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ON HER 120th birthday, Jeanne Calment – generally regarded as the oldest person ever to have lived – proved she still had her wits about her: “I’ve only got one wrinkle,” she wisecracked, “and I’m sitting on it.” Funny, but untrue. The Frenchwoman was, by then, extremely wrinkly. On the Fitzpatrick Wrinkle Scale, she would have been a shoo-in for the top category, with deep wrinkles and discoloured skin that had lost its elasticity.
Quelle surprise. She may not have been as old as she claimed, but she was at least 97. Anybody who lives to 100 or so can expect the same. Historically, this has been regarded by many as a purely cosmetic problem. Wrinkles, sags and bags are, in some cultures, considered unsightly or an unwanted sign of how old we are. Right or wrong, that has led to a centuries-long battle to fill them in or smooth them over. More recently, however, the war against wrinkles has moved onto a more urgent footing. Aged skin is much worse than young skin at all the vital things it does to help maintain your health.
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Moreover, emerging evidence suggests that, as skin ages, it releases a chemical cocktail around the body that could drive premature ageing of other organs. “If your skin is getting older, you are getting older inside, so be careful,” says at the University of Coimbra, Portugal. In other words, wrinkles may not just be a result of ageing, but also a driver of it. Which begs the question: could our fight to banish wrinkles help reverse the clock both inside and out?
The skin is the largest organ in the human body. Its main job is to act as a barrier between the inner and outer world, but it has many other functions too. It has a role in our immunity, it generates vitamin D, acts as a regulator of body temperature and water balance, is a rapid responder to minor wounds and a producer of the pigment melanin. Skin consists of two main layers, an outer one called the epidermis and the dermis that sits below it. Sandwiched between them is the dermal-epidermal junction, which anchors the layers together and is important for maintaining the skin’s structural integrity.
The epidermis is one of the first lines of defence against the hostile outside world. Its surface is a tessellated layer of dead cells forming a tough, waterproof and flexible shell, replaced continuously from a sheet of stem cells below. The epidermis is rich in hyaluronic acid, which destroys harmful compounds called free radicals generated by normal cell metabolism.
The dermis is mostly made of connective tissue – largely the proteins collagen and elastin, which make tissues strong and able to withstand stretching – but also contains cells called fibroblasts, which secrete collagen, elastin and hyaluronic acid and play a critical role in wound healing. Hair follicles are rooted in this layer, as is the skin’s blood supply.
Skin ageing
As skin ages, it degenerates dramatically. In the epidermis, stem cell proliferation slows down, leading to progressive thinning – we lose up to half this layer over our lifetime – and a roughening of its surface. . This contributes to , makes the cheeks appear deflated and can create hollowing around the eyes and heaviness in the jowls.
In the dermis, fibroblasts decline in number, resulting in , elastin and hyaluronic acid and a marked thinning of this layer too. The dermal-epidermal junction also starts to crumble, reducing the skin’s integrity. Together, this all contributes to further wrinkling and sagging.
On top of this, as skin ages, more and more cells enter a zombie-like state called senescence. Such cells have endured some sort of irreversible damage and need to be eliminated, but, in the meantime, remain alive and metabolically active, though they no longer divide. Senescence, which occurs throughout the body, is initially protective because it prevents DNA-damaged cells from becoming cancerous. Yet as time marches on, the mechanisms for clearing senescent cells out start to decline and they build up in tissues.
Senescent cell damage
This is bad news, as the cells pump out a toxic cocktail of inflammatory proteins that damage surrounding cells and connective tissue. The build-up of these cells has been shown to be a , including cataracts, cancer, clogged blood vessels, type 2 diabetes, osteoarthritis, Parkinson’s disease and Alzheimer’s disease. The build-up of senescent cells also correlates with .
The problems stemming from senescent cells are an inevitable result of the ageing process, but in the skin, they are exacerbated by external forces such as pollution, smoking, poor diet and, worst of all, sunlight.
Exposure to ultraviolet (UV) in sunlight causes a phenomenon called skin photoageing, which accelerates the natural ageing processes. There are two types of UV radiation. UVA penetrates the epidermis and dermis, damaging both; UVB only goes as deep as the epidermis. Both degrade collagen and elastin, which become disorganised and fragmented, leading to deep wrinkles and sagging. Even though natural ageing thins the skin, photoaged skin is thickened, which accentuates the appearance of wrinkles. UV also causes DNA damage to skin cells of all types, which accelerates their progression towards senescence.
Skin protection
The is a striking photograph (pictured below) published in the New England Journal of Medicine in 2012 of William McElligott, a 66-year-old truck driver who spent 28 years delivering milk around Chicago. The right side of his face is relatively free of wrinkles, but the left side – which faced the window of his driver’s side door – is thickened, sagging and deeply wrinkled. “The skin is older in the part that was more exposed to the sun,” says Cavadas. “It highlights the importance of skin protection.”
This isn’t just because it prevents cosmetic wear and tear and the risk of skin cancer, but also because evidence is building that “skin age” is correlated with general health, longevity and risk of death.
In 2013, a team from Unilever and several universities reported that in people in their 60s was correlated with the risk of cardiovascular disease, a classic health condition of older age.
Another study, from 2015, found that . A more recent paper reported that , and also had better overall cognitive functioning.
This is perhaps no surprise, as we know that people age at different rates and there can be a mismatch between chronological age – the number of years on the clock – and biological age, which is a measure of how far our bodies have descended down the slippery slope of the ageing process.
But Cavadas thinks it goes deeper than this. In an opinion piece last year, she and two colleagues proposed that skin ageing is a driver of whole-body ageing.
The hypothesis centres on senescent cells and their toxic leakages, known as the SASP (senescence-associated secretory phenotype). These include inflammatory proteins, compounds that affect the immune system, and protein-destroying enzymes. It is already well-established that senescent cells in one tissue can damage healthy cells in another, says Cavadas, and that the SASP is a leading cause of inflammaging, the low-level chronic inflammation that creeps throughout our bodies as we age and is linked with health conditions.
Skin-brain link
Cavadas put two and two together. Aged skin – especially when it is prematurely aged by UV damage – carries a heavy load of senescent cells. The blood vessels in the dermis could carry the cells’ toxic cocktail far and wide.
To find out if premature ageing really is triggering more widespread ageing throughout the body, Cavadas is initially exploring possible links between the skin and parts of the brain, in particular the hypothalamus and hippocampus. The former is a small region that controls many basic life-support functions, including metabolism, sleep, hunger, growth, reproduction and homeostasis, which is the body’s ability to maintain a steady state while still being able to adapt to change. The hypothalamus receives signals from far-flung parts of the body including the skin. The hippocampus, meanwhile, is involved in memory formation and is one of the first brain regions to be affected by dementia.
Wrinkle treatment should no longer be seen as a vanity project, but as a vital part of staying biologically young and healthy
The hypothalamus has emerged as a critical node in the ageing process, says Cavadas. “The hypothalamus has several important functions that we know become dysfunctional in ageing,” she says. , while middle-aged mice given implants of healthy, young hypothalamic stem cells live longer. , which is involved in triggering the secretion of sex hormones, and older mice in which this decline is halted show improved skin condition.
The hippocampus receives messages from the skin too. In mice repeatedly exposed to high levels of UVB radiation, the and the mice exhibit depression-like behaviour. This suggests there is an intimate link between the skin and the brain, which Cavadas calls the skin-brain axis. But she stresses that the idea of skin senescence contributing to hippocampal and hypothalamic dysfunction via the SASP, driving whole-body ageing, is still only a hypothesis.
Janet Lord at the University of Birmingham, UK, says the idea that ageing skin can cause problems around the rest of the body is sound, although evidence of a causative link is needed.
Cavadas hopes support for her idea may come from experimental drugs called senolytics, which destroy senescent cells, and senomodulators, which don’t kill the cells but stop them from dripping their poison. These drugs – collectively called senotherapeutics – are already in clinical trials for many age-related conditions and could be available as skin creams in as little as three years, says Cavadas.
Senolytic drugs
Experimental evidence suggests they will be safe and effective. In 2019, researchers mainly at Drexel University College of Medicine in Philadelphia, Pennsylvania, applied a drug called rapamycin, which is a senomodulator as well as a promising inhibitor of ageing in general, to the photoaged skin of a handful of male and female volunteers aged over 40. The drug , increased the amount of collagen in the dermis and improved the skin’s appearance. Another small experiment did the same with metformin, another senomodulator, and found that it . Using a senolytic to eliminate senescent cells from mouse skin , which also suggests a partial reversal of the ageing process.
To support her own hypothesis around wrinkles driving whole-body ageing, Cavadas is planning to test senolytics on animal models of aged skin to identify the effect they have on markers of brain health in the hypothalamus and hippocampus. “The evidence is still fragile, but, in a year, we will have experimental data,” she says.
“Overall, topical, and possibly oral, senotherapeutic treatments have tremendous potential to eventually become a standard of care for skin ageing,” says at the University of Minnesota’s Institute on the Biology of Aging and Metabolism. But they will have to get through clinical trials, says Cavadas, and we can’t expect miracles. “If you stop all the senescent cells in the skin, the rate of ageing will be at least diminished. I won’t say rejuvenation,” she says.
Anti-wrinkle treatments
Whether reversing skin ageing reverses whole body ageing will need to be seen. But there is another good reason to want to slow it down. , says , a plastic surgeon at the Royal Free Hospital, London. Its barrier functions weaken, wounds are slower to heal, sensitivity to touch declines and its immune defences are compromised. Aged skin is also more prone to cancer.
While we wait on senotherapy, what are our options? Many bathroom cabinets are already full of anti-wrinkle creams, some costing skin-sagging sums of money. These may well reduce the appearance of wrinkles, but, at present, there is limited evidence that they are genuine anti-ageing treatments, says Zargaran.
Yet there is something that is proven to work, cosmetically at least. According to at King Khalid University in Abha, Saudi Arabia, collagen is a paradigm-shifting innovation. by plumping up the dwindling connective tissue. Oral supplements are usually composed of collagen from marine fish, a byproduct of the fishing and aquaculture industries, which has been chopped up into small pieces so it can be absorbed by the gut. These treatments, however, do nothing to tackle senescent cells.
We do, however, have one method for preventing skin ageing already in our cupboards: sunscreen, which absorbs UV rays before they do damage to the skin. It is never too soon to start. Even though the first visible signs of skin ageing usually don’t appear until our mid-20s, the underlying processes are under way much earlier. Last year, an international team of researchers studied skin ageing in Asian women aged between 18 and 24 and reported that : dull skin, uneven tone, dryness, wrinkles and a lack of firmness.
Which all goes to show that wrinkle treatment should no longer be seen as a vanity project, but as a vital part of staying biologically young and healthy. Everyone should pay attention to that, because we all have skin in this game.
Graham Lawton is feature writer atĚýżěè¶ĚĘÓƵ
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