Blood donation improves skin aging through the reduction of iron deposits and the increase of TGF-β1 in elderly skin

Highlights

• Blood donation can increased dermal thickness and collagen content to improve skin aging in old mice.

• Blood donation induced significant alterations in transcriptional and metabolic profiles in the skin of old mice.

• Pathways related to inflammation and collagen metabolism were dramatically changed in elderly skin after blood donation.

• Blood donation increased skin collagen content which is associated with increased expression of TGF-β1.

Abstract

Skin aging is characterized by a wide range of physiological and structural changes, including wrinkling, dyschromia, and roughness, as well as the reduction of dermal thickness and collagen content. Here, we showed that blood donation increased dermal thickness and collagen content and decreased the number of senescent cells in old mice. Transcriptomic and metabolomic studies revealed blood donation significantly altered aging-related pathways in the skin of old mice. Molecular genes analysis indicated blood donation decreased the expression of genes associated with inflammation such as Fols1, Cox-2, and IL-1β, and increased the expression of collagen-associated genes including TGF-β1, TGF-β2, and Col3a1. The improvement of skin aging by blood donation was associated with the reduction of iron deposits and the increase of TGF-β1 in elderly skin. Our results suggested that appropriate blood donation could promote collagen re-synthesis and improve skin aging.

Introduction

Skin aging is a physiological process commonly defined as changes in physiological function and structural integrity of the skin that occur during aging, which is generally classified as intrinsic aging and photoaging. Skin aging is also characterized by wrinkling, roughness, sagging, thinning, and loss of collagen and elastin fibers (Jenkins, 2002, Mohamed et al., 2014). Collagen (type I and III) is the main component of the skin extracellular matrix (ECM). The collagen levels in the skin are regulated by the interaction of synthesis and degradation. Collagen biosynthesis decreases, and matrix metalloproteinases (MMPs), responsible for the degradation of collagen, increases during aging. The balance of collagen synthesis and degradation is disrupted during aging, leading to reduction of skin collagen levels and skin aging (Fisher et al., 2009, Quan et al., 2010, Sarbacher and Halper, 2019). Oxidative stress is regarded as a primary cause of skin aging, functioning through generation of reactive oxygen species (ROS) (Fisher et al., 2002, Lephart, 2016, Rinnerthaler et al., 2015). Oxidative stress induced by ultraviolet (UV) radiation and H₂O₂ results in upregulation of MMPs (MMP-1 and MMP-9), thus increasing collagen degradation to promote skin aging (Kim et al., 2018, Lee et al., 2018, Pittayapruek et al., 2016).

Iron was reported to accumulate in various organs including skin with age, and excess iron can induce oxidative stress through the generation of ROS by Fenton reaction (Cook and Yu, 1998, Massie et al., 1983). To avoid the toxicity of free iron, iron is mostly stored as ferritin in mammals. Nevertheless, some stressors like UV radiation, can release iron from ferritin, thus leading to ROS generation (Pourzand et al., 1999). And it's revealed that sun-exposed bodysites showed significantly higher iron content compared with non-exposed bodysites in humans. Iron is also involved in UV radiation-induced upregulation of MMP-1 and MMP-3 through catalyzing production of ROS (Brenneisen et al., 1998). Iron chelators treatment suppresses UV radiation-induced upregulation of MMPs and delays skin photodamage caused by UV radiation (Bissett et al., 1991, Brenneisen et al., 1998). Females can excrete excess iron by menstrual cycle, however, levels of iron and ferritin increase significantly in postmenopausal skin, possibly accelerating skin aging (Pelle et al., 2013). Indeed, skin collagen content and skin thickness decrease by 1–2 % per year in postmenopausal women (Brincat et al., 1987). Therefore, iron accumulation in the skin may be involved in the process of skin aging.

Although blood donation could lead to occasional side effects, including vasovagal reactions, needle injury, and iron deficiency (Crocco et al., 2009, Ji et al., 2018), and may slightly contribute to a higher risk of coronary heart disease (Bani-Ahmad et al., 2017), numerous studies have shown there are many health benefits of blood donation. Donors with regular blood donation exhibited reduced blood pressure, improved blood lipid profiles, and decreased risk of cardiovascular diseases (Adias et al., 2012, Kamhieh‐Milz et al., 2016, van den Hurk et al., 2017). Blood donation is an effective way to reduce iron stores, and about 200 mg of iron can be removed from the body by each whole blood donation (Cook et al., 2003, Kiss, 2015). As excess iron can catalyze the production of ROS, thus inducing oxidative stress to promote skin aging. Therefore, blood donation may improve skin aging through the reduction in skin iron.

In the present study, we found that blood donation reduces the signs of skin aging. Transcriptomic and metabolomic studies reveal that aging-related pathways were significantly changed in the skin of mice after blood donation. Blood donation leads to increased collagen synthesis and decreased collagen degradation, which are associated with the reduction of iron deposits in elderly skin. Our results indicate that appropriate blood donation has potential to be an anti-skin-aging strategy.