We have spoken before about intrinsic and extrinsic ageing, and that a significant percentage of the ageing you see on your skin is caused by environmental factors. Today we want to delve a little deeper into the ageing process and look at the role inflammation plays.
When we mention the word “inflammation” you probably have a memory of the last time you sprained your ankle and your foot ended up swollen. Or maybe you are thinking about that vacation when you were stung by a bee on your finger and your hand ended up looking like part of the Michelin man the next day. Right? Well, that is part of the story – inflammation is your body’s reaction to trauma and a side-effect of the healing process.
At a basic level inflammation happens when you are injured, and this sends a message to your body to start repairing the area. However, we are learning that inflammation is not a positive part of the healing process, it can have a negative result and impede healing. More importantly, in terms of aesthetics, inflammation is also associated with ageing on the skin (amongst other things). Ageing is a progressive degenerative process that is influenced by environmental and lifestyle habits. Some of our habits increase inflammation and age-related dysfunctions in the body, and some factors modulate (or control) them.
But first, what causes ageing?
Ageing itself is not a disease. Ageing results from an accumulation (over time) of changes at the molecular and cellular level in the body, which ultimately leads to changes in the tissues and organs. This results in disease and an increased risk of morbidity and mortality. It is now recognised that immune and inflammatory responses can lead to a variety of negative consequences. As we start to live longer lives these patterns are being recognised. In a complex process, organs lose their function and/or structural integrity as a result of age-related diseases - like skin changes and skin cancer. However functional and structural changes can themselves lead to age-related diseases, making this a bit of a chicken-and-egg scenario. While the cause of the ageing process is not fully understood, inflammation clearly plays a major role, inextricably linking inflammation and ageing.
Inflammation and its association with ageing
As we mentioned in the introduction, the inflammatory response leads to acute inflammation after a trauma or injury. This process is marked by heat, swelling, redness, and pain. However, in terms of ageing, the inflammation response is a chronic, low level, subclinical process that differs significantly in degree.
Many publications have reported on the close relationship between inflammation and ageing. Levels of inflammatory mediators typically increase with age even in the absence of acute infection or associated physiological stress. This chronic inflammation underlies many age-related conditions. However, a key question remains. Is inflammation a cause of the ageing process or merely a side-effect of ageing?
The mechanisms of inflammation in ageing
The redox stress hypothesis of ageing is based on changes in cellular reduction-oxidation balance, accompanied by age-related changes in the immune system. Other processes, such as endocrine changes and declining levels of sex hormones, are also thought to contribute to elevated inflammation in older age. In addition, several diseases, especially age-related diseases such as atherosclerosis and dementia, have strong inflammatory components.
Endogenous reactive oxygen species (ROS) are recognised to play a key role in inflammation – as increases in ROS lead to over-oxidation and irreversible changes in protein structure and function. The biological process to remove these accumulated damaged proteins causes inflammation, leading to a chronic inflammatory state.
Mitochondria, the primary sites for the cell’s energy (ATP) production, are essential for normal cell function and maintenance of the redox process in cells, as well as for regulating programmed cell death. Mitochondria are the main source for reactive oxygen species and, therefore, play an important role in redox stress. The mitochondrial free radical theory of ageing is based on oxidative damage to mitochondrial DNA (mtDNA) due to an overproduction of reactive oxygen species. This damage results in ageing. With age, mismanagement of the normal cell death process due to mitochondrial dysfunction results in increased inflammation and tissue injury.
Deterioration in the immune system
Oxidative stress is also thought to play a key role in the gradual decline of the immune system with age. This results in an over-stimulation of both the innate and adaptive immune systems. The net result of these processes is increased susceptibility to diseases plus increased morbidity and mortality due to infections and other age-associated diseases.
In addition, aged cells that demonstrate a reduction in viability demonstrate significant increases in production and secretion of many pro-inflammatory cytokines. Chronic inflammation, therefore, not only results from but also drives, low-grade inflammation.
Deterioration in the endocrine system
In addition to immune changes, the endocrine system is also impacted by an age-related reduction in function, most notably affecting sex steroid production. Levels of growth hormone and dehydroepiandrosterone (DHEA) decrease with age as well. Cortisol production, however, is increased.
Chronic raised cortisol production contributes to a breakdown of the immune system. A reduction of DHEA and growth hormone levels, combined with increasing levels of cortisol as we age, leads to increased inflammation.
Sex hormones also control the production of inflammatory cytokines. Studies indicate that interleukin-6 secretion is inhibited by both oestrogen and androgen. Many studies show an increase in interleukin-6 and other pro-inflammatory cytokines in women following menopause. Similar inverse relationships have been reported for testosterone levels and inflammatory markers in older men. As levels of these steroid hormones decrease with age, levels of inflammatory cytokines increase, contributing to chronic inflammation.
Telomere weakening and cellular break down
Telomeric DNA is lost during each replication cycle. With repetitive cycles over the life of a cell, this DNA eventually reaches a critically short length, which no longer supports further cell division. If shortened telomeric DNA is not repaired, cells with critically short telomere lengths become non-viable and die.
C-reactive protein (CRP)
Many diseases common in older adults have clear inflammatory components. Like in cellular ageing, it is likely that inflammation both reflects the development and progression of disease as well as promoting disease. Many studies of the association of disease and inflammation have focused on C-reactive protein (CRP) - used clinically as a biomarker, or circulating plasma marker, of inflammation. CRP is an acute phase protein produced in the liver; its levels are raised by pro-inflammatory cytokines like interleukin-6.
CRP is a marker of the general systemic response to inflammation. For acute illnesses such as sepsis, CRP levels can reach 10,000 mg/L; however, in terms of chronic inflammation, levels of interest are in the 1-10 mg/L range. CRP levels in this range, reflecting low-level chronic inflammation, directly correlate with the presence and extent of metabolic syndrome, diabetes, subclinical and clinical cardiovascular disease, dementia, macular degeneration, chronic obstructive pulmonary disease, renal disease, osteoporosis and cancer.
In addition to inflammatory cytokines and CRP, other factors such as obesity and smoking contribute to both disease and inflammation. Inflammation and obesity are highly interrelated; obesity is associated with diabetes and cardiovascular disease as well as with a growing number of other diseases that have inflammatory components, like dementia and cancer. Fat cells, especially those in visceral adipose tissue, are metabolically active and synthesize and release several pro-inflammatory molecules. Inflammation may also drive obesity.
Inflammation and the skin
The skin and its immune system manifest a decline in physiologic function as it undergoes ageing. External insults such as ultraviolet light exposure and chemical exposure from the use of cosmetics cause inflammation, which may enhance skin ageing even further, leading to cancer and signs of photo-ageing.
Chronic, low-grade inflammation is recognised as a major contributor to the ageing process of the skin. This phenomenon is called “inflammageing.” Inflammageing plays a role in the initiation and progress of skin ageing. UV radiation induces oxidative stress in epidermal cells, resulting in damaged cells with oxidized lipids. Oxidation-specific cells and oxidized lipids cause inflammation, leading to infiltration and activation of macrophages to remove the damaged cells and oxidized lipids. Activated macrophages degrade the extracellular matrix. Repeated UV radiation over-activates the immune system, causing damage to the dermis-epidermis junction. Overburdened macrophages release pro-inflammatory cytokines and ROS, the former causing chronic inflammation and long-term damage to the dermis, whilst the latter triggers oxidative stress-induced damage to the dermal extracellular matrix.
The ageing process explained above leaves the skin feeling rough (from a thickened layer of stratum corneum), sensitive to the environment (due to the thinning of the living epidermal cell layer) and with an uneven tone, often described as sallowness. The breakdown in collagen and elastin causes sagging, while lines and wrinkles start to appear in areas of increased skin activity, for example around the mouth and eyes. Functional disability shows up as dryness and uneven pigmentation. Liver spots appear due to a malfunction in the pigment-forming cells (the melanocytes). Skin with inflammageing is also more likely to develop acne, seborrheic skin conditions and rosacea.
What can you do to slow this process?
In order to understand how to delay or prevent age-related declines in function, it is important to distinguish between successful or healthy ageing and pathologic ageing. Some individuals survive to older age with relatively intact health, physical and cognitive function. However, there are significant differences in the rates of physical and cognitive decline amongst other individuals. Genes and gene-environment interactions likely play a key role in successful ageing. However, even in the absence of infection or trauma, inflammatory stimuli are inescapable, although certain environmental and lifestyle factors may be avoidable. Therapeutic interventions may also help to reduce the effects of inflammation and age-related disease.
Cigarette smoke is a well-known cause of disease and death. Smoke exposure directly stimulates immune and inflammatory responses.
Like with cigarette smoke, particulate air pollution is a major environmental factor contributing to inflammation, illness, and mortality. Higher levels of air pollution are associated with an increased incidence of cardiovascular and other diseases. Inflammation likely causes this increased risk. Even short-term exposure to particulate air pollution is associated with increased levels of inflammatory proteins.
Taking part in regular physical activity and sticking to a healthy diet increases your likelihood of successful ageing and decreases your risk for many associated diseases. Physical activity is also associated with an increased lifespan, a lower risk of functional and cognitive impairment, and lower levels of inflammatory markers in older adults. Exercise has also been reported to favourably impact immune function.
Anti-oxidant dietary supplements have not shown any benefit in modulating inflammation and disease. Diet is strongly linked to levels of inflammation and disease risk. A western diet – categorised by a low intake of fruits, vegetables and fibre plus a high intake of processed grains and saturated fat, particularly red meat – combined with a sedentary lifestyle, is associated with elevated CRP and a higher risk of chronic disease compared to a healthy or Mediterranean style diet. Conversely, the Mediterranean diet - with its high intake of fruits, vegetables, whole grains, fish and olive oil plus a low intake of red meat - is associated with lower levels of inflammation and a decreased risk of cardiovascular disease, dementia and some cancers (as compared to the western type diet). Poor diet may also accelerate telomere attrition and epigenetic alterations in DNA.
Caloric restriction - where caloric intake is reduced but levels of essential nutrients are maintained - has been successful in extending the average and maximum lifespans in several species. In rodents, limiting total calories consumed resulted in an increase in lifespan of as much as 50% when compared to animals allowed free-choice feeding. Evidence for a similar effect in humans can be found in the population of Okinawa, Japan, who reportedly eat fewer calories than the mainland Japanese population and have a larger proportion of centenarians.
Stress may also play an important role in causing inflammation. Stress is induced by a variety of factors including caregiving and socioeconomic status. Lower socioeconomic status - based on education, income and wealth - and pessimism are associated with higher levels of inflammation. In addition, psychosocial stress may also accelerate telomere break down; telomere length was reduced in those with lower socioeconomic status.
Hormone replacement therapy
While some hormone replacement trials have shown limited benefits, the negative side effects of HRT, including an increased risk of cancers, have been reported. There are no current recommendations for replacement therapy
In addition to cardiovascular disease prevention through the reduction of plasma LDL cholesterol, statins are being studied as anti-inflammatory agents. In the “Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (Crestor)” the potential for cardiovascular disease prevention in apparently healthy adults was examined, aimed not at reducing LDL cholesterol levels but at decreasing CRP. Trial data suggests that in this group of adults with LDL cholesterol levels below the threshold for lipid-lowering therapy (≤130 mg/dL) but with elevated CRP (≥2 mg/L intermediate to high risk) Rosuvastatin treatment may be beneficial both in terms of cardiovascular disease prevention and a reduction in non-cardiovascular mortality due to anti-inflammatory effects.
Other therapies aimed at reducing inflammation include direct inflammatory cytokine antagonists and the depletion of pro-inflammatory lymphocytes.
The role of Hypochlorous acid in reducing inflammation of the skin with Thoclor Labs GF1 and GF2.
From recent publications in medical journals, it is now known that Hypochlorous solution (HOCl) suppresses and reverses inflammation in the skin, as well as in wounds. This is due to the block effect that HOCl has on the protein messengers that activate the gene that is responsible for inflammation, ageing and disease. HOCl also counteracts the effects of IL-6, IL-2 and IL-1beta, which are raised in inflammation. When HOCl chlorinates tauramine (an amino acid) this then forms tauramine chloramine, which also has a strong anti-inflammatory effect.
The control of both acute and chronic inflammation is essential. Inflammation has no beneficial effect in or on the skin.
We recommend our GF1 Aftercare for cases of acute inflammation, as seen with skin manipulation treatments and procedures. GF1 inhibits and reverses redness, pain and a prolonged period of swelling. If GF1 is not used the recovery time is protracted, with an increased risk of PIH.
In all other individuals, a case can be made for the long-term control of inflammageing. This low-grade inflammation that is almost always present in the skin not only ages the skin at an accelerated rate but is also responsible for diseases like rosacea, acne, pigmentation disorders and cancer. By controlling inflammageing, we can control the accelerated process of ageing in the skin resulting from redox reactions to pollution, UV-exposure and circulating inflammatory mediators due to systemic inflammageing processes. For this, we recommend GF2 Skin Rejuvenation used twice a day, every day.
Apart from the control of inflammation, GF2 also will cause true skin rejuvenation (the reversal of the ageing process) to occur, with regular long-term use.
- Nancy Jenny. Inflammation in ageing: Cause, Effect, or Both? Discovery Medicine. June 2012.
- Chong-Hou, Sam Hsein-Kun Lu. The Role of Hypochlorous Acid as One of the Reactive Oxygen Species in Periodontal Disease. J Dent Sci 2009; 4(2): 45 - 54.
- Marcinkiewicz J et al. Differential effects of chlorination of bacteria on their capacity to generate NO, TNF-% and IL-6 in macrophages. Immunology 1994; 83:611−6.
- Fukuyama, T et al. Hypochlorous acid is antipruritic and anti-inflammatory in a mouse model of atopic dermatitis. Clin Exp Allergy. 2018; 48:78 – 88.
- Thomas H. Leung et al. Topical hypochlorite ameliorates NF-kB–mediated skin diseases in mice. J Clin Invest. 2013;123 (12):5361-5370 Stanford University School of Medicine, Stanford, California, USA.