Fibroblast Growth Factors in Skin Aging

This open access review examines what is known of the role of fibroblast growth factors in mechanisms relevant to skin aging, such as loss of collagen and elastin from the extracellular matrix. This type of paper always makes for an interesting read, and fully mapping the cellular metabolism of aging is the right goal from a fundamental science perspective. When it comes to near term intervention in the aging process, this sort of examination is less helpful, however. Yes, growth factor expression levels change in aging skin cells, and that has consequential effects. But this is in and of itself far removed from the underlying causes of degenerative aging. It is itself a consequence and not a cause. The most efficient way forward is to focus on causes, not to try to intervene downstream in the complexities of a disrupted mechanism. If a complicated metal structure is rusting to structural failure, you fix the rust, you don't try to rework the structure. The same principle applies here, alongside the ever important note that effect sizes tend to be small and unreliable in this sort of work.

Growth factors have become an important therapeutic option to avoid aging, because they are responsible for cell differentiation and maturation, being directly correlated with the minimizations of the topical esthetic changes resulting from age advancement. Growth factor proteins are naturally secreted by cells and interact directly or are sequestered by the surrounding extracellular matrix for presentation to cell surface receptors. The introduction of growth factors in certain damaged sites in the body seeking to stimulate regeneration is clinically related to regenerative medicine, where researchers intend to replace or repair damaged cells, tissues, and organs to effectively restore normal function.

Among the existing growth factors, we highlight the fibroblast growth factor (FGF), which induces the synthesis of type 1 collagen and therefore presents a relevant role in the process of skin aging control. Collagen is the protein responsible for the structure, elasticity, and firmness of the skin and it is produced by cells called fibroblasts. During the aging process, the proliferative and metabolic activity of fibroblasts decreases and their functions are impaired, leading to reduction of the synthesis of structural substances such as collagen, elastin, hyaluronic acid, and chondroitin. In addition, decreased levels of growth factors, reduced amount of collagen, abnormal accumulation of elastin, and reduction in the epidermal and dermal thickness were observed during the aging process.

The FGF family members increase the proliferation and activation of fibroblasts by stimulating the accumulation of collagen as well as stimulating endothelial cell division. With the aging process, fibroblasts have their activity diminished and consequently the synthesis and activity of proteins that guarantee elasticity and resistance such as elastin and collagen are also affected. Thus, in aged skin, there is a lower production of collagen by the fibroblasts and a greater action of the enzymes that degrade it. This lack of balance speeds up the aging process. Although the functions of FGFs are well characterized, their mechanisms of action are still not completely clear. It is known that it involves inter- and extracellular signaling pathways that may be related to the RAS-MAP kinases pathways, PI3K-AKT, PLC-γ, or STAT. Therefore, FGF cell signaling involves interactions with multiple cell signaling pathways and complex feedback mechanisms.

Activation of FGF-1 improves skin elasticity and induces the synthesis of collagen and elastin. One study investigated the impact of FGF-1 on skin cells; results showed that recombinant FGF-1 has a strong effect on cellular proliferation of keratinocytes and fibroblasts. FGF-2 reduces and prevents expression lines and wrinkles through the activation of new skin cells and stimulates the proliferation of cells of mesodermal, ectodermal, and endodermal origin, mainly fibroblasts and keratinocytes. Researchers aimed to evaluate an in vivo method for aged skin rejuvenation through direct injection of intradermal FGF-2. The following rejuvenating effects were observed: improvement of skin smoothness, atrophied skin thickness, and improved viscoelasticity. Keratinocyte growth factor (KGF) is a member of the FGF family. While most FGFs influence the proliferation and/or differentiation of various cell types, KGF appears to act specifically on epithelial cells. A study evaluating the ability of KGF to reduce the visible signs of aging. The results showed that eighteen of the twenty subjects experienced significant improvement.

Link: https://doi.org/10.1159/000501145

Comments

"If a complicated metal structure is rusting to structural failure, you fix the rust, you don't try to rework the structure. The same principle applies here, alongside the ever important note that effect sizes tend to be small and unreliable in this sort of work."

No man-made system comes even close to biological systems in terms of its capacity for self-repair. That's a point against the pessimists who think "oh, we can't even keep a car working indefinitely (we can but that's besides the point), how can we ever hope to do anything about biological aging when they're vastly more complex?", but it's also a point against damage repair always being the only or best option for a problem.

The more I learn about this, the more I am beginning to think that there's space for all 3 approaches to addressing age related disease burden; the SENS approach of identifying and repairing "damage", the approach that you call "merely slowing aging" in cases where it's potentially high impact (reprogramming/transposon inhibitors), and also more traditional geriatric approaches. Each has its pros and cons.

"Damage repair" of course is absolutely necessary wherever there's absolutely no physiological mechanism for addressing a problem, but you're going to need a HUGE panel of interventions to cover every possible damage, especially if "secondary damage" that occurs downstream of primary age-related damage doesn't resolve on its own.

Intervening in biological pathways is hard, and the system is very complex and opaque, but we're getting better, and while once this field was filled by largely futile interventions like CR, there are now potentially several low-ish hanging fruits (transposons and reprogramming) in this space that could have a substantial impact on the rate of certain forms of aging, and reverse some of the secondary damage that will be difficult to address with the SENS approach.

Traditional geriatric medicine on the other hand is the only one that seems capable of intervening in mature pathologies, and as others (including Aubrey de Grey) have pointed out, these treatments work a lot better in the uncommon cases where someone who isn't already frail is getting them.

Posted by: Dylan Mah at August 14th, 2019 12:04 PM

@Dylan Mah
By repairing the damage is also assumed that it repairs the repair mechanisms too. But it could very well be there case that the first thing to fail are repair systems. (And here senolytics are a partial proof, since reaching the inflammatory conditions let's the body heal). However, there are some types of damage the body cannot repair due to your limited regeneration capacity, even if we weren't some at all on tissue and cellular level. For example, in 500 years we would end up having so many scars that that some might be life threatening..

Posted by: Cuberat at August 14th, 2019 3:47 PM

"By repairing the damage is also assumed that it repairs the repair mechanisms too. But it could very well be there case that the first thing to fail are repair systems."

That's actually not at all self-evident. I'd like for that to be the case, but I don't think there can be an expectation that repair of the "primary damage of aging" alone will resolve aging except in people who have little to no secondary damage. You can repair the secondary damage, but there's way more types of that than there are of primary damage. Luckily unlike the primary damages of aging where they by definition are things the body has no ability to deal with beyond simply tolerating a certain amount of it,

"however, there are some types of damage the body cannot repair due to your limited regeneration capacity, even if we weren't some at all on tissue and cellular level."

The human body can't, yet the cells themselves contain the underlying template from which the entire organism sprang from. Cancer is probably the single biggest reason why post-developmentally organisms rely on incomplete or partial repair of damaged tissues; it's much safer that way, and "more evolvable" than for example adding a CRISPR-Cas9 like mechanism to augment RNA surveillance and cut viral DNA out of the genome when it gets incorperated. That's in reference to recent work indicating that transposons are a major component of genomic instability in cancer.

Posted by: Dylan Mah at August 14th, 2019 4:20 PM

Dermal injections sound interesting- so we can all look pretty while waiting on rejuvenation therapies to stop all this "50 jars of cream in the bathroom" nonsense. Until that's available FGF's are available topically from several companies. It's listed as -sh-Polypeptide-11.
Time for jar number 51!
If anyone knows an oral route to increase FGF expression systemically let us know.

Posted by: August at August 14th, 2019 7:49 PM

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