Gilad Lehmann and Nason Schooler at Understanding Aging: Biomedical and Bioengineering Approaches
Lipofuscin accumulates in the lysosomes of aging post-mitotic cells and progenitor cells, interfering with autophagy. Thus it has been proposed that the removal of this indigestible aging pigment may be a highly effective rejuvenation therapy. It has been known for over forty years that pulsed unfocused lasers can selectively destroy pigmented structures without harming the surrounding tissue. Aging researcher Nason Schooler offered his perspective on the potential benefits of the lipofuscin removal approach at the Understanding Aging scientific conference hosted by the Methuselah Foundation.
The following transcript of Nason Schooler’s presentation at the Methuselah Foundation conference entitled ”Understanding Aging: Biomedical and Bioengineering Approaches” has been corrected and approved by the speaker. Video is also available.
Unfocused Pulsed Lasers Selectively Destroy Lipofuscin
We have a simpler view of this problem. It is overly simplistic, but it’s compelling. The basic idea comes from Ulf Brunk in Sweden. Brunk and Terman have written a number of papers, and continue to do so, outlining this mitochondrial-lysosomal axis theory of aging.
It is very simple. The idea is lipofuscin is this aggregate of oxidized lipids and proteins that accumulates in autophagosomes or lysosomes. Lipofuscin itself we think is the problem. We think lipofuscin is sufficient to knock down autophagy as it accumulates. Eventually you get cells that are loaded with lipofuscin and the lysosomes cannot do their job of rejuvenating the cell. We think that many aspects of aging are the result. If that is true, this is where the whole idea of “removing the garbage” comes in. We think the garbage itself is the problem, and if we can get rid of it we can make some serious inroads into conquering aging.
My original hypothesis was that somehow, maybe we could use electromagnetic radiation to combat these pigments, whether their accumulation or whatnot. I really got onto this idea of specifically destroying this garbage, the lipofuscin (I’ll use lipofuscin as kind of a blanket term). The idea was, is there some way that we can use light, or infrared or radiation, any kind of electromagnetic radiation to get rid of these pigments? So, the first thing I do of course (this was like, last Fall), I start searching the literature like a madman and come across some fairly conventional things like photobleaching, photodynamic therapy, photobiomodulation… some of them were interesting and could be kind of useful, but not what I was really looking for.
Finally, I discovered this paper. It was written in 1983 and appeared in Science. It is by Rox Anderson, who is like a dermatology guru at Harvard Medical School still, I believe. This paper outlined a theory on selective photothermolysis. The idea of selective photothermolysis is also quite simple.
If you have a target in the cell or in tissue that is pigmented and dense, light will selectively interact with that target. In this paper, they used melanin as their target of choice, since melanin is everywhere. They’re dermatologists, so they were interested in melanin in the skin. They showed very elegantly that with a short-pulsed laser at the appropriate frequency, they could selectively destroy melanin. Here is a picure (a blow-up) of a melanosome, and here is the cell – it’s largely intact still, but w e get exquisite destruction. This was a coherent globule of stuff, and it’s been blown inside out; and when I saw this, I was like, “Wow, we are so close.” What if you could do this for lipofuscin? Come to find out, as I dug deeper, it’s already being done.
We have heard about macular degeneration in particular a few different times. There is a treatment called selective retinal therapy that is at the bleeding edge of ophthalmology research. They use lasers that are pulsed or scanned, so you get a short exposure, to selectively destroy RPE cells that are clogged with lipofuscin and excess melanin. It works wonderfully. Basically the cells that are defective in their recycling capability are knocked out, the RPE is repopulated with cells that do not have this problem, and right there – that’s a microcosm of what we think is the aging process organism-wide. If you could do the same thing for the entire organism, there you go. Dermatology is another great example. Sorry, I don’t have a lot of time to get into it.
Here is our concept. Take a pulsed laser, hit a large portion of tissue with it, and only the cells that contain lots of lipofuscin will be affected; and if we choose our parameters right, only the lipofuscin granules themselves will be affected, and we could leave things like neurons and cardiac myocytes that we don’t want to get rid of – we could leave them intact. So that’s the general idea, and selective absorption means selective destruction. This has been shown in a number of papers – if you want to search the literature on SRT, and also the dermatology literature talking about removing age spots and tattoos and all kinds of things.
So if we want to use this as a therapy, what are the things that could go wrong? What are the obstacles? One of them, of course, is if lipofuscin is not the key problem—it is a downstream issue; and if that’s the case this will be very illuminating, because we’ll find out. Another problem is that maybe we’ll kill cells; and in the current treatments that is what happens. With the more basic, cruder parameters they’re using, you do end up killing cells – and they want to. So it’s kind of an anecdote in a lot of these papers, that you can destroy a melanosome, for example, without destroying the melanocyte; because they really want to destroy the whole cell in a lot of these cases. But the key issue is the actual pulse—the length and the shape of the pulse, and if you choose those things correctly you can get exquisite confinement of damage, which has been shown in some of these papers. And of course the shape of the pulse is also important – lots of parameters to play with.
The final issue is, maybe the lasers won’t penetrate deeply enough. It’s just a laser, right? How can you get it to go clear through your skin? Well actually there is this kind of “optical window” around the near-infrared range, say 800 nanometers, where you can get penetration of 2~3 centimeters, and still have effective levels of your energy to do what you want to do, and this has also been shown. So as an engineer, I would say hey, give me two or three centimeters – that’s an engineering problem, but we can probably reach just about everything there; and of course you can optimize that by choosing your frequency and things like that.
So here is a little bit about our research. If I have some time, I guess I can go over it a little bit. We are using the worm C. elegans as our model. We happen to have a green laser right now, which is probably not the best frequency for the worms. Hopefully it won’t matter – they absorb well. The main thing we’ve found so far, I mean we’ve just got the lab set up and going, but what we have found that if you take younger worms that don’t have much of this lipofuscin in them – they’re pigmented, but not much lipofuscin – you don’t see much destruction. In fact I can’t blow a worm up, even with the maximum dose that we can muster with a lens and with this laser.
However, you try the same thing on a twelve day-old worm that has accumulated lipofuscin, and the worm will blow up with one tenth of the energy. So therefore that tells us we’re actually reaching the lipofuscin. You don’t have to have melanin in the cell with it to help it out; and that’s a perfect proof of concept. We have to move on and find sub-lethal doses, use this in a lifespan experiment, maybe get some electron micrographs and see what is going on. There is a lot that has to be done.
In conclusion, we can get ultra-fine selectivity with ultra-short pulses – and that’s crucial to keeping cells alive, and not killing cells, that we don’t want to kill. This is a rich field with lots of things to look into. I have kind of a list of things here. There’s all kinds of different models we need to try this in. In a nutshell, this is way more than me, a lowly graduate student can possibly do in a sane amount of time. That is the main reason I am talking at this point—I want to get more interest in this, and get some more people grinding away at this.
So I would just like to leave you with a couple key points here. Initial results in our lab have shown that lasers can selectively affect the lipofuscin, so we are on the right track. It has been proven to penetrate several centimeters in soft tissue, at least. This is useful as a treatment in us, in mammals, in mice, things like that—very encouraging. Also it’s proven to selectively destroy pigments, leaving the rest of the cells and tissues intact. I say “proven” because if you look at the literature, especially in ophthalmology, the dermatology literature, and it is definitely there. To me, I think this has very exciting potential to postpone aging.