A novel anti-aging concept could help make skin healthier and more youthful looking. It involves targeting rogue skin cells that stop dividing but refuse to die — a population of zombie-like cells, known as senescent cells, that Jaime Emmetsberger and her colleagues at The Estée Lauder Companies (ELC) are manipulating for cosmetic gain. Emmetsberger explains how modulating the senescent state could hold the key to skin rejuvenation.
Skin, as it ages, gets exposed to many internal stressors and environmental insults, all of which can induce cellular damage. In response, cells are faced with a choice of several different molecular paths, one of which involves permanent cell-cycle arrest — that’s senescence. The cells basically stop dividing and they start producing molecules that disrupt the function of neighboring cells and the surrounding tissues, leading to a decrease in the natural self-regenerative potential of the skin and a reduction in the collagen and elastin fibers that are associated with the skin’s elasticity and firmness.
Why focus so heavily on cellular senescence at ELC?
Senescence is known to be a major driver of skin aging, but there’s a lot about the process that we still don’t understand. Although we have studied cellular senescence for some time now, we formalized the senescence project about a year ago. Together with a multidisciplinary team of scientists spanning different groups across ELC, we are now looking for ways to prevent cells from becoming senescent as well as strategies for reducing the damaging inflammatory effects of senescent cells.
With so many different cell types and compartments in the skin, how do you even pinpoint these zombie-like cells, let alone begin to selectively manipulate them?
I have to say it is quite challenging because senescence is very complex. And what makes it all the more challenging is that each of those different cell types, once they become senescent, have different traits and characteristics. There really is no single universal biomarker for determining senescence. So we take a multi-dimensional approach to our analyses, using gene reporter systems as well as assessing several markers involved in senescence — including levels of beta-galactosidase [an enzyme with elevated activity in senescence cells], alterations in the expression of cell cycle regulators and proliferation markers, changes in cellular morphology and structure, plus characterizations of secretory phenotypes.
How do you study skin senescence in the lab?
We use a variety of cell culture systems, reconstructed skin models and surgical discard tissues from different age groups to study senescence in the skin. And we take advantage of different induction methods — radiation, say, or a DNA-damaging agent — to understand the effect of senescence triggers on different cell types. We want to know, for example, does a keratinocyte undergoing replicative senescence secrete a similar type of inflammatory molecule as a fibroblast undergoing senescence induced by ultraviolet radiation? By looking for similarities in response to these triggers, we hope to find approaches that address the various contributions to senescence in different skin cell types.
In August, The Estée Lauder Companies R&D announced a new joint initiative with Atropos Therapeutics to discover molecules that modulate senescence. Tell me about the partnership.
We thought it would be a very powerful collaboration because Atropos has unique model systems, artificial intelligence platforms and experience with senescent cells, all of which we felt could help us screen our large libraries of natural products for molecules that can induce seno-suppression — that is, spur cells not to choose that path of senescence but instead driving them into the path of programmed cell death. So, this is less about altering the senescent state and more of a preventative mechanism. Essentially, we’re trying to tell these pre-senescent cells to go down a different route. We are also partnering with other anti-aging and senescence experts, leveraging their expertise and technical approaches, to expand on our research on senescence induction, characterization and modulation.
How are these insights informing the development of new anti aging skin care technologies?
The goal for the senescence project is to help address the visible signs of aging. We are utilizing a multi-pronged approach including pathway redirection through senosuppression, targeting the effects of the senescence associated secretory phenotype, as well as, preventing senescence induction by protecting from insults and enhancing cellular damage repair processes. We’re going to incorporate what we learn about senescenceinduction pathways and the signaling cascades wrought by senescence-associated tissue declines to aid in our designs of new skin care technologies. We’re currently screening a lot of our materials to determine if they have senescence modulating effects. Once we have that understanding and we find some key targets, we’re going to zero in on those ingredients that can best address the negative effects of senescence.