Trifluoroacetyl-Tripeptide-2 to Target Senescence for Anti-aging Benefits

Skin aging is characterized by progressive changes in the regulation of cellular processes and miscommunication between cells and their immediate environment, the extracellular matrix (ECM). These malfunctions, which may result from physiological and/or environmental events, are most notably characterized by the increased activities of metalloproteinases (MMPs) and the reduced synthesis of their endogenous inhibitors, i.e., tissue MMP inhibitors (TIMPs),1–5 as well as the reduced biosynthesis of major ECM proteins.6 As a result, the extracellular matrix is no longer renewed and the skin shows the effects of aging.

In relation, levels of the cellular components involved in interactions between cells and their matrices are altered with skin aging and are responsible for less efficient interactions between cutaneous cells and the ECM. In addition, the regulation of many glyco-proteins changes with age, which impacts cellular functions. For example, syndecans such as transmembrane heparin sulfate proteoglycans participate in focal adhesion formation7 and play an important role in skin homeostasis by acting as co-receptors for growth factors.8 However, with age, syndecan expression decreases in keratinocytes9 and skin.10

Aside from these modifications of ECM macromolecules and molecules implicated in cell matrix interactions, age-related changes in cells themselves also must be considered. Recent work has shown that increased progerin synthesis, in conjunction with the shortening of telomeres, leads to cellular senescence in normal human fibroblasts.11 Thus, targeting such cellular impairment provides an interesting development path for anti-aging compounds. Many key roles of endogenous tripeptides such as glutathione, thyrotropin-releasing hormones and other tripeptides12 have been identified, and since the body uses tripeptides for cell communication, these compounds have been proposed as anti-aging agents to boost healthy skin functions and reverse skin damage mostly by enhancing fibroblastic collagen production.13 However, while most of the published data shows that these compounds may increase collagen synthesis, little is known about other properties such as their role in cellular aging.

The present study therefore looks at the broader anti-aging properties of tripeptides by specifically examining the effects of trifluoroacetyl-tripeptide-2a (TT2) on ECM protection, on the synthesis of proteoglycans in cell-matrix interactions, and on the synthesis of progerin, a protein recently identified as a co-inducer of cellular senescence. This ingredient was chosen as the best candidate based on the in vitro screening of a library of materials built from peptides having known physiological activity. In vitro studies were then conducted to assess the ability of this tripeptide to inhibit MMP-1, MMP-3, MMP-9 and elastase, to stimulate syndecan-1 expression in human keratinocytes, and to reduce progerin synthesis in mature human normal fibroblasts. Two in vivo studies were conducted to confirm in vitro findings using cutometry and fringe projection profilometry techniques.

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