The 50-50-50 rule says that by fifty, half of us have at least half a head of grey. Everybody says it in the field. It's wrong. The real figures are somewhere between 6% and 23%, depending heavily on ethnicity [1]. After more than two decades of working on the different cells and mechanisms that regulate your hair color, I thought it’d be a good idea to write a short piece and explain some things about hair greying and maybe dispel some of the misconceptions.
The hair itself doesn't actually turn gray
You see the hair on your head isn't alive, which is why you can cut it and not feel a thing. You can compare it to a finished thread and its color is determined underneath the skin before the strand is ever generated. The mini-organ performing this incredible feat, of making hair, be it blond or dark or whichever color you have, is your hair follicle. This unique structure is one of the very few in the body that demolishes itself only to rebuild itself in an ever long cyclical fashion for your entire life (if you are lucky, that is). Every cycle, it constructs a fresh pigment producing factory, runs it for a few years, then tears it down and rebuilds it all over again. Think Burning Man style.
So, your hair color isn't maintained but constantly manufactured. And graying is what it looks like when the manufacturing has come to a halt. A nice experiment used 150 scalp follicles from women in their 50s and 60s and asked: in a graying follicle, are the pigment cells malfunctioning or are they simply not there?
The answer was: they're missing
In fully white hairs, the pigment-producing melanocytes in the bulb are essentially gone [2]. Gray hairs are different: they can still contain some melanocytes that remain capable of producing and transferring pigment [2]. So this isn’t a binary thing, just black and white, that is. When we discuss hair, we commonly refer to a follicle as if it is either making color or not. Sort through a real head of hair and there's a third group: hairs that still carry pigment but just less of it [2]. Those faded hairs are on the path to becoming white. So, the fading you see on your own head is the clock count going down.
Here's the cool part when you really think about your hair. Even if it’s white you still have hair, (and many people find white hair appealing). But I don’t mean it’s great that you have hair although it definitely is. I mean the interesting part is that our white hair producing follicle keeps working and building hair. One of the Nobel laureates in my field had incredibly stunning thick white hair at a very old age. It simply stopped inserting color into it, which tells you something very revealing about the biology of the hair follicle. It doesn't run on just one kind of stem cell population, it runs on several types, and they don't act as one. The ones that build the hair shaft are still going strong, while the ones that make pigment dwindled away. They live together in the same neighborhood where they receive the same signals but they don’t share the same fate [2]. So whatever is emptying the pigment line isn't touching the tenants next door. It's incredibly selective and it suggests the fragility sits in the cell rather than in the ecosystem it lives in. And if you are already wondering, the stem cells making the pigment generating melanocytes are particularly vulnerable to stressors, more than their hair producing stem cell neighbors. Hence hairs which are white.
Now, why would a follicle run short of pigment cells at all?
The pigment producing cells reside in the bulb, which is next to the base of the hair. These cells are supposed to live for a transient time and then they are instructed to die. Remember the hair follicle is tearing itself down? It’s actually doing so by instructing mass suicide of all the cells in this region. And once that is over, the new cycle requires a fresh batch of cells. That batch comes from a reserve stem cell population that gives rise to these cells [3]. So an empty bulb isn't really a story about the bulb but a story about the stem cells not delivering. We assume the niche where the stem cells live, protects these unique cells by feeding them and keeping them active. In mice (and probably in humans), it’s exactly the opposite. Profile those cells and almost everything is switched off. The cell is tuned down, and being in that state is how it lasts for long timeframes, which in scientific terms is called quiescence [4].
So can you wake one up (if it’s been sleeping for too long)?
Yes but there is a catch. Simply forcing melanocyte stem cells into action may not be enough. Several mouse studies show that stem cells can be lost not only by dying, but by differentiating at the wrong time or in the wrong place [3,5]. In other words, activation without self-renewal may spend the reserve rather than preserve it. Our hypothesis is that the trick may be to gently wake these cells, just like my kids after a good night’s sleep, restoring productive activation while preserving their ability to self-renew, rather than exhausting the reserve. The question is just how but I do believe it’s possible. There is a mouse experiment I find really beautiful and informative. Block the signal driving the pigment factory and the coat becomes completely white. Then induce another cycle after removing the blockade and it grows back black as if nothing had happened [6]. So you can have a white head with the reserve entirely intact, and a white head with nothing left and they will look identical, from the outside.
So what have people actually tried?
The peptides. This is the commercially serious class and the most known is called Greyverse (very cool name I must say). It is an α-MSH agonist also called palmitoyl tetrapeptide-20 (PTP-20; admit that doesn’t have that nice of a ring to it) and it's sold on a published human study that's worth reading, because surprisingly there is no clinical measurement showing that the subjects' hair actually became less grey but there are some other interesting measurements [7]. I would love to see some real human data using it. I've experimented with this compound, so I'm not talking about it from outside. It has some effect though, but there is quite a gap between what it actually does and what it's sold as doing.
Another peptide you might come across is Silverfree (also a fun name), and I have some affection for how it's put together. The intent behind it is broad, covering the entire pigment-producing pathway. All of which is aimed squarely at the pigment cell, and that's a perfectly reasonable place to aim, provided the cell is still there. The efficacy figures for it live in the supplier's literature rather than in a journal, and I'd genuinely like to see this one published properly. There's a real molecule here and a sensible idea behind it, and it deserves a study you can actually sit down and read.
The building blocks. Then there's a whole other family that skips the signalling entirely and just hands over the raw material. Melanin is built out of tyrosine, an amino acid, so the thinking goes that if you deliver more tyrosine into the follicle you should get more pigment coming out the other end. And I want to be fair here, that isn't a stupid idea at all. It's the same instinct as sending more flour to a bakery that isn't turning out enough bread.
But it walks straight into the thing we started with. If there's nobody left inside the bakery, the flour just piles up by the door. Raw material only helps you when the cells that turn it into pigment are still around, and in a follicle that has already gone white, they aren't. You'll usually find this class bundled with an antioxidant and a line about stem cells, which is doing the real work in the marketing, though rarely in the data.
The botanicals. Plants have the longest history here by far. Polygonum multiflorum, which you'll see sold as He Shou Wu or fo-ti, has been used for grey hair for centuries, and there's usually something behind a tradition that persists that long. What there isn't, yet, is a clinical trial of the plant on its own.
The one properly designed study tested a tonic combining that plant with two others. Nicely designed, randomised, double-blind, placebo-controlled on women which is a serious piece of work by the standards of this field. It found significantly fewer new grey hairs than placebo, which is pretty nice. However, both investigators and the women themselves found no change at all on how grey the women's hair actually looked [8]. I don't read that as a failure so much as an honest result, and honest results are rarer than they should be.
The supplements. Despite a very large supplement market, convincing published evidence in humans that an oral supplement reverses ordinary age-related greying remains remarkably thin.
All of this doesn’t mean greying is inevitable. I don't believe it is, and my team and I have been working around the clock trying to see how we can scientifically tackle it in new ways.
We do try to understand what the biology is telling us. First thing perhaps is how do we keep the stem cells alive, since they are the first to go. Also how do we keep the pigment cells you still have in an ideal working order, because presence isn't the same as vitality.
I want to send you out to the world with some tools and questions. When something claims to block grey hair, I'd want you to ask three things: (I) Which cell does it work on? (II) Can it physically reach that cell? and (III) Once it reaches the cell, what is the molecular mechanism of action (how does it work)?
Most solutions out there offer very few answers to these questions.
So there you have it. Three simple questions. Use them on everything grey related you come across, and please, do use them on us as well.
References
1. Panhard S, Lozano I, Loussouarn G. Graying of the human hair: a worldwide survey, revisiting the '50' rule of thumb. British Journal of Dermatology. 2012;167(4):865-873. doi:10.1111/j.1365-2133.2012.11095.x
2. Commo S, Gaillard O, Bernard BA. Human hair graying is linked to a specific depletion of hair follicle melanocytes affecting both the bulb and the outer root sheath. British Journal of Dermatology. 2004;150(3):435-443.
3. Nishimura EK, Granter SR, Fisher DE. Mechanisms of hair graying: incomplete melanocyte stem cell maintenance in the niche. Science. 2005;307(5710):720-724.
4. Osawa M, Egawa G, Mak SS, et al. Molecular characterization of melanocyte stem cells in their niche. Development. 2005;132(24):5589-5599. doi:10.1242/dev.02161
5. Ueno M, Aoto T, Mohri Y, Yokozeki H, Nishimura EK. Coupling of the radiosensitivity of melanocyte stem cells to their dormancy during the hair cycle. Pigment Cell & Melanoma Research. 2014;27(4):540-551. doi:10.1111/pcmr.12251
6. Botchkareva NV, Khlgatian M, Longley BJ, Botchkarev VA, Gilchrest BA. SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. The FASEB Journal. 2001;15(3):645-658.
7. Almeida Scalvino S, Chapelle A, Hajem N, et al. Efficacy of an agonist of α-MSH, the palmitoyl tetrapeptide-20, in hair pigmentation. International Journal of Cosmetic Science. 2018;40(5):516-524. doi:10.1111/ics.12494
8. Jo SJ, Shin H, Park YW, et al. Efficacy and safety of Pueraria lobata extract in gray hair prevention: a randomized, double-blind, placebo-controlled study. Annals of Dermatology. 2013;25(2):218-222. doi:10.5021/ad.2013.25.2.218
