Longevity Briefs: A Promising New Target To Slow Skin Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The skin is the body’s largest organ and also the first to show visible signs of ageing. Aside from cosmetic changes, age-related changes in the skin like loss of elasticity and thickness also leave it more prone to damage and make it slow to heal, so there are many reasons to search for ways to slow or reverse skin ageing. To do that, we need to understand how skin ages, but many of the underlying mechanisms remain a mystery. One area lacking full understanding is the role of cellular senescence. This is the process in which cells stop dividing and enter a state of permanent stagnation, becoming ‘zombie cells’ that don’t contribute much to tissue function but also refuse to die.

Cells generally become senescent in response to accumulated forms of irreparable damage, probably as a safety mechanism to prevent runaway cellular division. Autophagy is a process in which damaged cellular components are destroyed and recycled, which is essential for keeping cells in good working condition and preventing senescence from occurring. However, autophagy becomes disrupted in older age and cannot keep up with the levels of damage that our cells sustain. In this study, researchers investigate p62 – a protein that is involved in autophagy – in the context of skin ageing. p62 had been found to be implicated in protecting against various diseases and in preventing senescence, and deficiencies in p62 were shown to shorten the lifespans of fruit flies. Researchers therefore wanted to investigate p62 might be a target for slowing skin ageing.

The discovery:

Researchers first examined human skin samples from individuals of different ages and found significantly lower p62 levels in older individuals. To test p62’s role experimentally, they then created genetically modified mice lacking p62 in their skin cells. These mice showed accelerated ageing symptoms, including less elastic skin, increased wrinkles, and reduced moisture. Young mice lacking p62 had similar signs of skin ageing to old mice with normal p62 levels, while old mice lacking p62 were even worse off. While this experiment obviously can’t be replicated in humans, a similar test was performed in human keratinocytes (cells found in the outer layer of the skin) grown in the lab. Using genetic techniques to block the production of p62, they were able to show that p62 deficiency promoted senescence in human cells, while increasing p62 levels had the opposite effect, roughly halving the rate of senescent cell accumulation.

Looking into the mechanism, researchers discovered that p62 interacts directly with another protein called USP7. USP7 promotes senescence by affecting a crucial pathway in the control of cell division. They found that p62 binding to USP7 prevented the activation of this pathway and thus slowed down senescence. In line with this, mutations in either p62 or USP7 resulted in increased senescence.

The implications:

This research suggests that the decline in p62 plays an important role in skin ageing and the rise in cellular senescence in old age, opening up exciting possibilities for developing new therapies. If senescence was already known to play an important role in skin ageing, you may wonder why more effort hasn’t been made to block senescence pathways that are already known to us. The issue is that these pathways fulfil other important roles, so inhibiting them isn’t necessarily a good idea. Furthermore, while senescent cells are detrimental in old age, they do also fulfil the important function of shutting down badly damaged cells. The hope with p62 is that, because we would be restoring a deficient protein to normal levels rather than shutting down a detrimental yet necessary process, the end result would be more desirable.

This research is a long way from yielding any human benefits, as we currently don’t even know if boosting p62 in animals actually slows skin ageing – this study only investigated the effects of p62 deficiency in live animals. There’s also the fact that slowing down senescence solves the first part of the problem, but not the second part: that the ageing immune system struggles to remove senescent cells. There is a class of drug (senolytics) that are capable of removing senescent cells, but research into their effectiveness in humans is still very much an ongoing process.