA directly.) The damage to elastin occurs when the unique chemical structure that provides the ability to recoil is affected. A little background.
Composition of the ECM
The ECM of vertebrates (that includes humans) is composed of complex mixtures of:
- proteoglycans, and
- in the case of bone, mineral deposits.
Proteins are comprised primarily of amino acids, structured in a variety of geometric configurations but nearly all also containing short chains of carbohydrates, making them more precisely glycoproteins.
Collagen is glycosolated (contains carbohydrate) which provides hydroxyl groups where linkage with sulfur- sulfur bonds occurs to join collagen molecules together into their triple helix configuration. It is built up from single repeating elements that are long, narrow molecules.
Proteoglycans are also glycoproteins but consist of much more carbohydrate than protein; that is; they are huge clusters of carbohydrate chains often attached to a protein backbone.
Elastin is Unique
Elastin is comprised of protein molecules that contain no carbohydrate and hence have few chemical linkages among the molecules. This accounts for their inherent elasticity. Thus they have loosely connected coiled structures that can be stretched and then return to their original shape.
The side chains are not based on carbohydrate residues attached to protein molecules, but rather four lysine amino acids that link together giving the molecule the ability to stretch to 1.5 times its length. The linkages are called desmosine and isodesmosin. Elastin is produced by fibroblasts (important in the skin) and smooth muscle cells (hugely important in the walls of arteries.) This type of elastin is often referred to as amorphous elastin which is found within elastic fibers that indeed do have associated scaffolding structures.
The Formation of Elastic Fibers
The elastic fiber is formed from the elastic microfibril (consisting of numerous proteins such as microfibrillar-associated glycoproteins,fibrillin, fibullin, and the elastin receptor) and amorphous elastin.
The microfibril scaffolds and organizes the deposition of amorphous elastin. Amorphous elastin forms from monomers of solubletropoelastin which is insolubilized and crosslinked into amorphous elastin by lysyl oxidase. Lysyl oxidase reacts with specific lysineresidues and by oxidative deamination generates reactive aldehydes and allysine.
These reactive aldehydes and allysines can react with lysine and other allysine residues to crosslink and form desmosine, isodesmosine, and a number of other polyfunctional crosslinks that join surrounding elastin molecules to build an elastin matrix and elastic fiber. As discussed above, these unique crosslinks are responsible for elastin’s elasticity. So, there you have the synthesis of elastin. Now, for where it really counts.
Elastin is Important in Skin, but Not Compared to These Other Tissues
I don’t want to minimize the desirability of maintaining youthful looking skin, but when put into perspective, the importance of high quality, functional elastin in the skin is nothing compared to its importance in arteries, veins, lungs, and other tissues.
Elastin serves an important function in arteries as a medium for pressure wave propagation, and to help maintain downstream blood flow during diastole, the period while the heart is refilling prior to its next contraction. During the heart beat, systole, when blood is rapidly ejected into the aorta, it is the elastic nature of the aorta and other vessel walls than enable them to quickly expand and then continue to exert elastic recoil to maintain blood pressure.
Total elastin ranges from 58 to 75% of the weight of the dry defatted artery. When arterial walls are stressed 35%, a minimum of 48% of the arterial load is carried by elastin, and a minimum of 43% of the change in stiffness of arterial tissue with aging is due to the change in elastin stiffness.
Elastin is also a recognized target for injury in COPD, chronic obstructive pulmonary disease. In COPD the ability of the small air-sacs to return to their deflated state is diminished, so airflow into and out of the structures, where blood takes on oxygen and gives off carbon dioxide, is hindered.
In emphysema, some of the little air-sacs are ruptured which reduces the blood/air interface for gas exchange. Elastin is a tissue component particularly susceptible to injury through toxins found in tobacco smoke and is also dramatically impacted in certain genetic conditions, such as alpha 1 anti-trypsin deficiency. In these cases, injury to elastin is not an inconvenience noticeable in the mirror; it is a threat to life.
What Else Can Go Wrong with Elastin?
Cutis laxa is a group of rare connective tissue disorders in which the skin becomes inelastic and hangs loosely in folds. In most cases, cutis laxa is inherited and can be autosomal dominant or recessive, or sex linked. Mutations in the elastic fibers of dermis have been identified in these conditions. Acquired forms have also been described.
Marfan’s syndrome is another genetic condition in which there are abnormalities in elastin. Individuals with Marfan’s syndrome are tall with lanky builds and longer than normal limbs. Defective tissue leads to subluxation of the lens of the eye but more importantly, can lead to fatal deterioration of blood vessel walls, the most notable aneurysms of the thoracic aorta which can rupture spontaneously.
Although born long before the development of the genetic testing that could confirm his diagnosis, you may recognize the most famous person that many medical experts agree most likely was afflicted with this condition.
Repair and Protection of Elastin in the Skin
Like topical collagen, topical elastin offers no reparative function to dermal tissue. The molecules are too large to be absorbed and simply layer on the surface. Likewise, elastin supplements will undergo digestion and result in absorption of constituent amino acids and small peptide. In fact, elastin powder has been applied to open wounds on rats without any perceived benefit in healing.
In a tissue culture study, retinoic acid (a.k.a. tretinoin) was shown to increase elastin synthesis in chick embryonic vascular smooth muscle cells up to 2.8-fold. There is some ground to believe that topical retinoids may also stimulate elastin synthesis in the human skin.
Skin rejuvenation is not just about producing more of the key components of the skin matrix, such as collagen and elastin. It is also about protecting the one you have from excessive degradation. Such degradation is caused primarily by the enzymes matrix metalloproteinases (MMP). There are many types of MMP and some are involved in breaking down elastin: MMP-2, MMP-9, MMP-12, and possibly others. Inhibiting these MMP may increase the skin content of elastin by reducing the rate of its degradation.
Controlled tissue injury procedures
Some skin rejuvenation procedures (e.g. lasers or medium-to-deep peels or deep dermarolling) work by inducing controlled tissue injury followed by skin remodeling, which leads to increased production of new skin matrix and skin remodeling. The predominant protein produced during healing is collagen but the synthesis of elastin increases as well.
As the primary signal molecules for many cellular functions, it should come as no surprise that cytokines are also involved with elastin synthesis and breakdown. When cells (e.g. keratinocytes, skin cells) are damaged, or have died, inflammatory cytokines are released that then communicate with fibroblasts. The inflammatory cytokines then cell up immune cells to begin the process of wound healing through the formation of granulation tissue. Proteases are released, breaking down collagen and elastin fibers. In healthy young humans, this process is rapid, and is replaced rather quickly when mesenchymal stem cells are called up from distant and nearby depots, e.g. bone marrow. They they turn off the inflammatory (destructive) process and coordinate the next phase of healing, heralded by rebuilding. They are responsible for turning off MMP’s.
In older humans the process is far less efficient, due to fewer mesenchymal stem cells, and the inflammation lasts longer. Older persons cannot mount the healing cytokine response of an infant. With aging, this takes it toll. Elastin rebuilding is greatly reduced, and the elastic quality of the elastin is lessened. The net result of all this is wrinkling and sagging of skin.
A particular pattern of cytokines, isolated in a laboratory from mesenchymal stem cells in culture, identical to those your own body produced in abundance when younger, can be applied therapeutically to augment repair and renewal of elastin. They can be used alone, as a key active ingredient in an anti-aging serum, or as an adjunct to controlled tissue injury procedures, to signal the matrix to generate new elastin.