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Senescent Cells in Skin Contribute to the Formation of Age Spots, and Can be Destroyed by Radiofrequency Treatment

Two quite interesting findings are presented in this open access paper. Firstly, the pigmented areas of skin called age spots are in large part generated by the presence of senescent cells and their detrimental effects on mechanisms of skin pigmentation. Secondly, one the skin treatments that has for years been touted as rejuvenating by vendors in the more dubious, unscientific end of the medical community in fact destroys a fair number of senescent cells and therefore might actually be a legitimate rejuvenation therapy, albeit limited to the skin. This is certainly a novelty, but I suppose that the research community might find more such cases as the understanding of senescent cells in aging continues to grow in detail and sophistication. There will be a certain amount of up-ending of expectations on all sides as rejuvenation therapies and their associated research communities make progress in the years to come.

A caveat on this research is that the portion using human data involves results obtained from only a few individuals, while much of the mechanistic examination in cells and tissues largely uses senescence induced in non-physiological conditions. Based on other research, cells made senescent in various non-physiological ways can differ in state significantly from those that arise naturally in the body. They are more or less vulnerable to different senolytics, for example. Still, this work is intriguing, a good start, and plausible when taken as a whole. I wouldn't be overly surprised to find it validated when a more extensive study is undertaken. One possible approach to independent confirmation is for the groups working on human trials of senolytic drugs to start paying attention to the age spots of their patients. This could be accomplished without excessive additional cost: a photographic record of hands and forearms, for example.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo

Pigmentation is an outcome of the interplay between melanocytes and neighbouring cells, such as keratinocytes and fibroblasts. Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Senile lentigo, also known as age spots, is one of the major changes associated with laxity and wrinkling during the ageing of skin. It is characterized by the presence of hyperpigmented spots in the elderly.

Cellular senescence is a fundamental ageing mechanism. Senescent cells and those with the related senescence-associated secretory phenotype (SASP) are known to be the main drivers of the age-related phenotype. During intrinsic and extrinsic skin ageing, the skin can contain senescent cells in epidermal and dermal compartments. Cellular senescence has been studied in dermal fibroblasts, which secrete factors that contribute to skin wrinkling. For example, the chronic secretion of matrix metalloproteinases by senescent cells is an important contributor to the degradation of collagen and other extracellular matrix components in dermal tissue. A decrease in the expression of transforming growth factor type II receptor appeared to be a critical event in age-related skin thinning. However, despite the important role exerted by neighbouring cells on the regulation of melanocyte biology, few studies have examined how senescent cells are involved in skin pigmentation, and it remains unclear whether senescent cells affect nearby epidermal melanocytes and influence ageing pigmentation.

In this study, we reveal what we believe is a novel mechanism whereby aged fibroblasts contribute to the local regulation of melanogenesis. We show that as an individual ages, pigmented skin contains an increasing proportion of senescent fibroblasts. Phenotype switching in these cells results in the loss of SDF1, and SDF1 deficiency appears to be a potent stimulus for the melanogenic processes that contribute to uneven pigmentation. These changes might be epigenetic. For example, the level of hypermethylation of the SDF1 promoter was remarkably different between hyperpigmented and perilesional skin.

The human skin, unlike other organs, undergoes photo-ageing in addition to natural ageing processes, and photo-ageing has been attributed to ageing pigmentation. Both processes are cumulative, and the most noticeable age-related changes therefore occur in the superficial layer of the skin. In the present study, we show that cellular senescence is especially likely to occur in fibroblasts located in the upper dermis of pigmented skin. Senescent fibroblasts are expected to influence melanocytes via cross-talk that can readily occur through a damaged basement membrane. We showed that senescent fibroblasts play a stimulatory role in pigmentation by upregulating the expression of the melanogenesis regulators MITF and tyrosinase in melanocytes.

Moreover, the impact of senescent fibroblasts on skin pigmentation was directly demonstrated when eliminating senescent cells with an intervention that reduced pigmentation. Microneedle fractional radiofrequency (RF) is a cosmetic therapy that induces skin rejuvenation via electromagnetic thermal injury. The microneedle RF device was chosen to manipulate only dermal cells, in which the microneedles generate thermal coagulation columns in the dermis, not in the epidermis. It was previously demonstrated that fractional laser treatment decreases the occurrence of senescent fibroblasts in aged dermis. Ten volunteers with senile lentigo were treated with RF, and skin samples were collected from 4 participants who agreed to undergo a skin biopsy before and at 6 weeks after treatment. Following RF treatment, the number of senescent fibroblasts was significantly reduced. The elimination of these cells was thought to be caused by RF-induced cell death. The elimination of senescent fibroblasts from senile lentigo was accompanied by skin lightening.

Comments

"One possible approach to independent confirmation is for the groups working on human trials of senolytic drugs to start paying attention to the age spots of their patients."

Are they using old enough patients to have age spots?

Posted by: Antonio at October 5th, 2018 3:15 PM

@Reason: Thanks. I've never heard of this journal and its interesting to learn about a new field I've never heard about.

Posted by: thomasa at October 5th, 2018 3:30 PM

@Reason: The publishing firm behind the journal also started the first Open Access (OA) journal, which is something we should support:

Our company has long history in open-access publishing. Our first open-access journal International Journal of Medical Sciences started publishing in 2004, at which time open-access (OA) concept was still at its initial stage and open-access journals were very few.

Our journals are well received by the scientific communities and gaining reputations as prestigious journals in their fields. It is evident that journals in biomedical fields are undergoing rapid transformation from the traditional subscription models to open access models. Articles published by Ivyspring International Publisher are made available in PubMed Central, the U.S. National Institutes of Health (NIH) digital archive of biomedical journal literature. Authors are also encouraged to self-archive the published articles in their own or institutional websites as well as governmental websites, library websites, without permissions required.

Posted by: thomasa at October 5th, 2018 3:45 PM

I believe I've heard grey hair is a result of senescent cells as well. I wonder if this treatment (or maybe even certain oral senolytics) would be effective in reversing grey hair.

Posted by: TysonsCorner at October 5th, 2018 4:49 PM

It looks like the first cosmetic rejuvenation biotechology intervention has been found, if Unity or Oisin's treatments remove or reduce age spots.

I think this will stick in the public's mind much more than a trial that reduces osteoarthritic knee pain. Look at how much attention papers on reversing hair greying get.

@TysonsCorner - I think hair greying is due to some form of oxidation in the hair follicle melanocytes, not senescent cells in the scalp.

It is a pity that age spots only affect very old people, and not those in their 30s or 40s.

Posted by: Jim at October 5th, 2018 9:46 PM

I am trying senolytics (D+Q low dose) right now, first treatment mid August, and among other immediate health improvements, I noticed that my hair stopped falling out. Prior to that I feared I might be bald in a few years' time. I am 80 years old, and I do have age spots but have not noticed any obvious improvement. I am due my last treatment in 2 weeks and then will have extensive blood tests done to get a more complete picture.
When I take my senolytics I stop ALL supplements - no rapamycin that week - exercise and get massages to support the body to cope with all the dead cells and help to eliminate them.

Posted by: Helga at October 6th, 2018 2:19 AM

>It is a pity that age spots only affect very old people, and not those in their 30s or 40s.

Arent sun spots the same thing actually? Being pretty fair skinned I have a lot of them on the shoulders starting from childhood.

Posted by: Andey at October 6th, 2018 2:50 PM

@TysonsCorner - Here is one (as far as I can see) anecdotal result --
"This NEW Cytokines Radiofrequency Scalp Treatment Can Turn Grey Hair Black"
http://www.beautyundercover.sg/Cytokines-Radiofrequency-Scalp-Treatment-Singapore-Hair-Growth-Grey-Hair-Black-Follicle-Salon/

On the other hand, here is an interesting list of substances that can restore lost hair color (Note that Dasatanib and other tyrosine kinase inhibitors are included) --
"Drugs That Induce Hair Color Changes"
https://owlcation.com/stem/Drugs-That-Induce-Hair-Color-Changes

Also not that some anti-cancer chemotherapy drugs that regulate apoptosis can also restore hair color. See ---

No dye: Cancer patients' gray hair darkened on immune drugs
https://medicalxpress.com/news/2017-07-dye-cancer-patients-gray-hair.html

Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer
http://jamanetwork.com/journals/jamadermatology/article-abstract/2642914

PD1 inhibitors and hair repigmentation: A desirable new side effect
https://onlinelibrary.wiley.com/doi/pdf/10.1111/dth.12560

Hair Repigmentation With Anti-PD-1 and Anti-PD-L1 Immunotherapy: A Novel Hypothesis-Reply
https://jamanetwork.com/journals/jamadermatology/article-abstract/2663945

Hair repigmentation associated with the use of brentuximab
https://www.sciencedirect.com/science/article/pii/S2352512617302369

Posted by: L Pagnucco at October 6th, 2018 2:58 PM

@Helga

Cudos, for the brain pioneers. Please be very careful. Can you share your protocol, and findings? How much did you pay for D?

Posted by: Cuberat at October 6th, 2018 4:31 PM

D was very difficult to source, no pharmacy in various European countries could supply D, exclusively cancer centres only. Reluctantly purchased a box of generic D - Lucidas - from BONHOA, in India, 20mg pills. Total cost, incl. shipping, money transfer etc £200.. No prescription needed.
I knew I had a problem with fibrosis, accumulation around internal organs and after years of digestive problems, was diagnosed with collagenous colitis, again a form a fibrosis. It had come to the point that I passed very little urine because of constant diarrhoea and/or fibrosis of the kidneys?. Within 24 hours of taking D+Q, I could pass an abundance of urine, and all the other symptoms have MUCH improved. The hair improvement was just a welcome side effect.
Because of my age and weight - 80 yrs. and 52kg - I decided to take only 40mg of D and 500mg of Q. That was mid August, I repeated the treatment in mid September, and plan 1 more in 10 days or so. I have not decided if I will increase it to 60mg of D. Have not made up my mind. Then wait a week and do blood tests.
I have not noticed anything negative, and I feel great.
I am well aware of side effects, it took me years of research to finally go ahead. The same with rapamycin. Have been following Reason's pages with great interest for years, and the valuable comments. Also attend conferences, like Aubry de Grey in Cambridge several years ago, and now the Undoing Agimg in Berlin.

Posted by: Helga at October 7th, 2018 9:08 AM

@Helga
It seems that you have got a genuine senolitic effect. And for your cases risk vs benefit tradeoffs are clearly in the benefit range. If you decide to increase the dosage, do it gradually. What is remarkable, is that both dasatinib and quercetin have very poor water solubility. I am not sure whether increasing the dose will really increase the bio availability.

@All
Can anybody tell me how does dasatinib get to the target areas by oral admission is it has very poor solubility both in water, alcohol, and I think in fats?

Posted by: Cuberat at October 7th, 2018 8:40 PM

@helga I am happy to hear about your results. I got the impression that you are living within the EU? I ask because i have trouble finding a source for Rapamycin. I can't get it shipped from outside the EU because of strict customs and there is not a single doctor in my country that legally could supply me with Rapamycin. I am considering buying it from a chemical supplier but that would force me to measure out dosages my self, id rather not. Where did you acquire it?

Posted by: Elkær at October 8th, 2018 3:35 AM

@Cuberat
It's great that Helga is responding favorably to the D+Q, but her responses can't be conclusively ascribed to a senolytic effect. Quercetin is a PGD2 inhibitor and people have reported successful hair regrowth using it. Prostaglandins are also implicated in fibrosis. Flavonoid bioavailability seems to be subject to a lot of interindividual variability, most likely due to differences in the gut microbiome - so the old 'YMMV' applies:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5183723/

Posted by: CD at October 8th, 2018 8:17 AM

@elkaer Yes Rapa is difficult to get, stock up on mine when I go on holiday! Happy to give more info to you private email.

Posted by: Helga at October 8th, 2018 9:36 AM

@CD
It could be some other non-senolitic effect,but most probably, Helga was trying difference supplements before without such great improvement. It is hard to guess the degree of senecent cells removal since we don't have meaningful non-invasive methods to assess the cenecsent load and the associated inflammatory secretion. And one single case can hardly make statistics. On top of that, having too good of a senolitic can lead to excessive lysis and organ failures, which want the car here. AFAIK, Dasatinib and quercetin tend to accumulate in the liver and kidneys as the organs with higher metabolism. If there was a senolitic effect it might be treated mostly to the kidneys.

But nevertheless, we have one anecdote that shows good tolerance and good effects of d+q in an agreed individual. With some good luck Helga might be one of the first people to get generation I rejuvenation therapy. And might be even reaching LEV.

Posted by: Cuberat at October 8th, 2018 8:27 PM

@Helga
For how's long do you take rapamycin? What is your protocol and observations? Did you try fisetin ? Do you plan on doing f+d+q treatment?

Posted by: Cuberat at October 8th, 2018 8:30 PM

@Helga That would be really nice of you, i might have to plan my next vacation accordingly. You can reach me at: ChristopherEAibsen@gmail.com

Chris

Posted by: elkær at October 9th, 2018 1:36 AM

@cuberat Reg. rapa, I have been on it for 1 year now, 2mg once a week. I have absolutely no side effects, I feared hi glucose, but it is lower than it ever was. I do take metformin - for years now - but only 425mg daily.
I have Dupuytren's in both hands, that definitely improved after 6 weeks on rapa. Coincidence? The condition is now totally tolerable. The WOW feeling came after 3 months, when I got the feeling of being able to conquer the world! No way to ever give it up.
I did blood tests after 6 months on rapa, sent the results to aging ai and my biological age came back with 40years, the best ever, vs chronological age of 80.
Your comments on senolytics reg. lysis, potential organ failure etc. I was well aware of that, that's why the low dose. I take NO prescription medication, but lots of supplements. Adelle Davies converted me back in the sixties.
I am on a 6 week holiday, when I am back home I shall take my last D+Q dose, have blood tests done and an eye check. Have trouble with my glasses recently, can't read the small print, BUT my old glasses -4 yrs + - give me perfect vision. Another D+Q side effect? or rapa side effect? I will never know for sure.
f=d=q is not in my plans, at least not yet.

Posted by: Helga at October 9th, 2018 4:05 AM

My 95 yr old mother has an amazing number of age spots...she is not in the best condition, but has a good appetite and manages to get around OK...if not too often. She is embarrassed by the spots...I tell her it must go along with being 95.

Old age is an interesting phenom...espec when you watch yourself and people you know getting older....and experiencing diseases.

Have heard of glutathione being used to reduce age spots. I take 250 mg / day of Setria...check on Amazon for people talking about using it to lighten skin...anecdotal. Also supposed to help cataracts.

This thing with fisetin reminds me of the same with resveratrol...probably not a good idea to overload on any one supplement? THINK synergy?

Posted by: fred at October 10th, 2018 8:27 AM

If all these newfound senolytics really work (Fisetin, Q+D, azithromycen) we shouldn't have to spend thousands of dollars to have our forearms treated with radiofrequency. It would be so much better to systemically elimate age spots all over the body. What will we use for that? Glutithione is not a senolytic and it takes ongoing IV doses to work with side effects. Which senolytic will eat up age spots?

Posted by: August at December 2nd, 2018 7:22 PM

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