The Skin and Science Series
In this blog series, we unravel the intricate science behind it all. Our aim is to empower you with knowledge so that you can make well-informed decisions about your skincare routine. From exploring the intricate workings of various skin types to understanding the powerful ingredients that transform our complexion - each instalment of this series promises to provide you with valuable insights and practical advice.
TL;DR
Ageing skin benefits greatly from antioxidants, as they combat the harmful effects of senescent dermal fibroblasts responsible for skin structure. Dermal fibroblasts lose mobility and functionality with age, produce less collagen which eventually ages our skin. Also, aged dermal fibroblasts produce aged-related factors that accelerate damage to neighbouring cells and propagate this effect. Certain antioxidants, such as EGCG, resveratrol, etc block these ‘age factors’ and can slow the premature ageing process. However, daily topical application is essential for sustained results. In the future, advanced senolytic therapies will eliminate these aged cells, offering a real breakthrough in anti-ageing skincare.
What Happens to Skin as It Ages?
While we may all benefit from topical antioxidants for general skin health, there is one group that stands to benefit the most – the ageing skin.
There is something peculiar that occur as skin ages. Macroscopically, we are all familiar with the typical tell-tale signs – fine lines, wrinkles, discolouration and loss of elasticity. However, it’s important to understand what is occurring within the skin at the microscopic level that gives rise to the macroscopic appearance. It has mostly due to a group of cells called Dermal Fibroblasts (DFs).
DFs are the second most abundant cell type in the skin, next to keratocytes and they are responsible for skin integrity so unsurprisingly they are a major target when it comes to aesthetics. They are highly active cells, constantly on the move as they crawl within the skin tissue to maintain the structure of the skin.
Why do fibroblast move around while other cells like keratocytes stay put? Keratocytes are the cells that make up the skin itself. They divide upwards to replace older skin cells when they slug off with time. Most importantly, keratocytes don’t move and are ‘glued’ together with other keratocytes.
This is because their role is chiefly to produce the dead layer of skin cells that maintain the skin barrier. Whereas fibroblast are free moving cells and move laterally within the skin where they make the skin scaffold and structure.
Cells that are highly mobile (move quickly) generally have a ‘spindle’ appearance – thin and slender. . Credit: Rachid El Morabiti from JEDI
Dermal Fibroblasts: The Architects of Skin Structure
Fibroblast make up collagen, elastin, hyaluronic acids, GAGS etc. These molecules strengthen the skin and give it’s ‘firmness and bounciness’. To make these molecules, fibroblasts need to move around and lay down these molecules across the skin.
But they are not just making new molecules, they are also degrading older molecules at the same time. There is a delicate balance of making new collagen and degrading old collagen and young healthy DFs do this well.
The delicate balance of collagen synthesis and degradation
The story changes when fibroblasts age. Aged fibroblasts make less collagen than they degrade, and this results in weaking the skin structure. Ageing is the major culprit and this process can either be natural which occurs with biological ageing or it may be accelerated (pre-mature) ageing due to chronic inflammation, Western diet, alcohol, UV exposure, DNA damage or other stressors to the cells.
We are seeing a dramatic rise in the above risk factors for accelerated ageing and unsurprisingly we’ve observed a further spike premature ageing in the post-COVID era – likely as a result of chronic inflammation associated with long COVID[1].
The Impact of Ageing and Stress on Fibroblasts
So, what happens to fibroblasts when they are chronically stressed and under pre-mature ageing? A lot.
Firstly, they change shape. They are no longer thin and slender. They are now much larger and rounder and filled with fat goblets. As a result, they don’t move around quickly…or much at all. They resemble adipocytes (fat cells), in both appearance and in function[2].
They are also less numerous in the skin. Chronic stress in DFs causes some to die (apoptosis) and others become functionally silent [3, 4].
Pre-maturally aged DFs then enter a state called senescence. This phenomenon is called ‘stress-induced (pre-mature) senescence (SIPS)’. This is a permanent state of dormancy. Senescent fibroblasts have entered an eternal sleep from which they do not wake. They are present, but they are not doing much. As mentioned earlier, they make little collagen or other important skin components (i.e. elastin, hyaluronic acid etc) [3, 5].
For Re-Dox blogs and offers, subscribe to our newsletter here.
In this state of slumber, senescent DFs are instead making matters worse for the skin. They are actively secreting factors that instruct neighbouring healthy dermal fibroblast to go to sleep. These secreted factors are collectively called SASPS – ‘senescence-associated secretary phenotype’[5, 6].
The Domino Effect: SASPs and Cellular Damage
Think of the bad apple analogy. One bad apple in a carton of healthy apples can turn the whole carton bad.
Similarly, DFs producing SASPs ‘infect’ healthy dermal fibroblasts which then also become senescent, producing more SASPS…and the cycle continues.
Too many senescent DFs eventually erode the ability of the skin to maintain it’s structural integrity and soon the physical signs of ageing appearance [7].
Adapted schematic illustrating the propagation of cellular senescence via SASP secretion [8]
The Challenge of Treating Premature Ageing Clinically
From a clinic perspective, it’s makes it more difficult to treat our clients who are experiencing pre-mature ageing. Why? Most of our techniques intent to target dermal fibroblasts – trying to trick them into making more collagen, elastin and other essential components of the skin.
An understated truth is that the effectiveness of our techniques depends largely on the health of existing DFs.
Healthy DFs can better respond to stimuli and syntheize more collagen compared to aged DFs. So, we can expect a high level of responsiveness from individuals with pre-existing healthy DFs, than those with pre-maturally aged DFs.
Compared to young/healthy DFs, prematurelly aged DFS which are senescent are not likely to respond to stimuli from microneedling, IPL, lasers, chemical peels and even biostimulators.
This is where certain antioxidants come in to help - antioxidants can break the cycle of SASPS.
With antioxidants, consistency is key
Certain antioxidants have been demonstrated to be effective blockers of SASPS[9]. They can silence the secretion of SAPS from senescent DFs which negatively affect neighbouring healthy cells. In this way, these antioxidants can slow down the pre-mature ageing process by acting at the cellular level. These classes of antioxidants are known as ‘Senomorphics’, and the list of antioxidant senomorphics is rapidly expanding. I have compiled a list of well-known antioxidant senomorphic compounds below, with the most well-researched and notable in bold.
- ECGC
- Resveratrol
- Catechin
- Flavonoids
- Apigenin
- Naringenin
- Fisten
- Quercertin
- Curcumin
The caveat? They are only as effective so long as you continually use them.
Adapted scheumatic demonstrating how antioxidant senomorphic compounds can block SASP production in DFs, breaking the cycle of ‘stress-induced (pre-mature) senescence’ (SIPS).
As SASPS are continually produced by senescent DFs, they require continually blocking through the efforts of senomorphic antioxidants. So topical antioxidants are the long game when it comes to starving off pre-mature ageing, particularly when it is linked to modern day risk factors for SIPS.
Conclusion: A Long-Term Strategy for Healthier Skin
In summary, daily topically application of antioxidants may be an effective strategy to slow down the ageing process by acting as senomorphic agents to prevent the spread of SIPS to otherwise healthy cells. Remember that senescent DFs are generally considered permanent, though we can act early to prevent the spread of this dormancy to other cells.
The eventual goalpost is to remove SIPS entirely from the skin and this approach is termed Senolytic therapy. While still very much in its infancy, there are already 5x clinical trials of Senolytic therapy using a combination of antioxidants and in some cases with anti-cancer drugs. Successful senoyltic therapy is truly the turning point for skin health and ageing, where it’s application will be second-to-none.
References
- Tizazu, A.M., H.M. Mengist, and G. Demeke, Aging, inflammaging and immunosenescence as risk factors of severe COVID-19. Immun Ageing, 2022. 19(1): p. 53.
- Gruber, F., et al., Cell aging and cellular senescence in skin aging - Recent advances in fibroblast and keratinocyte biology. Exp Gerontol, 2020. 130: p. 110780.
- Rebehn, L., et al., The weakness of senescent dermal fibroblasts. Proc Natl Acad Sci U S A, 2023. 120(34): p. e2301880120.
- Wlaschek, M., et al., Connective Tissue and Fibroblast Senescence in Skin Aging. J Invest Dermatol, 2021. 141(4S): p. 985-992.
- Zhang, J., et al., Aging in the dermis: Fibroblast senescence and its significance. Aging Cell, 2024. 23(2): p. e14054.
- Narzt, M.S., et al., Epilipidomics of Senescent Dermal Fibroblasts Identify Lysophosphatidylcholines as Pleiotropic Senescence-Associated Secretory Phenotype (SASP) Factors. J Invest Dermatol, 2021. 141(4S): p. 993-1006 e15.
- Smith, P. and B. Carroll, Senescence in the ageing skin: a new focus on mTORC1 and the lysosome. FEBS J, 2024.
- Zhang, Q., et al., Targeted delivery strategy: A beneficial partner for emerging senotherapy. Biomed Pharmacother, 2022. 155: p. 113737.
- Zhu, M., et al., Advancements in therapeutic drugs targeting of senescence. Ther Adv Chronic Dis, 2020. 11: p. 2040622320964125.
