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Senescent Cell Clearance and a Focus on Delaying Skin Aging

Skin aging is a fixation in the broader community beyond the sciences, perhaps the more so because there is no effective treatment to slow or turn back skin aging. Life-long exercise and calorie restriction are the only thing that works. When looking at what you can go out and buy, all that does exist are a few marginal cosmetic approaches that don't address the actual underlying processes, and beyond that a very large number of people lying through their teeth about what their products are capable of achieving. An enormous amount of money changes hands on the basis of those lies, enough to sustain sizable industries. The degree to which people know they are being taken and are engaged in purchasing "anti-aging" products for reasons other than believing it will do any good is an open question. Still, this is a great example of the way in which outright fraud can become both respectable and sizable enough to solidify a place in society, which in turn is one of the many reasons why we should question everything around us rather than taking any it for granted. Change is coming in this case, however, in the form of therapies that do in fact address the underlying root causes of skin aging, and will be capable of actually, measurably, undeniably rejuvenating old skin.

If we look at the root causes of aging, assembled from the gathered evidence of dozens of fields of research and expressed as the SENS research proposals, those most relevant to the aging of skin appear to be (a) declining stem cell function, (b) the formation of persistent cross-links in the extracellular matrix, and (c) growth in the number of long-lasting senescent cells. However, no-one today can tell you which of those is most important, nor the relative levels of importance. The only practical way to find out is to fix one of those problems and see what happens. They are all fairly independent of one another, and will be addressed by entirely different research groups and sections of the research and development communities. If pushed for an educated guess, I'd say that we'd have heard by now if it was the case that stem cell infusions produced noticeable differences in skin in older individuals, so beyond wound healing this seems likely to be a smaller effect than the other two. As for the ordering of those other two, I really have no idea and no intuition. One could argue coherently for either: the extracellular matrix is the basis for skin elasticity, and cross-links definitively affect that elasticity, but senescent cells cause a very wide range of harms, and are thought to exist in aged skin in sizable numbers.

Cells become senescent in response to internal damage or a toxic environment, among other reasons. This shift in state removes them from the cycle of cell division, and it is thought that this is primarily an evolved defense against cancer, blocking the most vulnerable cells from running amok should they suffer just the wrong combination of mutational damage. Most senescent cells destroy themselves via programmed cell death mechanisms, or immune cells are drawn to the secreted signals of senescent cells and dismantle them. Some senescent cells linger indefinitely, however, and over a lifetime substantial fractions of many tissues become composed of cells in this state. A study some years back found as many as 20% of the cells in aged baboon skin showed signs of senescence, for example. These lingering cells generate a mix of signals called the senescence-associated secretory phenotype, which boosts inflammation, can harm the surrounding tissue structures, and make nearby cells more likely to become senescent themselves. In turn higher levels of chronic inflammation contribute to the progression of all of the common pathologies of aging.

The present state of ignorance on the relevance of senescent cells in skin aging won't last much past the next two years. Two companies are presently working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology. In the former case, the technology has been demonstrated in rats. I have to imagine that for both companies, somewhere on the to-do list is the simple experiment in which one administers the treatment to aged animals and then measures the effects on skin elasticity and other physical measures impacted with age. That would be well within the capabilities of the Major Mouse Testing Project as well, using the recently discovered senolytic drug combinations if nothing else. If an approach can clear even a quarter of senescent cells in skin, that should be enough to draw conclusions on the impact to skin function. Beyond the knowledge gained, I can think of little better bait for publicity or potential funding from the big names in cosmetic science.

In the open access review linked below, the authors cover the approaches of destroying or altering the biochemistry of senescent cells as a class of approaches that could be used to delay skin aging. These researchers are associated with some of the existing groups working on the harmful biochemistry of senescent cells, as well possible methods to remove those cells or alter that biochemistry, such as the Buck Institute, and so they scrupulously avoid use of the word "rejuvenation." Removal of senescent cells is absolutely a very narrow form of rejuvenation, however. The presence of senescent cells is one of the defining features of old tissue, and they contribute to many of the processes of degenerative aging: inflammation, remodeling of surrounding tissues, failing tissue function, and so forth. Remove those cells and it is not unfair to say that the tissue in question is now closer in character to young tissue - a degree of rejuvenation has occurred, in other words. Of course that tissue still has amyloids, cross-links, failing stem cell populations, cells overtaken by damaged mitochondria, and so forth, but that is why we need a toolkit of various rejuvenation therapies, not just one tool.

Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review

Cellular senescence is a tumor-suppressive mechanism wherein cells are permanently growth arrested. Cells are induced to senescence by a wide variety of cellular perturbations, including nuclear DNA damage and mitochondrial dysfunction. Senescent cells are characterized by the secretion of several proinflammatory factors, a phenomenon called senescence-associated secretory phenotype (SASP). The accumulation of senescent cells with age is thought to contribute to impaired tissue homeostasis and to different age-related diseases. Lack of cell proliferation in senescent cells hampers the ability of tissues to regenerate after chronic and persistent injury, resulting in tissue damage. The proinflammatory and tissue-remodeling activities of the SASP also create chronic inflammation and alter tissue structure, which are the two main causes of age-related pathology. One fascinating hypothesis is that senescent cells might contribute in a cell and non-cell autonomous fashion to skin aging. Skin aging is associated with several pathologies, including lower protection from pathogens, increased irritation, loss of insulation, delayed wound healing and susceptibility to cancer, among others. Here, we summarize the evidence of the presence of senescent cells in the skin, and the potential for pharmaceutical interventions that eliminate the negative effects of senescent cells as methods to delay skin aging.

The impact of senescent cells on animal pathology was directly demonstrated when eliminating senescent cells through a suicide gene in a premature aging mouse model reduced selected age-related pathologies such as sarcopenia, cataracts, and loss of subdermal adipose tissue. Interfering with senescent cells may be beneficial for the overall health of the animal, and the development of specific interventions that target senescent cells may serve as a therapy to delay aging, including skin pathologies. This strategy can be achieved using three different approaches: (1) selective induction of cell death; (2) improvement of the immune system, and (3) inhibition of the SASP. The decline in immune function with age is consistent with the high number of senescent cells at old age, supporting the idea that the immune system may limit the number of senescent cells through clearance of these cells. Hence, it may be worth developing a strategy that boosts the immune cells capable of specifically eliminating senescent cells.

Removal of senescent cells and reducing the SASP are being considered as therapeutic strategies to delay the onset of age-related pathologies. Several drugs have already been identified that selectively target senescent cells. Some of them might have toxic effects when administered systemically for a long period of time: for example, ABT263 can cause thrombocytopenia in patients treated with an oral form of the compound. However, the toxicity might be highly reduced by developing drugs for topical treatment, an approach that would be suitable for skin interventions. The contribution of senescent cells to skin function is complex because they may be both beneficial and detrimental depending on the context; it is still unclear whether senolytic drugs will delay skin aging. Senescent cells are important for proper wound healing through their secretion of the SASP factor PDGF-AA and through their capacity to limit fibrosis, while chronic induction of cellular senescence through mitochondrial dysfunction may contribute to stem cell loss with age. Hence, proper testing of dosage and timing must be investigated to determine if these drugs would indeed reduce the negative impact on skin aging. Nonetheless, the possibility of selectively targeting senescent cells through pharmacological interventions posits a potential new solution to the functional decline associated with skin aging.

Comments

You argue somehow that there is a huge anti-aging industry with false claims: The cosmetic industry, that attracts a lot of money while "serious" anti-aging scientists are not well financed. It could be argued as well that a proven way to finance "serious" anti-aging is to make products for the cosmetic industry.

This is similar to what Qualcomm did, Andrew Viterbi did real science, if you do no know him, you will be surprised by the impact of his science on our modern technology, yet the company he founded makes billions Dollars each year.

Now the next question is how the "serious" anti-aging scientists can convince the cosmetic industry, that it can found value in this kind of research. The key is probably to be able to show consumers they can get results after days, not years. This means that the grand goal of "serious" anti-aging scientists, to attack aging as a single illness as in Sense, should be broken in numerous attainable goals with limited resources. There are some signs this is already ongoing.

We are in a period of free money, there are investors everywhere, but it won't last long, people should hurry to make presentations to VC.

Jean-Pierre

Posted by: Jean-Pierre Le Rouzic at April 7th, 2016 1:54 AM

I speculated previously that removing both senescent cells and glucosepane cross links might make people look younger, but Michael Rae pointed out that this may not be the case:

"@Jim: You've asked or made suggestions to that effect before, and I thought I'd addressed them - but a Google search of the FA! site suggests I must've been thinking of some other correspondent. I apologize if it seemed like I've been ignoring the question.

As Seth suggests, as with most conditions related to aging, there is no single form of aging damage responsible for the various changes that happen in skin as we age, and it's actually far from clear to me that glucosepane is the most important. The elastin protein that gives skin its elasticity becomes crosslinked and snaps, reducing its youthful ability to snap back into place when pulled, but there's a lot more to the visible and functional aging of the skin than loss of elasticity. The anchored system that supports the collagen-producing fibroblast cells degrades, leading fibroblasts to collapse and stop making new protein; the skin accumulates senescent cells, leading to SASP that spews out a range of inflammatory signaling molecules and proteolytic enzymes that degrade the supportive structures in the skin; the skin accumulates years of oxidative damage, leading to mutations; in many people, the dark pigment melanin that normally darkens our skin to give us an even tan clumps together into concentrated deposits known as "age spots" (often mistakenly attributed to lipofuscin in the anti-aging community, propagating an error first introduced by Pearson and Shaw) (and note that age sposts are both functionally one of the least important kinds of damage in aging skin and yet amongst the most visibly obvious such damage; ongoing rising oxidative stress distorts intracellular signaling, leading to aberrant keratinocyte function; etc. Like Seth, I don't have the chops to quantify all of that - and I doubt his dermatologist has them, either."

Also this SENS5 video seems to indicate that there is a lot more going on in extra cellular matrix remodelling than just senescent cells and glucospane:

https://www.youtube.com/watch?v=0id4WRNt2oI

Posted by: Jim at April 7th, 2016 5:42 AM

Yes as MMTP is testing D&Q it might effect skin as you suggest. We have two main objectives:

1: lifespan effects of Senolytics. Does it increase or reduce max lifespan?
2: What effects do Senolytics have on stem cells?

What we learn from this first phase very much dictates where our follow up Senolytics + Stem cells goes.

Posted by: Steve Hill at April 8th, 2016 7:57 AM

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