Clinical Trials Underway for New Skin Aging Targets

NEW YORK — Targeted at fundamental processes that control skin aging, several therapies are currently being tested for the promise of a regulatory-granted antiaging indication, according to an update on a potentially huge area of dermatology practice.

Across a broad array of intrinsic and extrinsic drivers of skin aging, molecular targets tested in early clinical studies promise both efficacy and acceptable safety, according to Helen He, MD, assistant professor of dermatology and director of Lasers and Cosmetic Surgery, Icahn School of Medicine at Mount Sinai, New York City.

Of the targets, inflammation might be the single most important one. It has a recurring role in driving and then preserving skin cell senescence, He said.

Aging Skin Is Largely an Inflammatory Process

“Chronic low-grade inflammation from decades of immune cell remodeling is now thought to be a major contributor,” He said in a presentation at the 27th Annual Winter Symposium — Advances in Medical and Surgical Dermatology (MSWS) 2024.

But once the process is initiated, senescent skin cells often acquire the senescence-associated secretory phenotype (SASP) that accelerates the inflammatory process by releasing cytokines, growth factors, proteases, and other immune modulators, according to He. This phenotype is implicated in cancer progression as well as wrinkle formation, so efforts to prevent the SASP transition are of great research interest.

Molecular studies of aging skin produce evidence of damaged DNA proteins, mitochondrial dysfunction, oxidative stress, downregulated collagen, and other processes that together and independently drive the adverse changes most closely associated with an aging appearance, He added.

These drivers of aging are not equally important across skin types and individuals, said He, explaining why skin aging therapies are likely to be individualized.

Among the best evidence of these differences is the slower relative rate of skin aging among Black persons and Asians relative to White persons, a phenomenon He said has been documented in published studies. 

However, the variability in the aging process can also be seen within skin types. Part of the effort to isolate molecular targets in preventing skin aging has been based on studies comparing gene expression of women with a skin appearance that is younger than their chronological age, according to He. These studies have generated insight into which processes independently drive skin aging.

The skin aging process also appears to evolve over time, according to He, who cited a 2018 study that evaluated gene expression among women from ages 20 to 74 years. In this study, which took biopsies from both sun-exposed and nonexposed skin, the study linked damage early in life to high relative concentrations of free radicals. Later in life, signs of aging were more closely linked to alterations in energy metabolism, followed by the development of senescent skin cells, and finally changes in the epidermal barrier.

Antiaging Strategies May Differ Over the Lifespan

“At each decade of life, the data suggested different targets for antiaging interventions,” He said.

Senolytics, a term coined to describe therapies for eliminating senescent cells, have been actively and avidly pursued for the skin at many research institutions. Examples of early work include the identification of quercetin, fisetin, and dasatinib. None of these ultimately gained a regulatory indication for the treatment of aging skin, but quercetin has been granted Generally Recognized As Safe status by the US Food and Drug Administration, permitting it to be marketed over the counter.

Most recently, the mammalian target of rapamycin inhibitor rapamycin has been shown to decrease markers of SASP and oxidative stress in the experimental setting. In a 2019 randomized clinical study with topical rapamycin, an improvement in skin appearance, including a reduction in wrinkles, was accompanied by a significant increase (P

Methyl estradiol propanoate (MAP), a topical estrogen analog, has shown promise for restoring collagen and improving the appearance of skin in postmenopausal women. Broken down in the systemic circulation if absorbed, MAP targets the beta-estrogen receptor, which is expressed in the skin but not the reproductive tract, which might be relevant to the safety of this drug, He reported.

A topical formulation of the senotherapeutic peptide, OS-01, which is already included in some over-the-counter products, was recently tested in a double-blind trial. In this trial, OS-01 was associated with a reduction in wrinkles and an improvement in skin texture and appearance. The benefits are attributed to a reduction in water loss and strengthening of the skin barrier.

Providing just a sample of initiatives to prevent or reverse the aging process in the skin, He said that progress can be traced to a more detailed understanding of the underlying process of skin aging.

Highly Targeted Agents Anticipated

Based on the studies of skin aging being conducted at her institution and others, “more targeted approaches are coming,” He predicted. 

Abigail K. Langton, PhD, senior lecturer at the Centre for Dermatology Research, The University of Manchester, Manchester, England, was the senior author of a 2023 overview in which a near doubling of worldwide expenditures for modifying aging skin was predicted by 2030 and was asked to comment on this research.

Focusing on topical agents that included both prescription therapies and cosmeceuticals, Langton said the explosion in interest comes from the intersection of clinical advances and patient demand.

“Recent advances in skin aging science, combined with growing consumer awareness, are fueling the development of innovative therapies,” Langton said. She is most excited about the opportunities to slow the aging process in the skin with topical agents.

“Topical treatments remain the preferred choice for skin rejuvenation as they act directly on the skin to address signs of aging effectively, offering precision and safety with minimal risk,” Langton said.

Consistent with the summary by He, Langton believes that the coming choices for prevention and rejuvenation of aging skin will be both more effective and more precise.

Nazli Karimi, MD, PhD, a lecturer in the Department of Physiology, Hacettepe University, Ankara, Turkey, an author of a more basic review of the physiology of aging skin, also published in 2023, further supported what she sees as important and fundamental progress in this area.

“The momentum in this field is undeniable,” said Karimi, who also was asked to comment. “Therapies that target cellular repair mechanisms, antioxidants, and senescence-modulating interventions hold great promise, not just for aesthetic improvements but for enhancing overall skin health and quality of life.”

Expressing optimism about the major advances she seems coming, Karimi added, “It’s inspiring to see how science is beginning to address not just the symptoms of aging skin but also its underlying processes, giving people the possibility of healthier skin as they age.”

He, Langton, and Karimi reported no potential conflicts of interest. 

Ted Bosworth is a medical journalist based in New York City.