AGEING AND EPIGENETIC CLOCK

The analysis of global demographic data suggested that there is a limit to the human lifespan. However, human life expectancy has increased steadily over the past century in most countries. What we do know is that aging doesn’t just depend on our genes. There is nothing determinative in our genome that programs us to age. It is done by the so-called epigenetics.

Epigenetics is the field of biology that studies the influence of the environment and lifestyle on the expression of genes without changing their DNA sequence and has recently attracted an increasing interest in cosmetics. We live between 30% and 40% longer than 100 years ago, but our genome remains the same.

Recent studies based on animal models have shown that alterations in DNA methylation, histone post- translational modification, chromatin organization as well as remodeling, influence healthspan and lifespan. The most abundant type of DNA methylation in eukaryotes is cytosine 5-methylation, which is regulated by DNA methyltransferases (DNMTs). It has been recently shown that DNA methylation levels and, in particular, the pattern of 5-methylcytosine are altered during ageing. This DNA methylation status can be used to predict chronological age in a variety of tissues, such as blood, kidney and liver and has therefore been termed the ‘epigenetic clock’.

The treatment and prevention of epidermal senescence are now being explored. Potential targets include DNA methyltransferases (DNMTs), hyper- or hypomethylated DNA, histone modifications, novel epigenetic modifiers, and miRNAs. It is believed that reversing these modifications is an attractive method for rejuvenating the states of aged skin.

Potential rejuvenation strategies have been described. Metabolism and epigenetics are intrinsically linked and work together to influence the ageing process. The effects of caloric restriction (CR) on healthspan and lifespan result, at least in part, from the prevention of ageing-associated global changes in DNA methylation, histone modification and chromatin remodeling. The lifespan extension effect of CR may be partly attributable to reprogramming the circadian clock.

Nuclear reprogramming seems to be capable of resetting the ageing clock. Somatic cells are induced to regain pluripotency by a variety of reprogramming strategies, the most common of which involve overexpression of the four Yamanaka factors OCT4, SOX2, KLF4 and MYC (collectively known as OSKM). OSKM-reprogrammed mouse nuclei can give rise to viable embryos that can develop into fertile adults that do not exhibit premature ageing, suggesting that the chronological age of donor nuclei has been reset. In 2016, laboratory mice were rejuvenated thanks to cell reprogramming. The advances of Professor Shinya Yamanaka, 2012 Nobel Prize winner for the discovery of reprogramming, were applied, showing that with the addition of (Yamanaka factors) cells could return to a previous state with the properties of embryonic stem cells. The idea is “it is not about living longer, but about having a better quality of life, especially in the last years of life”. Given that most diseases are associated with aging (only 1% have a genetic cause), trying to rejuvenate a cell would indirectly mean that this disease takes more years to appear.

Drugs, compounds and supplements with antiaging properties that extend longevity in model organisms (for example, mouse, D. melanogaster and C. elegans) have been identified, which may help to reset the ageing clock.

Thanks to epigenetics, we can respond to how the environment (sun exposure, pollution, radiation, etc.) and habits such as food, stress, medications, etc., affect the epigenome during the aging of our skin.

Epigenetics is a tool with enormous potential for the cosmetics sector. In this sense, a series of ingredients are appearing with the ability to regulate some epigenetic mechanisms through the expression of microRNAs, DNA methylation and post-translational modifications of histones, with the objective of restoring chromatin structure in skin cells. For example, extracts from chamomile (Matricaria recutita L.) or red grape pulp are rich in apigenin (5,7-dihydroxy-2- (4- hydroxyphenyl) -4-benzopyrone), a flavonoid with a wide spectrum of activities (anti-inflammatory effects, low toxicity and ability to penetrate the different layers of the skin). It has been described how this active can produce changes in DNA methylation, on histone deacetylase activity and also its effect on the reestablishment of the expression of the anti-oxidant factor Nrf2 through the epigenetic regulation of this gene. Calendula Officinalis Flower Extract, can regulate the expression of hsa-miR-29a. This miRNA has been shown to inhibit the expression of type I and type III collagen genes, as well as being involved in the regulation of elastin. Additionally, miR-29 has an anti-aging effect thanks to the inhibition of histone deacetylase HDAC11 and histone methyltransferase EHMT2, which regulate the levels of methylation of histone H3K9, essential in the processes of cellular senescence. The human tripeptide GHK, glycyl-l-histidyl-l-lysine, has been used for the treatment of wounds as well as for its antiaging benefits. Recent studies have shown that in epidermal stem cells, GHK upregulates an antisenescence transcription factor p63 and increases the expression of other proteins abundant in youthful skin such as collagen, glycosaminoglycans, and decorin.

All the investigations that are being developed will offer us new ingredients, capable of regulating the expression of genes involved in the epithelial structure, the elimination of epigenetic modifications related to cellular senescence, the activation of new mechanisms of cellular defense or repair of damaged DNA related to genetic instability.

These advances and the identification of new epigenetic active ingredients, will allow in the near future the development of a new generation of cosmetics against cellular aging, that will not only consider the individual’s own genetic nature but also its interaction with the environment and its lifestyle.

References

Zhang, W. et al. The ageing epigenome and its rejuvenation, Nature Reviews, 21, 137-148 (2021).

Simpson, D. J. et al. Cellular reprogramming and epigenetic rejuvenation. Clinical Epigenetics, 13:170 (2021).

Luo, S. et al. Epigenetics of skin disorders, in Medical Epigenetics (2nd Edition) (T.O. Tollefsbol, ed.), Volume 29 in Translational Epigenetics, 231-250, Academic Press, London (2021).

Wagner, W. The link between epigenetic for aging and senesce. Frontiers in Genetics, 10:303 (2019).

Mena, S. et al. Epigenética y envejecimiento. NCP 348 (2016).