Inflammaging: How Subclinical Inflammation Accelerates Ageing in Skin

‘Inflammaging’ is a term first coined by Franceschi et al. in 2000, and refers to accelerated ageing caused by low-level chronic inflammation.  Effectively cells are placed in a permanent state of low-level inflammation triggered by cumulative effects of UV light and pollen, particulates, vehicle emissions,  nitrogen/sulphur gases, household chemicals, plasticizers, and fragranced candles.

This paper will look at the links between long-term low-level chronic inflammation and accelerated ageing in the skin.  It has long been established that external factors such as UV light and harsh chemicals can cause skin to age prematurely, by which we mean the skin loses flexibility, wrinkles, becomes less smooth, and develops discoloured patches.

The Roles of Reactive Oxygen Species

Our skin faces daily challenges from UV radiation, allergens, and pollution such as environmental chemicals, particulates, and reactive gasses from exhaust emissions.  The latter are especially prevalent in city environments where so many of us live and work (for a recent review, see Kim et al. 2016). One of the key mechanisms by which these entities damage the skin has been identified as reactive oxygen species (ROS). These are like hyperactive toddlers within our cells racing around, crashing into things, knocking them over, and damaging them. Only in this case, the things being damaged are not teacups or precious vases but the DNA and other important compounds in the cell.  

It would seem logical then to try to eliminate ROS from our cells, and we can do this by applying antioxidants, whether through our skincare products, through our diet, or better still, through both. However, ROS is only part of the problem. Research has shown that ROS can also play a positive role inside the cell, where they can act as signaling molecules and regulate the cell’s healthy operation (Kandola et al., 2015, Wolfle et al., 2014). Just as a small dose of a drug will alleviate the problem but a large dose may cause harm and generate unpleasant side effects, so excessive levels of antioxidants may have a negative impact.

Hence ROS have a role in both healthy and unhealthy cells. Clearly, there is a deeper story about the role of ROS and how they cause harm. Science is only just beginning to understand that deeper story, but the understanding we are gaining is leading us to a much more important and fundamental understanding of ageing and well-being.    

The mechanism for many of the symptoms of skin ageing is reasonably well understood and results from the breakdown of collagen, which is a vital component in the structure of the cells of skin.  Collagen is broken down by enzymes called Matrix Metaloproteinases (MMPs), which in turn are activated by an increase in signalling factors and other enzymes in the cell.  MMPs break down collagen and elastin, which are the structural components of the extracellular matrix. Effectively, they act as the scaffold for the skin cells. Breaking down this scaffold results in loose and wrinkled skin associated with ageing.  

The key to understanding how ROS impacts this is not just what ROS does but also how it does it.  It has long been known that excessive ROS leads to the breakdown of collagen and increases levels of inflammation-causing molecules, and for a long time, it was thought that the direct actions of ROS on proteins and DNA in the cell were the cause of the damage, but we now see a more subtle and nuanced pattern emerging. The key ‘villain’ is not ROS but rather the response of cells themselves to excessive levels of ROS. One of the effects of reactive oxygen and similar reactive molecule species is to trigger inflammation responses in cells (Bosch et al., 2015). Put simply, excessive ROS exacerbates a secondary set of fundamental cellular reactions.

Much research has been focused on reactive oxygen species as the main causative agents for these metabolic activities; however, the link between reactive oxygen species and increases in signalling factors is still poorly understood. There is evidence that mitochondrial reactive oxygen species play a key role in triggering the production of pro-inflammatory cytokines  (Naik and Dixit 2011).

Inflammation – a range of severities 

It can also be a low-level chronic condition in the cells. Inflammation is mediated by signalling molecules called cytokines. These are somewhat like messengers which move within and between cells alerting them to what their neighbours are experiencing and telling the cells how to react. When cells produce too much ROS, cytokines are produced to signal that the cell is under some sort of ‘strain.’ Unfortunately, the cytokine vocabulary is pretty limited and uses the same ‘message’ for all types of stress, including open wounds, infections, disease, and allergens. A cell under strain gives the same message as a cell under attack, and thus the body launches its standard ‘anti-attack’ response, which we know as inflammation.

When most of us think about inflammation, we think of common ailments such as hay fever, where we get runny noses and itchy, irritated eyes. Inflammation is not just the redness and itching we get from, say, an insect bite. In some cases, more serious inflammation arises in conditions such as asthma and ultimately, for some people, in anaphylactic reactions because they have become hyper-sensitised, giving rise to life-threatening over-reactions by the body to allergens.

However, there is another form of inflammation that is not readily apparent. This is low-level chronic inflammation.  In this case, we may not feel a specific ill effect; typically, the only effect would be slight irritation of the skin and perhaps a general feeling of lethargy or unease.  Because there are no clear symptoms, it makes this much more difficult to identify; however, as we live in a world where we are constantly exposed to allergens and irritants, it is important to better understand how this will affect more than skin and general well-being.

Chronic long-term inflammation can be likened to listening to a radio turned slightly too loud. At first, it may feel uncomfortable, but our ears accommodate the volume after a while, and we cease to notice. However, we are still exposed to prolonged levels of slightly excess volumes, which will damage our hearing over time.  If we are exposed to sudden loud noise, we will be aware of the discomfort and take steps to avoid it; however, for long-term low-level chronic exposure, the damage is being done without awareness.  And in a similar way, long-term chronic low-level inflammation can cause premature ageing and generally decrease well-being without our being aware of it.  However, once we are aware of the problem, we are then in a position to be able to take steps to avoid ill effects.

Inflammation and Ageing

Recent research has shown that many similar cellular activities are triggered as a result of an immune response to injury or infection.  When one of these happens, the cells enter a state of stress, and one component of that stressed state is the release of molecules called cytokines and the triggering of a series of changes within the cell.  We now know that these changes look very similar to the changes we see in prematurely ageing cells.  Indeed the term given to cells and the state is senescence which means ageing or old.  Furthermore, research has shown that senescent cells release various signalling molecules that signal to the neighbouring cells, causing them to change to a more highly stressed state (Campesi et al. 2007).

These changes are a result of an inappropriate response to minor irritants, as though these are major skin challenges. For example, the appropriate response against infection is to allow white blood cells to reach the affected area to attack the infection. This, in turn, necessitates the local breakdown of the extracellular matrix (ECM), which comprises collagen and elastin. Therefore, the cell signals to produce more matrix metalloproteinase, which digests collagen and decreases collagen synthesis. Collagen loss is a key market for prematurely aged skin. 

Much of the work on premature ageing has focused on the effects of UV light and there is clear evidence that excessive exposure to UV does indeed accelerate ageing in addition to causing damage to DNA and other molecules within the skin cells.  As a protective mechanism against ROS damage, the skin has evolved a defence mechanism in the form of vitamin D. Synthesis of vitamin D by the skin requires sunlight.  Vitamin D is known to be both a UV protectant and also a potent anti-inflammation molecule. However, the metabolic picture is further complicated by evidence that UV light induces Cyclooxygenase-2 (COX-2) expression. COX-2 is an enzyme that synthesizes prostaglandins which have been shown to be potent promoters of inflammation.  (Tripp et al 2003). Thus it can be seen that the cell is in a permanent and delicate state of balance, termed homeostasis, between multiple, sometimes conflicting, signalling molecules and cellular activities.  The real damage from long-term chronic inflammation is the disruption of this inter-cellular balance.  So we can say that part of the triggering action of the environment which causes premature cell ageing is the same mechanism as the reaction to cell injury or infection.  This reaction we call inflammation. 

The UV paradox

That the skin is able to provide twofold protection against UV damage by synthesising vitamin D gives rise to the UV paradox whereby the healthy skin requires exposure to sunlight and thus UV to synthesise vitamin D. A lack of vitamin D results in poor health, both in the skin and generally in the body, and can ultimately manifest itself in the form of the disease Rickets.  From this, we can see that small doses of UV are both healthy and beneficial; however, excessive doses of UV overwhelm the cell’s natural defence mechanisms and cause ageing.  Although UV exposure is an important component of premature skin ageing it is not the only factor, and in a modern city environment, UV protection alone will not be enough to prevent premature ageing.

It is known that chronic low-level inflammation is especially triggered by particulate matter and chemicals in the atmosphere and more well-known allergens such as pollen.  We believe that this makes the typical environment in a large city intrinsically ageing.  Therefore any future products designed to protect against skin ageing must take into account counteracting chronic low-level inflammation in the skin. 

Future trends

Much of the current research being carried out in academic labs around the world is trying to find the precise links between reactive oxygen species, damage to cellular components, and the intercellular signalling pathways of molecules which trigger inflammation.  As this information becomes more clearly known, it is possible to target specific inflammation pathways to dampen the information response. Indeed clinical research already indicates that long-term chronic inflammation may be a factor in diseases such as Atherosclerosis, Parkinson’s disease, Alzheimer’s disease, and even age-related macular degeneration (Sheridan 2017).   

It can be seen that there are multiple pathways active simultaneously, acting and counteracting,  balancing and counter-balancing, to maintain skin cell homeostasis. The next generation of truly effective skincare products will have to be developed with this dynamic multi-factorial system at the core. Their effect will be to turn the volume down within the cell and thus protect the cell from long-term damage.  The aim will be to calm down and soothe the cells and give them a rest from being permanently on alert.

It is anticipated that knowledge of multiple components and interactions will have to be modelled and products active against several targets and pathways developed, probably with synergistic activities, to create breakthrough skincare products that will address what is perhaps the most fundamental and pressing need, as we move increasingly to cities and urban living globally.