Disruption of Elastin in the Aging Skin, and the Little that Can Presently Be Done About It

The flexibility of skin, and other elastic tissue such as blood vessel walls, depends upon the structural arrangement of elastin in the extracellular matrix. Elastin is largely laid down during the developmental period of life, and not much repaired thereafter. Disruption of this structure is progressive over time, and is a major contribution to the changing physical properties and appearance of aging skin. The effects on blood vessels and other internal tissues are more important: loss of elasticity in blood vessels cascades to cause a great deal of downstream damage and dysfunction via its effects on blood pressure, on development of atherosclerosis, on supply of nutrients to tissues, and so forth.

Repair of elastin is a challenging problem. One cannot just add elastin to a tissue and hope for improvement, as the precise structure, amount, and interactions with other components of the extracellular matrix are all important. The only realistic approach is to guide cells into performing the same work of elastic depositition that occurred in early life. This is not a solved problem, as it is quite possible to trigger behavior that leads to unhelpful or even harmful elastin deposition, in which the structure and amounts are incorrect. Regulatory networks must be clearly identified and then manipulated in the right ways.

Some therapies tested over the past few decades do manage to create some improvement in measures of tissue elasticity, with good evidence for this improvement to involve elastin deposition. The use of minoxidil, for example, was originally introduced as a way to treat age-related hypertension. The side-effects at the necessary doses are significant and health-threatening, however, such as cardiac edema. A great deal of work remains to produce a viable elastic deposition approach that could be widely used.

Clinical Relevance of Elastin in the Structure and Function of Skin

Elastin is the main component of elastic fibers, which provide stretch, recoil, and elasticity to the skin. Normal levels of elastic fiber production, organization, and integration with other cutaneous extracellular matrix proteins, proteoglycans, and glycosaminoglycans are integral to maintaining healthy skin structure, function, and youthful appearance. Although elastin has very low turnover, its production decreases after individuals reach maturity and it is susceptible to damage from many factors. With advancing age and exposure to environmental insults, elastic fibers degrade. This degradation contributes to the loss of the skin's structural integrity; combined with subcutaneous fat loss, this results in looser, sagging skin, causing undesirable changes in appearance.

The most dramatic changes occur in chronically sun-exposed skin, which displays sharply altered amounts and arrangements of cutaneous elastic fibers, decreased fine elastic fibers in the superficial dermis connecting to the epidermis, and replacement of the normal collagen-rich superficial dermis with abnormal clumps of solar elastosis material. Disruption of elastic fiber networks also leads to undesirable characteristics in wound healing, and the worsening structure and appearance of scars and stretch marks. Identifying ways to replenish elastin and elastic fibers should improve the skin's appearance, texture, resiliency, and wound-healing capabilities. However, few therapies are capable of repairing elastic fibers or substantially reorganizing the elastin/microfibril network.

Current intrinsic treatment modalities, which stimulate or modulate endogenous elastin, typically involve cosmetics and topical skincare products. However, given the complexity of tropoelastin production, assembly, and crosslinking, there is limited evidence that topical skincare products can reach the dermal layers of the skin or sufficiently stimulate elastin production.

Successful extrinsic treatment modalities to replenish elastin may require delivery of structurally intact tropoelastin or elastin; most experimental strategies have utilized elastin fragments that are inappropriate for in vivo elastin assembly. Proposed therapies for the connective tissue disorder cutis laxa provide other potential targets for restoring elastin. For example, although no specific treatments for cutis laxa exist, it has been suggested that the disordered elastic fiber assembly in this disease might be corrected by supplementing certain carrier molecules that have a role in the secretory pathways for elastolytic enzymes involved in elastin production. Other potential therapeutic strategies for increasing elastin production include stimulation of elastin gene expression. However, because tropoelastin expression and elastin production are substantially reduced in adult tissues, even large increases in their expression are unlikely to be physiologically relevant.

Considering tropoelastin is the main component of elastin, a more viable approach to repairing elastic fiber networks may be to use recombinant human tropoelastin-based treatments. The recombinant human tropoelastin may act as a substrate for skin fibroblasts to promote collagen production and glycosaminoglycan deposition, contributing to tissue repair and improved hydration in skin. A recent study showed that surgical delivery of exogenous tropoelastin via a collagen-based dermal substitute leads to the development of an extensive elastic fiber network in the deep dermis. Recombinant human tropoelastin has demonstrated early promise for wound repair, scar prevention and treatment, cosmetic applications, and aesthetics; it can be used by skin cells as a substrate to produce new elastic fibers. The applied use of tropoelastin for these indications is therefore a promising area of study.


How much would the SENS idea of clearing away AGE's help with the functionality of tissues with elastin? Can we get away with a very effective AGE clearance and no elastin rejuvenation/replenishment?

Posted by: GREGORY S SCHULTE at July 9th, 2021 5:12 PM

Gregory: we won't really know the answer until we actually do it, but in my view it's unlikely that AGE crosslink breaking alone will be adequate, even in the initial push for LEV (and certainly not indefinitely).

Fortunately, there is a very promising rejuvenation biotechnology for dealing with a significant subset of elastin damage. As previously highlighted on FA!, Elastrin Therapeutics uses nanoparticles functionalized to bind to damaged elastin to deliver EDTA and other therapeutics directly to the site of damage. This not only removes a significant cause of stiffening and dysfunction, it also enables some level of repair, which could be further enhanced in future iterations and/or with novel future rejuvenation biotechnologies.

Posted by: Michael at July 9th, 2021 10:39 PM

"Regulatory networks must be clearly identified and then manipulated in the right ways."
That doesn't seem a SENS aproach to me. Is it?

Posted by: Josep at July 10th, 2021 4:08 AM

From the publication unfortunately retracted by authors due to technical errors in the experiments: "... both elastin fragmentation and smooth muscle cells (SMCs) depletion were significantly attenuated in Fasudil treated mice."
Fasudil (early HA1077), like minoxidil, lowers blood pressure. Fasudil was originally characterized as a calcium antagonist that differed from previously known calcium entry blockers such as verapamil, diltiazem, and nicardipine in that it could prevent arterial contractions when other calcium channel blockers did not work.
It is a pity that no one later tested Fasudil's ability to act on the safety of elastin.

Posted by: Dmitry Dzhagarov at July 10th, 2021 11:43 AM

What about a strategy to increase elastin by decreasing elastase through certain plant substances?

"Anti-elastase activities were observed for nine of the extracts with inhibitory activity in the following order: white tea (~89%), cleavers (~58%), burdock root (~51%), bladderwrack (~50%), anise and angelica (~32%). Anti-collagenase activities were exhibited by sixteen plants of which the highest activity was seen in white tea (~87%), green tea (~47%), rose tincture (~41%), and lavender (~31%)."


Posted by: Brad at July 10th, 2021 12:55 PM

I think this effort is futile unless you ablate the crosslinked and damaged elastin. The best way to do that is via radio frequency micro needling.

Posted by: JohnD at July 10th, 2021 4:11 PM

It's been over 3 years since Allergan bought out a biotech with an actual promising treatment.
So far they have released NOTHING. I don't know if they are just dragging their feet, going for fda approval , or simply buying off a technology that could have made all their other beauty products such as botox obsolete.

Read about it here

Posted by: august33 at July 14th, 2021 9:39 PM

The ironic angle in this matter is the fact we can easily test skin elasticity on the back of our hands.
Simple biohacking. do a followup on a patch of skin for a year, see what happens.

There are billions of people who would invest money into their appearance, yet nobody came up with promising solutions.

it is like the whole field of aging in miniature.

maybe the FDA will approve of a simplistic therapy after 20 years

Posted by: Aryeh at July 15th, 2021 5:03 AM
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