From Wrinkles to the Skin-Brain Axis

By Min Zan

Let’s talk about wrinkles – those lines on our skin that show up as we get older. Graham Lawton has found that wrinkles might not just be about looks; they could actually make our bodies and brains age faster.
Take Jeanne Calment, for example. On her 120th birthday, she joked about having only one wrinkle, but in reality, she was quite wrinkled. She might not have been as old as she claimed, but she was at least 97, and by that age, most people have wrinkles. In some cultures, wrinkles are seen as not looking good or as a sign of getting old, leading to a long history of trying to hide or fix them.
But now, people are realizing that wrinkles might be more than just a cosmetic issue. Ageing skin doesn’t do as good a job of keeping us healthy as young skin does. There’s even evidence that as our skin gets older, it releases chemicals that could make other organs age faster, too. Cláudia Cavadas from the University of Coimbra in Portugal warns that if your skin is ageing, you might be ageing inside too. So, the question is, can we slow down ageing both on the outside and inside by fighting against wrinkles?
Our skin is the biggest organ in our body. Its main job is to protect us from the outside world, but it also does many other things. It helps with our immune system, produces vitamin D, controls our body temperature, and responds quickly to small injuries. The skin has two main layers: the outer one, called the epidermis, and the dermis beneath it. Between them is the dermal-epidermal junction, which holds the layers together and keeps the skin strong.
The epidermis is like a shield against the world, made up of a layer of dead cells that are replaced continuously. It contains hyaluronic acid, which fights harmful compounds generated by our cells. The dermis is mostly connective tissue, with proteins like collagen and elastin that make our tissues strong. It also plays a role in healing wounds, and our hair follicles and blood supply are in this layer, too. Wrinkles may be a sign that our skin isn’t as healthy as it used to be, but by understanding more about our skin, we might find ways to stay healthier and maybe even look a bit younger.
As our skin gets older, it undergoes significant changes. In the top layer, called the epidermis, the growth of stem cells slows down. This leads to the layer becoming thinner over time, and its surface becomes rougher. We lose up to half of this layer during our lives. The glue holding the cells together weakens, and the water and fat content decreases. This causes the folds from the nose to the mouth to deepen, the cheeks to appear deflated, and hollow areas around the eyes with heaviness in the jowls. The lower layer, the dermis, also experiences a decline in fibroblasts, which affects the production of collagen, elastin, and hyaluronic acid. This layer becomes noticeably thinner. Additionally, the connection between the epidermis and dermis weakens, further reducing the skin’s strength. All of these changes contribute to more wrinkles and sagging.
Another issue that arises as skin ages is the presence of “zombie cells.” These cells enter a state called senescence, where they are alive and metabolically active but no longer divide. Initially, senescence is a protective mechanism to prevent damaged cells from turning into cancer. However, as time goes on, the body’s ability to clear these senescent cells declines, and they start to accumulate in tissues. These cells release harmful inflammatory proteins that damage nearby cells and connective tissues. The build-up of senescent cells is linked to various age-related conditions such as cataracts, cancer, clogged blood vessels, type 2 diabetes, osteoarthritis, Parkinson’s disease, and Alzheimer’s disease. It also correlates with defects in elastin and increased wrinkling.
These problems associated with senescent cells are a natural part of ageing, but external factors like pollution, smoking, poor diet, and especially sunlight can worsen them. Exposure to ultraviolet (UV) rays in sunlight accelerates the natural ageing process, causing a phenomenon known as skin photoaging. There are two types of UV rays: UVA and UVB. UVA penetrates both the epidermis and dermis, damaging both layers, while UVB only reaches the epidermis. Both types degrade collagen and elastin, causing deep wrinkles and sagging. Photoaged skin appears thickened, even though natural ageing makes the skin thinner. UV rays also cause DNA damage, speeding up the process of cells becoming senescent.
An example of photoaging is seen in a photograph of a 66-year-old truck driver, William McElligott, published in the New England Journal of Medicine in 2012. The side of his face exposed to the sun while driving showed more wrinkles, sagging, and thickening compared to the less exposed side. This highlights the importance of protecting the skin from the sun.
Taking care of your skin is not just about looking good or avoiding skin cancer. There’s growing evidence that the “age” of your skin is connected to your overall health, how long you might live, and your risk of death.
Research from Unilever and several universities in 2013 showed that the amount of facial ageing in people in their 60s was linked to the risk of cardiovascular disease, a common health issue as people get older. Another study in 2015 discovered that how old people looked in photographs taken in 2001 predicted their chances of dying over the next 12 years. A more recent study found that older individuals who appear younger than their actual age were less likely to have conditions like cataracts, osteoporosis, age-related hearing loss, and chronic obstructive pulmonary disease. They also had better overall cognitive functioning.
We know that people age differently, and sometimes, our bodies age faster or slower than the number of years we’ve lived. Dr Cláudia Cavadas and her colleagues believe that skin ageing plays a big role in the ageing process of the whole body. They focus on senescent cells, which are cells that have stopped dividing and release harmful substances known as the SASP (senescence-associated secretory phenotype). These substances include inflammatory proteins, compounds affecting the immune system, and enzymes that break down proteins. Senescent cells in one part of the body can harm healthy cells elsewhere, leading to “inflamageing” – a chronic, low-level inflammation linked to various health problems.
Cavadas believes that aged skin, especially when prematurely aged by sunlight, carries a lot of senescent cells. These cells release harmful substances into the blood vessels in the dermis, which can then spread throughout the body. To understand if premature skin ageing affects the overall ageing process, Cavadas is investigating potential connections between the skin and parts of the brain, such as the hypothalamus and hippocampus. The hypothalamus controls essential life functions like metabolism, sleep, hunger, growth, reproduction, and homeostasis. It receives signals from various parts of the body, including the skin. Understanding these connections might help us find ways to slow down the ageing process and stay healthier for longer.
The hippocampus helps us remember things and is one of the first parts of the brain affected by dementia. Dr Cavadas believes that the hypothalamus is crucial in the ageing process. It performs important functions that may not work properly as we age. Studies with mice show that those with fewer stem cells in the hypothalamus age faster, while middle-aged mice given young, healthy hypothalamic stem cells live longer. Aging hypothalamuses also produce less gonadotropin-releasing hormone, which is related to sex hormones. When this decline is stopped in older mice, their skin condition improves.
The hippocampus gets messages from the skin, too. In mice exposed to a lot of UVB radiation, the hippocampus makes fewer new cells, and the mice show behaviour similar to depression. This suggests a close link between the skin and the brain, known as the skin-brain axis. However, Dr Cavadas emphasizes that the idea of ageing skin causing problems in the hippocampus and hypothalamus through the SASP, leading to overall ageing, is just a hypothesis.
Dr Janet Lord from the University of Birmingham supports the idea that ageing skin can affect the rest of the body, but she believes more evidence is needed to establish a direct link.
Dr Cavadas is hopeful that experimental drugs called senolytics, which remove senescent cells, and senomodulators, which stop these cells from releasing harmful substances, could support her idea. These drugs, known as senotherapeutics, are already being tested for various age-related conditions and might be available as skin creams in about three years. Studies using senomodulators like rapamycin and metformin have shown positive effects on ageing skin, increasing collagen and improving appearance.
To test her theory about wrinkles influencing overall ageing, Dr Cavadas plans to use senolytics on animal models with aged skin and study their impact on brain health markers in the hypothalamus and hippocampus. While the evidence is still developing, she believes experimental data will be available within a year.
Dr Paul Robbins from the University of Minnesota sees great potential in senotherapeutic treatments for skin ageing, but Dr Cavadas reminds us that they must undergo clinical trials, and we shouldn’t expect miracles. She suggests that stopping senescent cells in the skin might at least slow down the ageing process, though she doesn’t promise complete rejuvenation.
Whether reversing skin ageing can reverse overall ageing remains to be seen. However, there’s a good reason to slow it down. David Zargaran, a plastic surgeon, explains that aged skin performs worse than young skin in many ways. Its barrier weakens, wounds heal slower, sensitivity declines and immune defences are compromised. Aged skin is also more prone to cancer.
While waiting for advanced treatments, many use expensive anti-wrinkle creams, but their anti-ageing effectiveness is limited. According to Hend Al-Atif from King Khalid University, collagen is a proven cosmetic solution. Research shows that both topical and oral collagen supplements help delay wrinkling by plumping up connective tissue. However, they don’t address senescent cells.
One method we already have in our cupboards to prevent skin ageing is sunscreen, which absorbs UV rays before causing damage. It’s never too early to start using it. Visible signs of ageing usually appear in the mid-20s, but the underlying processes begin earlier. Research on Asian women aged 18 to 24 found subtle signs of facial ageing, emphasizing the importance of wrinkle treatment for staying biologically young and healthy. It’s not just about vanity; it’s about everyone’s biological well-being.

Reference: New Scientist April 2023

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