Fibroblasts in Old Skin Lose their Functional Identity

Researchers here describe the character of fibroblasts in old skin as a loss of characteristic function and identity. The fibroblasts begin to take on aspects of other cell types, and thus the character of skin changes for the worse. In the publicity materials this decline in cell function is described as a cause of aging, but that should probably be taken to mean that the researchers consider it a contributing cause to age-related pathology rather than a root cause of aging per se. Dysfunction of this nature has all the signs of being a downstream consequence in aging, cellular misbehavior that is a reaction to earlier processes, such as the accumulation of molecular damage within and between cells, or the changes in cell signaling that results from that damage.

With age, our tissues lose their function and capacity to regenerate after being damaged. The main conclusion drawn from recent findings is that these fibroblasts lose their cell identity, as if they had "forgotten" what they are, and consequently their activity is altered, thus affecting tissue. The new study reveals the cellular and molecular pathways affected by ageing and proposes that they could be manipulated to delay or even reverse the skin ageing process.

Dermal fibroblasts are key for the production of collagen and other proteins that make up the dermis and that preserve the skin's function as a barrier. The activity of these cells is also crucial for the repair of skin damage. As we age, the dermis loses its capacity to produce collagen, and consequently its capacity to repair wounds is also significantly impaired. A single-cell analysis confirmed the loss of fibroblast identity in aged animals. Using sophisticated computational tools, scientists observed that aged fibroblasts show a less defined molecular conformation compared to young fibroblasts and come to resemble the undefined cell states observed in newborn animals.

"The elderly face many problems in this regard because their skin does not heal properly and its barrier properties are decreased, thus increasing the risk of skin infections and systemic infections. The notion that the loss of cell identity is one of the underlying causes of ageing is interesting and one that we believe hasn't been considered before."



Hello @Reason, it's me again. How do you diferenciate causes of consequences? Thanks

Posted by: Josep at November 9th, 2018 7:32 AM

* causes from consequences

Posted by: Josep at November 9th, 2018 7:33 AM

Researchers really need to concentrate on rejuvenating the fibroblasts. That begins with improving DNA repair technology and techniques. It could be as simple as that.

Posted by: Biotechy Marcks at November 9th, 2018 8:29 AM

The skin is not the only affected tissue type. Probably the internal organs, vascular walls and muscles are affected too

Even senolitics can bring a lot of low-hanging fruits here. Probably 90% of this identity loss is due to the chronic inflammatory signals form the surrounding tissues...

Posted by: cuberat at November 9th, 2018 8:37 AM

Mechanostress is another possible cause of epigenetic changes.

I've been wondering about how much impact somatic repeat expansions have on aging, not just of the CNS but other systems and organs. The rates of this type of mutation vary a great deal across tissue types. Repeat expansions may cause epigenetic alterations.

Posted by: CD at November 9th, 2018 9:55 AM

Lets face it. Most of the skin damage on our hands and face is caused by UV rays, X-rays and other harmful rays coming from the sun. just look at your hands, the skin on the underside is always less damaged than the skin on the backside of your hands. You don't have any brown spots or AGE damage on the unexposed side of your hands, though I guess you eventually get some damage in the form of wrinkles there too. My personal solution is to stay out of the bright, high angle sun as much as possible, and to take supplements I think will help with DNA repair or collagen replacement. You need a balance of hydrophobic and hydrophilic substances like lipophilic vitamin C, the right collagen types. I also take melatonin, resveratrol and Niagen (NAD+) at bedtime. The idea is to activate the sirtuins and provide the energy source they need to accomplish repair of single strand and double strand DNA breaks. More importantly, you need to activate your FOXO3 SNPS, and perhaps other FOXO genes which are needed for stem cell activation. Doing these things, I believe I have reversed 20 years of aging in my hands over the last year.

Posted by: Biotechy Marcks at November 9th, 2018 9:56 AM

@Josep: A cause of aging occurs during the course of operation of normal, youthful metabolism.

Posted by: Reason at November 9th, 2018 11:29 AM

@Biotechy Marcks

It is implied but not mentioned explicitly that the damage we are talking about is the damage with which the body's repair mechanisms cannot cope. For example, the outer layers of the skin, the mucosa, and stomach lining get replaced very often. So event, a major damage to them can be well tolerated. While even minor damage to the fibroblast's DNA can render bad results over the years

Posted by: cuberat at November 9th, 2018 12:28 PM

Elena over at LEAF posted an interview with a Moscow clinic who are looking to inject freshly delivered fibroblasts (from in vitro expanded fibroblasts, not iPSCs I think) in to the skin as a cosmetic procedure to restore collagen synthesis. If this dysfunction is "secondary damage", a result of the altered signalling environment, rather than intrinsic fibroblast damage as Reason suggests, then this Moscow groups approach will be ineffective.

Posted by: Jim at November 9th, 2018 9:45 PM

Biotechy Marcks, How do you activate your FOXO3 SNPS? I've done everything else you mention for over a year with no change in hand skin aging. I do take my Niagen in am however, like bottle says, why night?

Posted by: August at November 9th, 2018 10:01 PM

@ AUGUST: My main purpose is to repair damaged DNA, which is why I take Niagen at bedtime with the other supplements so that a high amount of usable energy is available especially to repair double-stranded DNA breaks. Repair of these breaks requires a lot of NAD+ energy. FOXO3 activators are resveratrol, curcumin, pterostilbene, nd purple anthocyanidins. Reference: Google Geres Dengle, FOXO can be elevated by (the substances I have listed).

Posted by: Biotechy Marcks at November 10th, 2018 10:04 AM

@ August: PS. If you do not have longevity SNP's of FOXO3, you may not get rejuvenation benefits. I have at least 13 SNP's that have shown to have longevity benefits in various studies around the World.

Posted by: Biotechy Marcks at November 10th, 2018 10:42 AM

PS: Green tea is another substance that increases FOXO3 activation, and is also known to be especially useful in maintaining healthy skin.

Posted by: Biotechy Marcks at November 10th, 2018 6:23 PM

@reason in one of the results of that article they cultured both fibroblasts from the young and old, and after just one passage they were indistinguishable. Meaning that the signals in the old are truly the cause of the change. And you are right.

Posted by: Moses at November 12th, 2018 2:49 AM

So they cultured dissociated old fibroblasts in flat flasks in growth medium and they then began to exhibit the same gene expression profile as young cells in situ or young cells in culture?

I interpreted Reason's post the way Moses did, that the gene expression profile changes are the result of some other form of damage, but not necessarily intrinsic to the fibroblasts - as you and Cuberat suggested, the altered signalling environment (by which I'm assuming you both mean circulating SASP). In that case, as you noted, the Moscow project might not work very well by itself.

Posted by: CD at November 12th, 2018 9:26 AM

@CD yes they cultured fibroblasts from both the old and young mice, and they saw no difference between the two. I have access to the article only at the university, so if you want i can cite them later.

Posted by: Moses at November 12th, 2018 11:00 AM

Thanks for the info, no citation needed.

Posted by: CD at November 12th, 2018 12:53 PM

The Niagen (NR) directions say to take it in the am since NAD+ levels (might*) have a circadian pattern showing two peaks - a large one in the am and a smaller one in the afternoon (1). Timing the dose to coincide with the larger natural peak might be helpful for reaching an effective dose. It also may have an impact on maintaining circadian rhythms. Exercise increases NAD+ levels, so exercising in the am might aid in achieving an effective dose.

But if Biotechy has had success with dosing before bed and you want to try it, why not...

1 -

* in the video Brenner does not say that studies in humans have shown this pattern - it appears he is extrapolating from mice.

Posted by: CD at November 13th, 2018 8:53 AM

This article proposes that when cells epigenetic identity is lost and they become "blander", less specialized - in skin cells, the answer may be partly to do with microRNAs.
One miRNA in particular was noticeably more abundant in older people's cells: miR-30a.

All that said, paradoxically there are also plenty of studies suggesting miR-30a acts as a tumor suppressor and lots of other good stuff.

So do you attempt to down-regulate or up-regulate miR-30a? And how?

Posted by: August at November 21st, 2018 1:10 PM

I've been interested in nucleic acids and have taken RNA for decades. It is possible that RNA supplements and topical creams help skin by increasing signaling.
Although effective delivery is a challenge as NAs need to enter into the nucleus of cells to elicit a therapeutic response. If you hear of something other than expensive microneedling (sigh) to get it in let me know.
This 2015 article may help:
"Nucleic acid delivery into skin for the treatment of skin disease: Proofs-of-concept, potential impact, and remaining challenges"
More interesting information on nucleic acids and cell signaling can be found here:
To quote the patent application "The present invention is based on the surprising recognition that basic DNA lead binding proteins such as HMG-proteins to enable a cell to a state that allows de-differentiation.....nucleic acids, transcription or translation products of proteins of the HMGA family, a substantially embryonic expressed protein family, a dedifferentiation or "rejuvenation" of cells and tissues ultimately, the proliferation potential of fibroblasts and the migration of epithelial cells increased. nucleic acids, transcription or translation products of proteins of the HMGB family, especially HMGBl solve essentially a signal chain that leads to angiogenesis or neovascularization......Above all, the age-related slowdown and decrease in cell regeneration, which is influenced, among other things due to hormonal changes and hereditary factors can be counteracted by the inventively used basic DNA-binding proteins or nucleic acids coding.

Posted by: August at January 6th, 2019 2:40 PM
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