Genetic integrity for a rejuvenated skin look

Being an essential part of this vital code, deoxyribonucleic acid (DNA) contains informational elements encoding the genetic instructions utilised in the development and functioning of almost all living organisms. It consists of two long chains of nucleotides twisted into a double helix and joined by hydrogen bonds between the complementary bases adenine (A) and thymine (T) or cytosine (C) and guanine (G). The sequence of nucleotides determines the hereditary features of each individual and the maintenance of its integrity is essential for proper functioning and survival. Unfortunately, keeping the genetic code free from mutations is a particularly daunting task as, contrary to being inert, DNA is a chemical entity subject to assaults and errors induced by different factors.1,2 Apart from the intrinsic biochemical instability of DNA, its strands suffer the constant influence of endogenous and exogenous genotoxic agents (oxidative stress, environmental conditions...) and mistakes during their replication.1,2 In fact, it has been estimated that an individual cell can suffer up to one million DNA changes per day.3 Although genetic mutations are part of life and sometimes imply evolutionary benefits, some of them can be deeply detrimental and generate alterations or even cellular death, with the consequent effects at a macroscopic level. Thus, in order to allow time for repair before any DNA error is propagated to daughter cells, cell cycle checkpoints are induced to arrest the cellular cycle when the damage is detected.4 The DNA damage response also leads to the induction of transcriptional programs, enhancement of DNA-repair pathways and initiation of cellular death (apoptosis) when the level of injury is severe.5 Failing to repair such DNA lesions may result in severe damages involved in a variety of genetically inherited disorders and ageing in humans.2,5,6 As any other organ, the skin suffers the consequences which imply a negative effect on its functionality, properties and its overall appearance, looking noticeably older. DNA damage and instability can be caused by a range of sources, including environmental and external reasons like UV exposure, pollution and chemicals, but also inner factors like subproducts of certain processes and reactions (oxidation and radical species) or the DNA replication process itself. Oxidative agents from external or internal sources (cellular metabolism for example) like reactive oxygen species can cause the oxidation of specific DNA bases (the most common damage) and deamination or the total removal of individual bases (AP sites).2,6,7 Heat or radiation exposure, for example, can cause breaks in DNA strands while UV rays can induce the creation of pyrimidine dimmers (distorting the natural structure of the DNA), cyclobutane pyrimidine dimers (CPDs) being one of the most widespread.1–8 Besides, pollution contains polycyclic aromatic hydrocarbons (PAHs) that are potent damaging atmospheric elements from which benzo(a) pyrene diol epoxide (BPDE) is a common marker. Unexpectedly, diet is another relevant factor in genetic stability. Deficiencies of certain vitamins including B12, B6, C, E, folate or niacin, or of iron or zinc appear to mimic radiation in damaging DNA by causing strand breaks, oxidative lesions or both.9,10 Finally, the very same process of DNA replication during cellular division is prone to error, which can occur after DNA is separated into the two strands to be faithfully copied by the DNA polymerase to create two double-stranded DNA molecules.1

Natural DNA repairing mechanisms

DNA-repair processes exist in both prokaryotic and eukaryotic organisms, and many of the involved agents have been highly conserved throughout evolution. Cellular cycle needs to be arrested so that such repair mechanisms have time to amend the damage and ensure that the necessary temporal structures for such repair do not cause any additional error.5 These checkpoint pathways are surveillance mechanisms that monitor DNA structure and are involved in the activation of the DNA-repair process and transcriptional programmes, the movement of DNA-repair proteins to sites of DNA damage and the induction of cellular death in specific cases.5 Characterised by a conserved DNAbinding domain named forkhead box (FOX), FOX transcription factors are a family of essential proteins implicated in regulating the expression of genes involved in vital functions in many species ranging from yeast to humans.11,12 Based on phylogenetic analysis, forkhead proteins are classified into subfamilies differentiated by a final letter (FOXA-FOXR). Concretely, the FOXO subfamily controls the genes connected with cellular metabolism, differentiation, renewal, repair, apoptosis, proliferation, longevity and general ageing in many organisms going from nematodes (roundworms and others) and cnidarians (Hydra genus) to mammals, comprising humans.13–17 For example, the Hydra genus has long attracted attention from natural scientists due to its unlimited lifespan (thanks to the indefinite self-renewal capacity of its stem cells).17 The FOXO group is regulated by a pathway where insulin, phosphatidylinositol- 3-kinase (PI3K) and protein kinase B, also called Akt, are crucial.11,12,14,18 The first evidence of such control was found studying a developmental arrest phenotype called Dauer in the Caenorhabditis elegans worm, which is associated with reduced metabolic activity, increased resistance to oxidative stress and expanded lifespan.11–15,19 This nematode has a rapid life cycle and its pattern of senescence is vastly known, which facilitates its study.13 Genetic analysis of this nematode proved that DAF-16 (FOXO factor) promotes the entry into the Dauer phase in response to physical or environmental stress.11,12,14,19 To counteract it, an insulin receptor-like protein (DAF-2) inhibits the transcriptional activity of DAF-16 that leads to the Dauer stage through the activation of PI3K and Akt.11,14,19 This basic molecular insulin-signalling pathway is conserved trough evolution, indicating its relevance in longevity in multiple organisms.12,15 In fact, insulin regulating cellular arrest implies that the more insulin, the less cellular arrest and damage repair. Separately from this main pathway, there is an identified parallel mechanism that seems to also control the Dauer phase and that becomes activated by growth factors, like TGF-.14,18 The FOXO factors detailed in C. elegans have homologues with the same activity in other organisms. The mammalian homologue of DAF-16 includes four FOXO elements: FOXO1, FOXO3 (or FOXO3a), FOXO4 and FOXO6, FOXO3a being a key factor in humans.12,15,16