What is inflammaging and how it induces skin aging

Inflammation is one of the most common processes in the human body. Thanks to inflammatory process, the body responds to different factors, endogenous or exogenous, protecting it. Yet, inflammation can also occur in non-pathogenic situations such as aging, a process called immunosenescence or inflammaging (inflammation + aging).

What’s inflammaging

Stress and continuous exposure to different allergenic elements produce a chronic state of inflammation that is characteristic and associated with aging. Inflammaging is characterized as a mild and chronic systemic inflammation [1]. Such is its importance, that it is considered the basis of many diseases related to aging such as dementia, type 2 diabetes or arthritis [2]. Inflammaging (or immunosenescence) is produced by the action of different cytokines such as interleukins IL-1 and IL-6, and Th2 lymphocytes [3]. The mechanisms that most influence skin aging are DNA damage in dermal cells and increased oxidative stress, both processes related to inflammaging. In this blog, we already discussed the effects of stress on the skin and early aging.

Oxidative stress in inflammaging

Oxidative stress can lead to the activation of pro-inflammatory pathways in the body [4], which contribute to the pathogenesis of many age-related diseases. Aging cells have high levels of reactive oxygen species that damage DNA [5].

Oxidative stress produced as a result of immunosenescence is linked to cardiovascular diseases related to aging. While mitochondrial reactive oxygen species and pro-inflammatory cytokine production increase are implicated in neurodegenerative diseases and tumour formation [6].

Oxidative stress also influences other diseases related to aging such as rheumatoid arthritis and diabetes. In the case of diabetes, levels of advanced glycation end products (AGEs) increase, just as they do during aging. These products, by binding to their receptors (RAGE), produce a pro-inflammatory response that leads to cellular senescence. Therefore, RAGE are considered as pattern recognition receptors, similar to those that regulate innate immunity. This immunity plays a central role in inflammation and contributes to aging [7].

With aging, the circulation of RAGE receptor ligands increases, leading to an increase in their expression. This increase could favour persistent low-grade pro-inflammatory processes, which in turn, could drive a greater expression of RAGE. This progressive vicious cycle of events places RAGE firmly in the spotlight as a key player in inflammaging [8].

Skin inflammaging

Skin aging is caused by two types of processes called intrinsic and extrinsic aging, and which we talked about in a previous post. In both cases there is an increase in oxidative stress and inflammation.

The increase in oxidative stress produces the activation of the complementary system, that is part of the immune system and is expressed in multiple skin cells such as keratinocytes, fibroblasts and macrophages. Increased oxidative stress activates the production of complement C3 in keratinocytes. This, by binding to its receptor, activates macrophages that infiltrate the epidermis, degrading the extracellular matrix and releasing pro-inflammatory mediators, which ends up causing chronic inflammation and damage to the dermis [9].

In addition to the damage to the dermis, inflammaging is responsible for another characteristic of aging such as spots on the skin. In the area of ​​the spots there is an increase in the number of melanocytes and the inflammatory response compared to the area around them [10].

Inflammaging in neurons

The neurons of the skin are part of the peripheral nervous system, these neurons are responsible for detecting stimuli such as touch or temperature and are the initiators of signs of discomfort such as itching.

The peripheral nervous system has a great capacity for regeneration, which allows the functional recovery of the axons that are located at a great distance from its soma. This ability diminishes with age; macrophages and Schwann cells become less effective in their function of repairing axons damaged as a result of the inflammatory environment around the nerves. In fact, the persistent inflammatory state, that occurs during aging, reduces the efficiency of nerve regeneration due to macrophage infiltration and a high expression of pro-inflammatory markers [11].

The use of anti-inflammatory therapies, such as acetylsalicylic acid treatment, has been shown to be effective in decreasing the inflammatory response of macrophages and accelerating the recovery of peripheral nerves [11]. This indicates that reducing inflammaging could be a development path for future regenerative applications.

Image by ? Mabel Amber, who will one day from Pixabay

How to prevent inflammaging

Physical exercise

Playing sports has antioxidant effects on tissues, specifically on adipose tissue, skeletal muscle, the immune system and the cardiovascular system [12]. This effect occurs thanks to macrophage infiltration and the release of pro-inflammatory and anti-inflammatory cytokines [13].

Antioxidants

The use of antioxidants directly reduces oxidative stress, protecting against damage caused by reactive oxygen species. Antioxidants are present in many fruits and vegetables such as resveratrol. This antioxidant, present in fruits such as grapes, decreases the pathways of inflammation regulated by NF-κβ and favours the inhibition of pro-inflammatory cytokines such as IL-1 and IL-6 [12]. Despite the promise of these results, a greater number of studies with statistically significant evidence are required in order to arrive at a precise recommendation on the consumption of antioxidants for the prevention of inflammaging.

Others

There are few studies and some controversy regarding the use of pharmaceutical drugs to reduce the effects of inflammaging:

• Metformin: is a drug used to control diabetes whose use can induce metabolism associated with dietary restriction, thus limiting the development of diseases associated with aging and inhibiting the expression of genes that code for multiple pro-inflammatory cytokines [12].
• Statins: are drugs used to lower blood cholesterol levels. Regarding inflammaging, a decrease in IL-2 and TNF-α levels in blood has been observed after 8 weeks of treatment [14].

However, the use of metformin and statins to reduce inflammaging is not sufficiently supported, so more studies are needed to evaluate different pharmacological strategies to prevent the effects of inflammaging.

References

1. Fulop T, Witkowski JM, Olivieri F, Larbi A. The integration of inflammaging in age-related diseases. Semin Immunol. 2018 Dec;40:17-35.
2. Fülöp T, Larbi A, Witkowski JM. Human Inflammaging. 2019;65(5):495-504.
3. Alcalá-Pérez D., Cobos-Lladó DE., Jurado-Santa Cruz F. «Inflammaging»: envejecimiento inflamatorio. Rev Cent Dermatol Pascua (2018) Vol. 27, Núm. 3.
4. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked?. Free Radic Biol Med. 2010 Dec 1; 49(11):1603-16.
5. Finkel T, Holbrook NJ. Oxidants, oxidative stress and the biology of ageing. Nature. 2000 Nov 9; 408(6809):239-47.
6. Zuo L, Prather ER, Stetskiv M, Garrison DE, Meade JR, Peace TI, Zhou T. Inflammaging and Oxidative Stress in Human Diseases: From Molecular Mechanisms to Novel Treatments. Int J Mol Sci. 2019 Sep 10;20(18):4472.
7. Teissier T, Boulanger É. The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology. 2019 Jun;20(3):279-301.
8. Frimat M, Teissier T, Boulanger E. Is RAGE the receptor for inflammaging? Aging (Albany NY). 2019 Sep 8;11(17):6620-6621.
9. Zhuang Y, Lyga J. Inflammaging in skin and other tissues – the roles of complement system and macrophage. Inflamm Allergy Drug Targets. 2014;13(3):153-161.
10. Noblesse, E.; Nizard, C.; Cario-Andre, M.; Lepreux, S.; Pain, C.; Schnebert, S.; Taieb, A.; Kurfurst, R. Skin ultrastructure in senile lentigo. Skin Pharmacol. Physiol., 2006, 19 (2), 95-100.
11. Büttner R, Schulz A, Reuter M, Akula AK, Mindos T, Carlstedt A, Riecken LB, Baader SL, Bauer R, Morrison H. Inflammaging impairs peripheral nerve maintenance and regeneration. Aging Cell. 2018 Dec;17(6):e12833.
12. Romero-Cabrera A, Amores-Hernández L. El envejecimiento oxidativo inflamatorio: una nueva teoría con implicaciones prácticas. 2016; 14: 591-599.
13. Park, -M.,   Myers,   M.,   &   Vieira-Potter,   V.   J.   Adipose   tissue   inflammation   and   metabolic dysfunction: role of exercise. Missouri medicine, 111(1), 65-72.
14. Navarrete-Reyes AP, Montaña-Álvarez M. Inflammaging. Envejecimiento de origen inflamatorio. Rev Invest Clin. 2009; 61: 327-336.

Cover image by  Sabine van Erp from Pixabay