Making time for renewal

When night falls, a remarkable change comes over the skin. During sleep, its cells leap into action, dramatically ramping up DNA repair, protein production and cell division. This flurry of activity is aimed at fixing the damage caused by the day’s environmental onslaught, such as UV rays and pollution, damage that can lead to visible ageing.

These intricate processes require complex coordination, a task that falls to the skin’s internal clock, its circadian rhythm¹ (see ‘A hard day’s night’). This system ties repair to the night hours, when UV rays and other damaging influences are absent or minimized. "However, we know through our research that this machinery, which is perfect when it's working, is dysregulated through ageing, stress levels, lack of sleep, and so on,” says Nadine Pernodet, who heads a research team at the Estée Lauder Companies in Melville, New York. Now, her team has found a way to tap into the epigenetic processes that regulate skin’s natural circadian rhythm and repair. The findings could lead to new cosmetic products that help to slow visible skin ageing.

All in the timing

Ageing results from accumulated damage. In the skin, cells lose their ability to produce the structural protein collagen and their capacity to naturally repair. The damaged skin cells promote inflammation and the production of reactive oxygen molecules that compound the harm. Slowing the march of damage could therefore slow ageing, but doing so means first unravelling myriad processes underpinning the skin’s defences. “It is a very big puzzle where you have to work out all these different angles to help the skin cells stay healthier,” says Pernodet.

One piece of this puzzle is circadian rhythm. Almost every cell in the body contains a set of ‘clock’ genes whose activity oscillates over 24 hours, and which, in turn, direct the rhythmic activity of many other maintenance and repair functions. Coordinating this web of clocks is a central pacemaker in the brain, which receives timekeeping information from the retina, as it detects light, and transmits it via the nervous and hormonal systems. Circadian rhythms deteriorate with age, as the clock mechanisms themselves accumulate damage². Disrupted circadian rhythms have been linked to metabolic disorders and other diseases, such as cancer, adding to the impetus to understand the fine detail of how the clocks are regulated.

Until recently, much of the research into circadian rhythm has focused on metabolically active organs such as the liver. Over the past few years, however, researchers have started to regard the skin as a model system. “The skin is a really cool organ,” says Paolo Sassone-Corsi, who studies circadian biology at the University of California, Irvine. As well as being accessible, it is an immediate interface with the outside world and is touched by light, the main timekeeping cue, he says. “So this is a perfect example to study.”

Sassone-Corsi’s team has recently developed model systems where the circadian clock has been switched off in every tissue except the one being studied³. Pernodet, who wanted to get closer to the cellular mechanisms controlling timing and repair for skin, was fascinated by these studies. There was a further draw: Sassone-Corsi’s experience with epigenetics, broadly defined as cellular mechanisms that modulate gene expression without altering DNA sequences. Pernodet had been interested in epigenetics since starting work at The Estée Lauder Companies in 2007. Sassone-Corsi has a body of work stretching back more than 20 years showing how the mechanisms governing circadian rhythm are intimately intertwined with epigenetic mechanisms such as changes in chromatin remodelling.

Pernodet was particularly interested in microRNAs, short stretches of RNA that alter activity of messenger RNAs, the molecular intermediaries that ferry information to the cell’s protein synthesis machinery. Humans express at least 2,000 microRNAs, or miRNAs, which have been shown by scientific studies to exert a significant influence in the cell⁴. Each miRNA targets a specific set of messenger RNAs and they form a key part of the cell’s ability to respond quickly and flexibly to changes in its environment. “MicroRNAs are appealing because of their dynamic nature,” says Sassone-Corsi. The field has grown rapidly in the last 10 years and miRNAs have emerged as important regulators of normal processes such as development, cell division and DNA repair in mammals. Their involvement in common conditions such as cancer and cardiovascular disease has led to the development of experimental therapies that mimic or block miRNA activity, some of which are now in early-stage clinical trials.

Sensing stress

Of particular interest to Pernodet was a growing body of work pointing to a role for miRNAs in the circadian clock⁵, and how that might translate in skin. To find miRNAs of interest, Pernodet’s team compared human fibroblasts taken from donors ranging in age from 19 to 62. In preliminary findings, presented in an abstract⁶ given at the Society for Investigative Dermatology meeting in May, they described a known inflammation-associated microRNA, miR-146a⁷, whose presence was related to skin circadian rhythm and whose expression was reduced in older cells. Inhibition of miR-146a seemed to suppress activity in one of the cellular clock genes, PER1, and to lead to an increase in cellular damage as well as other changes seen during ageing, such as reduced collagen production and increased inflammation. A full report of these experiments is in progress.

Pernodet hypothesises that miR-146a is involved in sensing environmental stressors and activating the cell’s natural repair mechanisms, meaning that lower levels of miR-146a expression in older cells exacerbates age-related damage. “You enter a vicious cycle during the ageing process, and we want to slow it down,” she says. To that end, her team has identified an extract from the baobab tree (Adansonia digitata) that seems to increase miR-146a levels in older fibroblasts and improves cellular repair and protein production. The team is now developing formulations to deliver the extract in a cosmetic treatment product.

For Sassone-Corsi, miR-146a has the additional attraction of being a foothold into teasing out the fine molecular detail of how circadian rhythm is regulated. His team plans to work with Pernodet to look for genes, proteins and other molecules that interact with the miRNA. While it’s now a rather unusual role reversal for basic scientific research to benefit from cosmetics research, Sassone-Corsi sees real value in such collaborations flourishing in the future. “It is time for those sorts of collaborations to multiply,” he says. “It’s a win-win situation that brings goodies both ways.”

We are very sad to learn of the recent, sudden death of Paolo Sassone-Corsi. We wish his family, friends and colleagues all the best. His science will ensure that his legacy lives on.