TGF-β is Involved in the Loss of Fat and Bacterial Defenses in Aging Skin
TGF-β is a problematic protein that is involved in the regulation of chronic inflammation and many other processes important in aging. Unfortunately, presently available means of suppressing TGF-β activity have potentially serious side-effects, as TGF-β has important functional roles in many tissues, even in later life, while it is at the very same time causing a broad set of problems. This is a challenge found in many places in medicine: it is rarely enough to be able to globally increase or diminish the activity of a given protein, as its relationships with the operation of cellular metabolism are usually quite complicated. Here, researchers show that, on top of all of the other issues laid at the feet of TGF-β, it blocks the ability of fibroblasts in aging skin to transform into fat cells and generate antibacterial defenses.
Dermal fibroblasts are specialized cells deep in the skin that generate connective tissue and help the skin recover from injury. Some fibroblasts have the ability to convert into fat cells that reside under the dermis, giving the skin a plump, youthful look and producing a peptide that plays a critical role in fighting infections. Researchers have now discovered the pathway that causes this process to cease as people age.
Don't reach for the donuts. Gaining weight isn't the path to converting dermal fibroblasts into fat cells since obesity also interferes with the ability to fight infections. Instead, a protein that controls many cellular functions, called transforming growth factor beta (TGF-β), stops dermal fibroblasts from converting into fat cells and prevents the cells from producing the antimicrobial peptide cathelicidin, which helps protect against bacterial infections.
"Babies have a lot of this type of fat under the skin, making their skin inherently good at fighting some types of infections. Aged dermal fibroblasts lose this ability and the capacity to form fat under the skin. Skin with a layer of fat under it looks more youthful. When we age, the appearance of the skin has a lot to do with the loss of fat." In mouse models, researchers used chemical blockers to inhibit the TGF-β pathway, causing the skin to revert back to a younger function and allowing dermal fibroblasts to convert into fat cells. Turning off the pathway in mice by genetic techniques had the same result.
Link: https://www.eurekalert.org/pub_releases/2018-12/uoc--usd122118.php
Now that we know TGF-β causes sagging and wrinkles by preventing formation of dermal fat, should we toss all of our skin lotions containing growth factors? As for the systemic problem, balance should be the goal but people over 50 probably have too much. The diabetes drug pioglitazone has been shown to help increase dermal fat in those who have lost it due to HIV drugs. A couple studies show a healthy increase in dermal fat with a decrease in viscarel fat in healthy people taking it low dose. This is interesting as it relates to the above study because ppar-gamma reduces TGF-β expression. Pioglitazone is the safest drug that can meaningfully increase ppar-gamma. Perhaps the anti-aging appearance effects of low dose ( 7.5 mg per day) Pioglitazone are related to TGF-β suppression via ppar-gamma activation.
Perhaps the TGF family member Myostatin is the culprit here, just like it is with muscle loss. This study makes me think so....so specifically targeting Myostatin with epicatechin, waiting for the promising biotech drug SRK-015 to come out, or eliminating Myostatin via gene therapy ala Elizabeth Parrish, would take care of the fat loss problem without the downside. Thoughts?
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5360019/#!po=10.0000
Interesting result, though jumping straight to the cosmetic potential is one of my pet peeves about a small subset of members of the anti-aging community. Some people are driven mainly by vanity it seems.
Still, elucidation of mechanisms and effects may have other useful applications, and as someone who wants more kids, looking a bit younger might make it easier for me to find a girlfriend with the requisite youth and fertility. To this end, I wonder what the potential is to administer small-molecule TGF-β inhibitors topically so as to avoid the myriad unknown systemic side effects.
Is anyone familiar with the basics of delivering drugs into the skin and no farther? This might be a potential candidate: https://en.wikipedia.org/wiki/SB-431542
The ellagitannin corilagin inhibits tgf-beta1 signalling specifically in fibroblasts:
https://www.jci.org/articles/view/94624/figure/1
@Mike Guetta
I don't know if it can penetrate the skin far enough, but there exist creams with high quantities of raspberry extract -- which contains ellagitannins that inhibit tgf-beta. Maybe mix some DMSO in? :-)
Adding FSS Ursolic Acid Liposome PF up to 10% concentration in your favorite skin cream would be another option. Ursolic Acid doesn't so much reduce TGF as it prevents it from binding to fibroblasts. Ursolic Acid is also interesting as a supplement.
Quote from
https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1006685
"We found that with ageing TGFβ may lead to a prolonged inflammatory response in older individuals, resulting in more damage than it normally would in a younger individual suggesting a once protective pathway can now lead to prolonged damage. A better understanding of this change may allow us to develop drugs to repair this pathway, and re-establish its once protective effect."
" ...TGFβ is protective when it signals through the Alk5 pathway...Age is believed to be the major driving factor for conversion of Alk5 to Alk1 signalling..When the balance shifts toward Alk1 signalling, this causes increased Smad 1/5/8 phosphorylation [21] which enhances chondrocyte hypertrophy, terminal differentiation and matrix breakdown by MMPs such as MMP-13 "
"Although overexpression of Alk5 has not yet been tested as a potential treatment for patients, the model suggests that this may be a particularly effective treatment as it prevents Alk1 from becoming the dominant receptor."