Melanocytes are the Only Epidermal Cells to Show Signs of Senescence with Aging
Lingering senescent cells arise in every tissue, and their presence is a cause of aging. These errant cells secrete a potent mix of molecules that rouse the immune system to chronic inflammation, degrade tissue structure, and change the behavior of surrounding cells for the worse. The more senescent cells, the worse the effects. Researchers are beginning to look more closely at cellular senescence in aging skin, and the results from the study noted here are particularly interesting. That melanocytes are the only skin cell type to show the canonical signs of senescence is unexpected.
Nonetheless, the negative effects of senescence still exist in this case, and reinforce the expectation that senolytic drugs that reach the epidermis sufficiently well will be capable of reversing skin aging to some degree, just as they have been shown to reverse measures of aging in other organs. Given the present state of knowledge, I expect the benefits of senolytic therapies on skin to be minimal until later life. The skin aging that occurs between 20 and 50 is probably not driven to any great degree by senescent cells, as senescent cell burden most likely scales with age in a similar manner to cancer risk. There will no doubt be clinical trials in the years ahead, and firm numbers where today there are only expectations, but skin aging isn't all that high on the priority list for most of the companies and research groups working in the field.
Over time, cells in the body can be damaged by external exposures, like ultraviolet radiation from the sun, or internal ones like oxidative stress. On the skin this appears as wrinkles, dryness, or age spots. In the skin, changes occur so the outermost layer called the epidermis gets less nourishment, becomes thinner and is easier to breach. To understand this process on a cellular level, researchers began looking at different cell populations in skin to see if any cell type was associated with skin damage more so than another.
The team initially thought that one type of cell that is abundant in skin and divides often, called keratinocytes, would drive senescence. However they report that melanocytes, the cells which produce the pigment responsible for skin color, fit the senescence profile and released pro-inflammatory factors that could affect surrounding cells and induce skin aging. "Melanocytes divide very little throughout our life and constitute 5-10% of the cells in the basal layer of the epidermis. They showed a variety of molecular markers of cellular senescence in the aging skin. We found that melanocytes became senescent without telomere shortening, which is not surprising since they hardly divide. But melanocytes showed DNA damage specifically at telomere regions irrespectively of their length due to oxidative stress."
To confirm that melanocytes were really the driver of skin aging, the team built a 3D human epidermis in the lab, and found that melanocytes alone could induce several features of skin aging in the model. They also reported that the effect of the senescent melanocytes could be moderated by treating the model with the senolytic drug ABT-737 or by the mitochondrially targeted antioxidant MitoQ that protects mitochondria.
Link: https://discoverysedge.mayo.edu/2019/10/21/researchers-identify-cells-that-drive-human-skin-aging/
Very interesting. I would say that the wrinkles are caused rather by the deeper layers of the skin like collagen and elastine cross-links.
Having great hair and she spots can not be directly correlated with a common underlying process, I think
Skin aging really ought to be a high priority, I think an 80 year old having skin restored to 20 would get spectacular attention and be super easy to crowd fund.
So mito-q suppresses damage - facinating! Oral or topical? And opinions please- as a mitochondrial antioxidant is mito-q or methylene blue better? It's certainly a lot easier/cheaper to add m blue to your body lotion than mito-q. I also have pause about mito-q due to this study that got everyone excited in 2017, https://www.nature.com/articles/s41598-017-02419-3
I switched from mito-q to meth blue due to this study statement, I quote: "To our surprise, treatment with MitoQ at 100 nM, as suggested by previous studies16, 21, did not reduce but drastically increased mitochondrial ROS level (Fig. 1C). Additionally, MitoQ treatment did not promote but inhibited cell proliferation in both normal and HGPS cells"
Was I wrong to replace mito-q ( both orally and topically) with methylene blue?
How can we start biohacking with ABT-737 now?
Hi August, just a 2 cents.
I would wager mitoQ, under regular circumstances, probably causes mitohormesis. The mtROS elevation while taking mitoQ seems a sign of that. It may also be dose dependent, just like hormesis. MitoQ acts like CoQ 10, ubiquinone/-nol, it is an electron donor and diverter. That's how it quenches mtETC leakage. Here, like CoQ or tocopherol vit.E it can act as mitohormetic. In doing so, it will activate NRF2/ARE/EpRE/HSP/HO/SIR/DAF/FOXO and the redox..so a big hormetic response that, by the redox, will detoxfy the 'end products' of mtROS elevation. It's a very fine line between the redox and oxidation by ROS. Tightly regulated at the mitochondrial membrane potential.
Albeit, mitoQ is more like a healthy slowed aging promoter, hormesis is not something that reverses aging but slows it (like CR and auto/mitophagy. Or like flies that are fed asc-2-phosphate live 160% lifespan due to life hormesis caused by mild stress toxicity of this form of ascorbate). Studies showed that ROS elevates, with age, and this contributes to the advancement on epiclock by the damages they cause (faster demethylation of global methylome by cumulating nDNA lesions, deletions, DSBs, telomere uncapping, etc). Thus, we must either stop ROS elevation with age or fing a way to restore telomere (sans telomerase) to avoid Hayflick in undividing postmitotic cells. The reason why hormesis is beneficial despite ROS elevation is because it primes the body (autophagy, redox, etc) to respond to the mild stress insult. This cause temporary toxicity (to be detoxified) and this toxicity 'slows' down DNA synthesis/the metab (eIF2), it evens causes granular formation to withstand said hormetic stress. This, in turn, slows all metabolic kinetics, which are part of/lead to damages accrual (as part of regular metabolism). Toxicity also affects the methylome, mild toxicity is capable of Enhancing methylation. Which leads to erasing DNA imprints by methyls formation. It's better to erase aging signature than try to play catch up trying to mop up the damages. Repairing damages seem our only viable solution until we can better harness the epigenetics (not holding my breath because of bureaucratic tape).
Just a 2 cents.
Possibly important to treatment of Vitaligo. I do not see any other applications. The Dermis is at least 20 times thicker than the epidermis so this would be irrelevant to wrinkles. I should think topical application would be more effective than oral consumption.
Thank you CANanonymity, so appreciative of your insight! If MitoQ works through mitohormesis should we avoid taking glutathione with it on an empty stomach in the morning? Would glutathione negate the slight uptick in ROS provided by the MitoQ? The ROS uptick is desirable (see below) so I'm concerned that G or any other antioxidant (C, E, Selenium, etc) will quench it......
"ROS can be beneficial for the cells. In response to mild cellular stress, mitochondria generate low levels of ROS, which in turn act as signaling molecules and protect the cells from further damage by initiating an adaptive response. This process is known as mitohormesis."
Re August, Thank you for that. Just a 2 cents.
I would wager yes, and no. But, I'll say, more, no.
Yes, because as you stated, ROS are beneficial/signaling the 'body response (hormesis)'. And, during night/morning fasting (with empty stomach) the body slows metabolism during night sleep to repair/remove junk (such as brain neuron recalibration, brain junk excretion and wound healing/deep sleep/REM GHs released from pineal/glands that rebuild tissue) but upon awakening the next morning there is metabolism acceleration/normalization; when it normalizes,
the metabolic speed will be faster = higher ROS production (of metabolism) at the mitos. This will mean (the need for glutathione to restore a reduced milieu, for ROS oxidize the milieu, while GSH (glutathione) restores reduced state (unoxidized, or rather, 'less consequentially oxidized milieu (there is oxidation but the 'weight' of it is irrelevant because total thiol sulfur pool (GSH/Csy) is more than sufficient to offset the oxidation problem'. It's measured as GSH:GSSG ratio (reduced (GSH):oxidized (GSSG) ratio))). But, as said, we don't wish to extinct ROS emission neither...thus, waiting would allow you to benefit of hormesis...and then, later, to increase the GSH, time-strategically; allowing the hormesis and later ROS quenching/milieu restoring.
Glutathione might negate a bit of that hormetic effect. Though, I doubt it, because hormesis, itself, actually Increases glutathione (via NRF2 (nuclear response factor 2) goes in the nucleus and then it targets activation of Gamma-cysteine ligase (Glutathione production enzymes). It is a Response...to the rise of ROS...to negate them...but, ROS are permanent. Glutathione in the mitos is tightly regulated (one study mitochondrial study determined that mitochondrial glutatione determines the fate of mitos and their 'survivability'). Thus, we could think that Under high stress load (high ROS) than yes Glutathione would quench the fastest (it is the most abundant tripeptide (Cys(teine)-Gly(cine)-Glu(tamate)) thiol in all cells and in cytosol/ECM).
Timing it is best and seeing how your body reacts (it dépends on your current health state, for, the body is a constant 'yin-yan', it will (re)adapt to the situation/health/time of day/environ/calories...
In any case, Glutathione is probably the best supplement yet, there are other ones like melatonin, lycopene, tocotrienol, asc-2-pho, mitoq and astaxanthin, which are very quenching (even More than glutathione itself)...but GSH is not just that, it is 'redox regulator' not just a ROS quencher; it is (epi)genome talker (it communicates with epigenome). It's why studies with any other antioxidants failed to obtained the same results (unless they supplied the building amino blocks that compose it). THere is also NAD+, B3 and NAC (N-Acetyl-Cysteine), 1 block of it.
All of them do not do what GSH does, they, themselve, act, by increasing GSH itself (via activating gamma-cysteine ligase/GSH production and GSSG recycling to GSH (Glutathione Reductase). Heck, just to tell you, the longest living seanimal is a clam and it maintains its redox for this long (530 years); by the Nerst Equation (mV milieu equation) is has a Surplus of total glutathione (it is thus in 'reduced' state, all the time; oxidation is Very Low in it, for at least 200 years). Likewise, for bowhead whales (living 210 years) or greenland sharks (living 400-500 years, this was proven by eye len amino acid L-to-D racemization technique that determines age of the eye len of these sharks). One thing is certain, they have low heart beats (greenland sharks and Icelandic clams live in the (iceland) north...it's cold near 0oC water...their heart beats 1 per minute; hence, their metabolism is (dead?)...hence, they can live half-a-millenia.I am betting more on bowhead whales, for they are mammals like us, and have a heart beat a bit slower, not that slower (like 30-50 beats min..thus, if they can reach 200 years at that heart rate it'S good a sign for us (because great sea turtles live up 175 years...and have also a low heartrate..but again, nowhere near as (deadbeat) heartbeat as the clams and northern sleeping green sharks).
Just a 2 c.
Imagine the media attention if it was senescent melanocytes that were turning hair gray, and injections into the scalp reversed grey hair.
@jimofoz
Some cancer patients day that after dasatinib they gray hair reversed back to darker state. We can imagine a topical solution of DHMO with fattening, quercetin and fusetin applied to the skin reducing age spots, grey hair and improving elasticity.
CANanonymity - Glad to know that taking Glutithione is a good thing. I will do 2 mitoQ capsules upon awakening, Then later take my NAd (nuchiodo), lycopene, tocotrienol, vitamin C, K, D. multi, PQQ, selinium, sulphorapane, carcinine, curcumin, fish oil, white willow, and pterostilbene at lunch. Once I again achieve an empty stomach in the afternoon I will take the Glutithione along with Methylene Blue, Taurine and B-12. Before bed will be magnesium, melatonin, and glycene.
Does that sound good - or too many antioxidants in general? I eat very healthy. Also, I was concerned about the following mitoq study - but is the study result just the desirable effect of hormesis?
https://www.researchgate.net/publication/324211246_The_targeted_anti-oxidant_MitoQ_causes_mitochondrial_swelling_and_depolarization_in_kidney_tissue
Jimofoz, DHMO may be problematic? - there is a lively discussion on using fisetin topically, perhaps with nano-emulsions, on Longecity here (starting around page 16)
https://www.longecity.org/forum/topic/102477-fisetin-senolytic/page-18
Rere That is quite the supplements regimen, Nothing to add. You are on your way for a longer healthspan (and, thus, lifespan), for sure. Just make sure to actively 'listen' to your body...not one body responds exactly the same - even in huge pro-health conconctions of supplements. Sometimes, certain, supplements 'turn sour' (litterally..like omega 3 / fish oïl turning rancid...and taking that is poison / by the oxidized PUFAs in it; make sure your fish oïl is pristine and if you take capusles that they are completely hermetic/unexposed to O2 or 'past due date' (rancid), choose the best (paying more s*cks..but for your health..there is no substitute, if you want to live longer and in health (your health deserves the best product; if you go with cheap crap (I say cheap...there is good cheap stuff..not all of it), your health will suffer and in these cases. it is Better to Not take it altogether). Certain antioxidants turn Pro oxidants or negate some aspect of regular metabolic function (if 'too much')...it happens. It's also why dosing & timing (and 'seeing' how your respond) is very important, for each one, specifically (since, as said, no one responds Exactly 100.00000% same).
It is not too many antioxidants but just make sure to Watch your health at it goes, if you feel healthier and with more energy (no ills/aches/pains...)and you did a check up on your blood/body sings....and things are going...then, for now, there seems no reason to slack...but it may happen later that you need to slow down a bit. And 'restart' the body. Because our body becomes accustomed and 'dependent' on these supplements...their effect can even 'wane/weaken' with time/habit of it. So, sometimes, sparsing it helps to keep it 'fresh'.
Thank you for that study link, the mitoq study causing mitochondrial membrane potential depolarization is, most likely, an after effect of 'stronge hormesis'...and,so, yes...hormesis is not without its faults. It is, after all, a 'mild stress' (''when a small stress is beneficial'') and mild stresses can become Bigger stresses (stress kills you), but Not if you 'maintain it' 'mild/low'....and then the body 'responds to it' beneficially (by the signaletic 'hormetic 'stress response''). 'Oxidative Stress Resistance'. If you can resist it, for evolution, that'S a good thing, you're surviving and thus, selected for (a hardy one); whereas, when weaker (it's harsh like that), you succomb to it (thus unselected and to removed/does not make specie survival but attrition of it). It's cold and mean, there is no feeling only 'biosurvival imperative' (it's why some of the most 'unrighteous/unlawful/unmoral' actions commited by animals (in lawless animal kingdom) continue to happen and these animals continue to reign (as lawless/ethicless animals) - they are here since millions of years and still going; showing ethics/laws/etc...are an artificial construct of human society. Out there, it'S only kill or be killed - to transfer your 'killer' genes to your progeniture/offspring (and thus make specie survive).
Just a 2 cent.
PS: You do not need to stop mitoQ, just (low) dose it/Check vitals, to not make Extreme hormesis, because that is poison/toxic hormesis (causing such...as the study shows...toxicity/loss of ATP/and thus mito swelling and kidney failure). Only low/mild hormesis beneficial, as soon as you overdo it, it turns bad (so must dose/time mitoq).
Thanks for everyone's comments. For those interested in skin aging this article is a big deal and deserves further exploration. A puzzle seems to emerge if you also read this article:
This study identifies a mechanism of immune evasion that may contribute to the persistence of senescent cells in dermal tissues.
https://www.nature.com/articles/s41467-019-10335-5
The gist theorizes that despite creating a robust immune attack, dermal scenescent cells can Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells"
It seems that the upregulation of HLA-E with aging protects theses bad cells from immune attacks. Senolytics can send in the immune soldiers but can they seek out theses hidden cells? Elevated HLA-E seems to ptrotecT them. "Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.... Taken together, these findings suggest that HLA-E expression contributes to the persistence of senescent cells in tissues. HLA-E may therefore represent a novel target for the therapeutic elimination of senescent cells in age-related diseases."
So how do we reduce the expression of HLA-E prior to hemolytic therapy so more rogue cells can be sought out and destroyed, at least in skin? HLA-E expression by senescent cells is regulated by p38.
So.... Basically we could possibly inhibit p38 in order to reduce HLA-E prior to therapy, allowing the immune system to find more cells. After extensive searching I found a natural inhibitor of P38,
while Several compounds from natural products inhibit p38, Itsworth googling .I settled on NB, sold as a citrus peel extract called sytrinol. I'll dose before fisetin next time.
It's late, I need to explore further but wanted to share and possibly hear other interpretations of the above study.
P Sustained p38 mitogen activated protein kinase (MAPK) activity, closely associated with induction of MMP-9 under stress condition, was markedly reduced by NB treatment, sytrinol.
I think that some of what you said in this post is wrong.
There is no evidence that senescent cells only starts to have a significant effect on the body after the age of 50. Senescent cells level are increasing with age and there is no reason to think that they don't have a major role in skin aging of people younger than 50 or 40. It important to remember that the list of age related damage types that proved to be a direct cause of skin aging is already small.
And I don't sure if you say that melanocytes are the only cells in the epidermis become senescent but there are many recent studies before and after this research who mentioned senescent Keratinocytes which are one of the main cells in the epidermis.