Studying skin aging never gets old: The potential role of oxytocin

By Warren R. Heymann, MD
Oct. 14, 2020
Vol. 2, No. 41

Every day, dermatologists address patient concerns about their aging skin — whether they are presenting for medical, surgical, or cosmetic problems. Extrinsic factors such as ultraviolet light and smoking resulting in a leathery, coarsely wrinkled appearance are well recognized. Intrinsic, chronologic aging causing thin, dry, finely wrinkled skin and sagging is less well understood. All tissues undergo aging, in which a proportion of cells experience a type of age-related deterioration known as cellular senescence. In the skin, this affects epidermal keratinocytes, the dermis (in collagen, elastin, and extracellular matrix), and adipocytes. (1, 2) Unquestionably, both intrinsic and extrinsic factors may work in concert resulting in cutaneous aging.

According to Gruber et al: “Within the past five years technological advances like lineage tracing of cells in model organisms, intra-vital microscopy, nucleic acid sequencing at the single cell level, and high resolution mass spectrometry have allowed to study aging and senescence of individual skin cells within the tissue context, their signaling and communication, and to derive new hypotheses for experimental studies in vitro.” One of the major cells demonstrating senescence is the dermal fibroblast as manifested by aberrations of DNA and telomeric shortening. The secretome of senescent cells, the so-called senescence associated secretory phenotype (SASP) is a cocktail of immunomodulatory and proteolytic mediators (2), including IL-6, IL-8, chemokines, extracellular matrix-remodeling proteases, and growth factors. (3)

Faragher asserts that senescent fibroblasts demonstrate reduced collagen production accompanied by increased collagenase coupled with the antiproliferative and proinflammatory SASP cytokines. This has sparked an interest in developing senolytics — agents that can either destroy senescent cells or at least revert those cells to growth-competent phenotype. (4)

Oxytocin is a peptide hormone comprised of 9 amino acids that is synthesized in neurons of the supraoptic nucleus and paraventricular nucleus of the hypothalamus. These neurons project to the posterior pituitary, where oxytocin is released into the blood for delivery to the peripheral tissues as well as into the brain and is considered a neurohormone. Oxytocin acts through its receptor which is a class I G-protein-coupled receptor. Oxytocin facilitates birth, lactation, maternal behavior, neocortical growth, and maintenance of the cortical blood supply. Although oxytocin has major roles in parturition and lactation, its effects may be far-reaching. It has been demonstrated that oxytocin participates in social attachment and bonding, associative learning, memory, and stress responses. Oxytocin has shown potential in treating atherosclerosis by lowering fat mass and cytokine levels, improving glucose tolerance, lowering blood pressure, and relieving anxiety. Oxytocin is viewed as a promising treatment for obesity and type 2 diabetes. (5,6)

Cho et al investigated the mechanism of oxytocin in preventing cellular senescence in normal human dermal fibroblasts (NHDFs) isolated from the skin of female donors of different ages. NHDFs from young and old donors were exposed to conditioned medium from senescent or control NHDFs in the presence or absence of oxytocin for 3 days and were continuously subcultured for 12 days. Age-associated signs of senescence including decreased proliferation rate, elevated p16 and p21 levels, and positivity for senescence-associated β-galactosidase expression were then examined. The authors found that oxytocin suppressed SASP in NHDFs, with the effect depending on the age of the donor’s NHDFs. The inhibitory effects of oxytocin required signaling by oxytocin receptor-mediated extracellular signal-regulated kinase/Nrf2 (nuclear factor erythroid 2-related factor 2), a factor in antioxidant defense. Age-dependent antisenescence effects of OT are closely related to hypermethylation of the oxytocin receptor gene (OXTR), with increased DNA methylation of OXTR being associated with a reduction of gene expression in NHDFs derived from old donors. Their findings highlight a potential role of oxytocin in the prevention of skin aging, which could set the stage for novel anti-aging strategies. (3) It would be fascinating to repeat this study using NHDFs from men.

Approximately 10 years ago, in my mid-50s, I had the experience of looking into the mirror behind the bar at a wedding reception of my friend’s 30-year-old son, where I was among the young groomsmen. I hadn’t recognized how old I looked until that moment. Shortly thereafter, I was next to a renowned cosmetic surgeon in the speaker-ready section of the AAD meeting, where she was preparing a lecture on the aging face. I asked her politely what she would recommend. After scrutinizing my features, followed by a moment of silence, she exclaimed, “My goodness…I really don’t know where to begin!” My approach over the last decade has been remarkably cost effective and pain-free. I don’t look in the mirror very much. Maybe oxytocin will help — if not my skin, at least my mood regarding my appearance!

Point to Remember: Oxytocin may have cutaneous anti-aging effects and also promote overall health.

Our Experts’ Viewpoints

Jeffrey S. Dover, MD, FRCPC
Associate Professor of Clinical Dermatology, Yale University School of Medicine
Associate Professor of Dermatology, Brown Medical School

Understanding the cellular and molecular basis of aging will enhance our ability to develop better ways to slow the natural aging process. Cellular senescence, the transition of many different mitotic cell types to a permanently nondividing state accompanied by a profound change in phenotype, is now recognized as a primary cause of aging and ill health in mammals. Chronic inflammation is associated with normal and pathological aging. Senescent cells secrete a complex of proinflammatory factors referred to as the senescence-associated secretory phenotype (SASP), which can have detrimental effects on surrounding cells. SASP includes the release of interleukin (IL)-6 and IL-1, chemokines, extracellular matrix-remodeling proteases and growth factors.

The last time I gave oxytocin any thought was during my OB GYN rotation in medical school. All I remember from then was that oxytocin is a neuropeptide that is released into the circulation from the neural lobe of the pituitary gland and that it plays an essential role in parturition and lactation. It turns out that it not only has a role in reproductive and social behaviors — recent studies have shown that oxytocin is involved in cardiovascular regulation, maintenance of osteoblast-adipocyte balance, and muscle regeneration. Plasma oxytocin levels markedly decrease with age, especially in postmenopausal women. Oxytocin administration has been shown to reverse age-associated atherosclerosis, osteoporosis, sarcopenia, and fat mass gain.

Exposure to SASP components induces senescence in a paracrine fashion, consistent with the evolutionary role of senescence as a tumor-suppression mechanism. In this new study, oxytocin suppressed SASP-induced cellular senescence in normal human dermal fibroblasts (NHDFs), depending on the age of the NHDFs’ donor. Oxytocin essentially blocked the induction of paracrine senescence by the SASP in cell strains derived from young females by oxytocin-receptor-mediated ERK signaling.

While these results are exciting and may represent a new approach to aging, one concern is that by reversing SASP-induced cell senescence we may be interfering with tumor suppression. There is no such thing as a “free lunch.”

1. Cho SY, Kim AY, Kim J, Choi DH, et al. Impact of oxytocin on skin ageing. Br J Dermatol 2019; 181: e148.

2. Gruber F, Kremslehner C, Eckhart L, Tschachler E. Cell aging and cellular senescence in skin aging – recent advances in fibroblast as keratinocyte biology. Exp Gerontol 202; 130: 110780.

3. Cho SY, Kim AY, Kim J, Choi ED, et al. Oxytocin alleviates cellular senescence through oxytocin receptor-mediated extracellular signal regulated kinase/Nrf2 signalling. Br J Dermatol 2019; 181: 1216-1225.

4. Faragher RGA. Oxytosin as a novel antidegenerative? Br J Dermatol 2019; 121: 1122-1123.

5. Ito E, Shima R. Yoshioka T. A novel role of oxytocin: Oxytocin-induced well-being in humans. Biophys Physicobiol 2019; 16: 132-139.

6. Reiss AB, Glass DS, Lam E, Glass AD, et al. Oxytocin: Potential to mitigate cardiovascular risk. Peptides 2019; 117: 170089.

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