Cellular senescence, skin ageing and cellulite
Is cellulite (and skin ageing) a senescence condition?
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Cellular senescence, mitophagy and senolysis
Cellular senescence is especially common in skin and fat tissue
Senescence of the combined skin/adipose organ in the hypodermis, called cellulite
Is cellulite a senescent body organ?
If cellular senescence is an important aspect of skin aging and cellulite, how do we fight it?
Senolytics for anti-ageing and cellulite prevention
Senolytic molecules in anti-aging creams and cellulite creams
Senolytic molecules in nutritional supplements
Senescence, senolytics and long Covid
Fat tissue, aging, and cellular senescence
Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols
Biochemistry of adipose tissue: an endocrine organ
Skin aging, cellular senescence and natural polyphenols
Skin senescence: mechanisms and impact on whole-body aging
Check our professional consultancy for a masterclass in radiofrequency, ultrasound cavitation, cellulite and skin tightening
Cellular senescence, mitophagy and senolysis
Cellular senescence, literally meaning “cell aging”, is the process by which cells stop dividing and enter a senile stage, characterised by dysfunction and the spreading of inflammation.
Cellular senescence leads to the production of pro-inflammatory mediators that can spread inflammation to thousands of other cells in the vicinity of a group of senescent cells or even throughout the body.
Cells normally enter cellular senescence after approximately 50 cell divisions (mitoses) and this normal process is known as "replicative senescence". When a cell enters senescence it is selected to be cleared by the immune system, in a process called senolysis.
However, cells may enter senescence prematurely due to other stress factors, such as environmental and internal damaging events, abnormal cellular growth (e.g. cancer), oxidative stress etc.
When a cell’s mitochondria are damaged by oxidative or other stress and become dysfunctional, they are cleared from the cell by a process called mitophagy. A cell with faulty mitochondria becomes dysfunctional and senescent.
From the above it becomes apparent that:
Mitochondria should be protected from oxidative and other stress
If mitochondria become damaged they should be cleared by the cell (mitophagy)
And if a cell cannot repair its mitochondria and become senescent, it should be cleared itself by the immune system (senolysis)
Cellular senescence is especially common in skin and fat tissue
At this point I can hear you ask: “What’s with all this technical introduction? Why is senescence so important for skin anti-ageing and even for cellulite prevention”?
Because cellular senescence is very common in skin and adipose tissue, leading to dysfunction, inflammation and tissue damage and aging.
Skin is the largest organ in the body and in overweight individuals adipose tissue becomes the largest body organ, bigger than skin itself. Plus adipose tissue is the largest endocrine organ of the body too.
We can see here that the two largest body organs are also the ones that are:
the most affected by cellular senescence
implicated in cellulite, the main subject of this website
Senescence of the combined skin/adipose organ in the hypodermis, called cellulite
In people with cellulite, where adipose tissue inside the hypodermis (deepest layer of skin) becomes enlarged, we have a mix of senescent skin and senescent adipose tissue, at the same time.
Cellular senescence quite often starts from oxidative stress, either directly (direct oxidative stress damage) or indirectly (indirect mitochondrial damage caused by oxidative stress, via inflammatory or other signalling pathways).
We know that:
oxidative stress (which causes senescence)
inflammation (also causes and is caused by senescence)
fibrosis (the result of myofibroblast senescence)
glycation (also causes senescence)
…are four very important aspects of cellulite.
Is cellulite a senescent body organ?
So clearly cellular senescence plays an important role in cellulite, if not THE most important. So we can view cellulite as a combined senescent adipose/skin organ.
If cellular senescence is an important aspect of skin aging and cellulite, how do we fight it?
As mentioned above, there are two ways to fight senescence: to prevent it before it happens and to reduce it when it happens.
A diet low in sugar, fried/overcooked/charred food and hydrogenated fats, as well as stopping smoking and reducing alcohol drinking (all major causes of oxidative stress, inflammation and glycation) can help prevent senescence and thereby skin ageing and cellulite
Antioxidants and natural anti-inflammatory molecules (polyphenols and carotenoids), found in abundance berry fruits, citrus fruits, vegetables, herbs and species are very important is preventing cellular senescence and consequently skin ageing and cellulite
Readers of this website will notice that these are our standard advice for both anti-ageing and cellulite prevention/reduction and this advice also holds true if we see skin ageing / cellulite under the prism of cellular senescence.
We make it clear again and again that healthy eating, rich in polyphenols and carotenoids and low in junk molecules (fried oils, charred proteins, sugar etc) are essential to prevent cellulite and skin ageing (not to mention cancer, cardiovascular disease, diabetes etc).
Senolytics for anti-ageing and cellulite prevention
The new thing here is the use of key polyphenols that also have a specific senolytic effect on skin and adipose tissue.
It has emerged over the last few years that the following natural molecules have a strong senolytic effect, i.e. they have to ability to clear senescent cells and thereby help eliminate the effects of senescence in the whole body - including skin, fat tissue, skin tissue and cellulite.
These senolytics are as follows, in order of effectiveness and importance, and especially the top four ones, in bold type)
Fisetin (from apples and strawberries)
Quercetin (from citrus fruits)
EGCG (from green tea)
Curcumin (from turmeric)
Catechins (from cocoa and green tea)
Resveratrol (from berry fruits)
Ellagic acid (from pomegranates)
Procyanidins (from berry fruits, pine bark extract)
Senolytic molecules in anti-aging and cellulite creams
From the top four molecules, EGCG and curcumin (the white version), are included in a very small number of high quality anti-ageing / anti-cellulite creams in a substantial concentrations.
(Most such creams are diluted commercial junk, even expensive ones. Sorry, but this is the inconvenient truth.)
Quercetin, although super important, is too yellow to be included in skincare (clothes will become yellow in no time).
There are no products on the market with significant concentration of fisetin (there are just a few diluted junk ones).
And there are very, very few creams on the market with catechins (cocoa flavanols), ellagic acid and resveratrol, but these are secondary molecules when it comes to senescence.
Procyanidins are too purple / blue / red to be used in skincare.
All in all, EGCG and “white” curcumin are the only important senolytic molecules contained in some rare anti-ageing / anti-cellulite creams in sufficient concentrations.
Senolytic molecules in nutritional supplements
The good news is that all the above senolytic molecules can be found in several nutritional supplements.
Just choose a reputable brand (very important) with a high concentration of senolytics per capsule (always important).
DISCLAIMER: This article does not constitute medical diagnosis or advice. Always consult a healthcare practitioner before using a supplement, especially in high doses.
Senescence, senolytics and long Covid
The Covid-19 virus, as well as many other viruses (such as the epstein-barr virus / EBV and other herpes family viruses), are known to damage the mitochondria and cause cellular senescence and fatigue.
The end result can be fatigue (remember, mitochondria are the powerhouses of the cell), immune dysfunction, inflammation, chronic fatigue syndrome (CFS), long covid etc.
In these cases, a combination of senolytics could offer precious help.
Personally, I had great results by taking for a few weeks 2,000mg of quercetin, 1,000mg of curcumin and 500mg of EGCG.
(I found that fisetin, apparently the most effective senolytic, repeatedly gave me numbness on the lips, which freaked me out, so I stopped it. Of course different people would have different results and at different doses but that was my experience.)
DISCLAIMER, again: This article does not constitute medical diagnosis or advice. Always consult a healthcare practitioner before using a supplement, especially in high doses.
There is a lot to be said about long covid and chronic fatigue syndrome and at some point I would like to write my personal experience of CFS, long covid and senolytics, when time allows.
In the meantime, let’s stick to the point that cellular senescence does cause whole body aging, skin aging and that it most probably is an important factor in cellulite.
Although senescence is already implicated in skin aging, don’t expect to see any paper dealing directly with the cellular ‘senescence-cellulite’ connection. This is because:
Most papers regarding senescence deal with important medical conditions
Most papers regarding cellulite treatments are based on fake data and are not worth the paper they are written on (they are basically advertising material for cellulite equipment companies and cosmetic surgeons - sorry again, but this is the inconvenient truth)
Every few years, of course, the occasional brilliant paper on cellulite anatomy and physiology is published, but these are literally a drop in the ocean.
So expect to see a paper connecting cellulite to cellular senescence by 2035 and whenever it materialises, we will be the first to present it.
And expect the glossy mags, glossy websites and glossy instagram pages to talk about it by 2045 - or whenever some celebrity TV doctor makes a fuss about it…
Fat tissue, aging, and cellular senescence
Research paper abstract: Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age-related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state. Other mesenchymal progenitors also can acquire a pro-inflammatory, adipocyte-like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro-inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress-responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent-like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro-inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.
Possible Mechanisms of Oxidative Stress-Induced Skin Cellular Senescence, Inflammation, and Cancer and the Therapeutic Potential of Plant Polyphenols
Research paper abstract: As the greatest defense organ of the body, the skin is exposed to endogenous and external stressors that produce reactive oxygen species (ROS). When the antioxidant system of the body fails to eliminate ROS, oxidative stress is initiated, which results in skin cellular senescence, inflammation, and cancer. Two main possible mechanisms underlie oxidative stress-induced skin cellular senescence, inflammation, and cancer. One mechanism is that ROS directly degrade biological macromolecules, including proteins, DNA, and lipids, that are essential for cell metabolism, survival, and genetics. Another one is that ROS mediate signaling pathways, such as MAPK, JAK/STAT, PI3K/AKT/mTOR, NF-κB, Nrf2, and SIRT1/FOXO, affecting cytokine release and enzyme expression. As natural antioxidants, plant polyphenols are safe and exhibit a therapeutic potential. We here discuss in detail the therapeutic potential of selected polyphenolic compounds and outline relevant molecular targets. Polyphenols selected here for study according to their structural classification include curcumin, catechins, resveratrol, quercetin, ellagic acid, and procyanidins. Finally, the latest delivery of plant polyphenols to the skin (taking curcumin as an example) and the current status of clinical research are summarized, providing a theoretical foundation for future clinical research and the generation of new pharmaceuticals and cosmetics.
Biochemistry of adipose tissue: an endocrine organ
Research paper abstract: Adipose tissue is no longer considered to be an inert tissue that stores fat. This tissue is capable of expanding to accommodate increased lipids through hypertrophy of existing adipocytes and by initiating differentiation of pre-adipocytes. Adipose tissue metabolism exerts an impact on whole-body metabolism. As an endocrine organ, adipose tissue is responsible for the synthesis and secretion of several hormones. These are active in a range of processes, such as control of nutritional intake (leptin, angiotensin), control of sensitivity to insulin and inflammatory process mediators (tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), resistin, visfatin, adiponectin, among others) and pathways (plasminogen activator inhibitor 1 (PAI-1) and acylation stimulating protein (ASP) for example). This paper reviews some of the biochemical and metabolic aspects of adipose tissue and its relationship to inflammatory disease and insulin resistance.
Skin aging, cellular senescence and natural polyphenols
Research paper link: https://pubmed.ncbi.nlm.nih.gov/34884444/
Abstract: The skin, being the barrier organ of the body, is constitutively exposed to various stimuli impacting its morphology and function. Senescent cells have been found to accumulate with age and may contribute to age-related skin changes and pathologies. Natural polyphenols exert many health benefits, including ameliorative effects on skin aging. By affecting molecular pathways of senescence, polyphenols are able to prevent or delay the senescence formation and, consequently, avoid or ameliorate aging and age-associated pathologies of the skin. This review aims to provide an overview of the current state of knowledge in skin aging and cellular senescence, and to summarize the recent in vitro studies related to the anti-senescent mechanisms of natural polyphenols carried out on keratinocytes, melanocytes and fibroblasts. Aged skin in the context of the COVID-19 pandemic will be also discussed.
Skin senescence: mechanisms and impact on whole-body aging
Research paper link: https://www.sciencedirect.com/science/article/abs/pii/S1471491421003191
Abstract: The skin is the largest organ and has a key protective role. Similar to any other tissue, the skin is influenced not only by intrinsic/chronological aging, but also by extrinsic aging, triggered by environmental factors that contribute to accelerating the skin aging process. Aged skin shows structural, cellular, and molecular changes and accumulation of senescent cells. These senescent cells can induce or accelerate the age-related dysfunction of other nearby cells from the skin, or from different origins. However, the extent and underlying mechanisms remain unknown. In this opinion, we discuss the possible relevant role of skin senescence in the induction of aging phenotypes to other organs/tissues, contributing to whole-body aging. Moreover, we suggest that topical administration of senolytics/senotherapeutics could counteract the overall whole-body aging phenotype.
Section snippets: Skin senescence as a systemic aging trigger: Aging is defined as a progressive process of physiological decline, leading to frailty, age-related conditions, and ultimately to death. Cellular senescence, a defence mechanism in response to damaging stimuli, was highlighted as one of the hallmarks of aging, contributing to a decline in tissue functionality with old age. Senescent cells cease to proliferate while remaining metabolically active, secreting factors known as the senescence-associated secretory phenotype (SASP). • Skin aging and senescence: The skin is the biggest organ of the human body and provides a physical barrier against the environment and, thus, is permanently exposed to environmental aggressors. During the human lifetime, the skin shows relevant changes that enable differences to be recognized between the skin from a child or from an older person. Skin aging is induced by chronological aging, also known as intrinsic aging, or by environmental factors, such as air pollution, smoking, poor nutrition, and… • Markers of skin senescence: Skin senescent cells exhibit the classic markers of cellular senescence. The expression of SA-β-galactosidase in skin cells has long been identified both in vitro and in vivo. This marker is one of the most widely used markers of senescent cells. However, not only is its activity lost in fixed tissue samples, but the technique also lacks specificity, since its activity has been reported in non-senescent cells. In addition, cell cycle inhibitor upregulation, chromatin… • Impact of cellular senescence on skin aging: Growing evidence shows that senescent cells accumulate and contribute to skin aging. Skin from older donors had increased melanocyte p16 expression, and the senescent phenotype of these cells is mainly acquired by length-independent telomere damage [16]. Moreover, melanocyte telomere damage foci were positively correlated with age-related skin features, such as flattening of the epidermal–dermal junction. Additionally, the authors showed that SASP from senescent melanocytes induced…. • Impact of skin senescence on whole-body aging: Evidence suggests that skin senescence propagates the aging phenotype to other tissues or organs. Interestingly, different studies suggest that the skin mirrors health status, mortality risk, and longevity. In fact, studies that examined whether skin wrinkling in sun-protected areas and/or facial appearance correlated with familial longevity, disease risk, and mortality showed that reduced skin wrinkling in sun-protected areas was significantly… • Does eliminating skin senescent cells by using topical senolytic drugs delay whole-body aging? Emergent strategies to counteract aging include senescent cell elimination by using senolytic drugs. The senolytic drugs dasatinib (D) and quercetin (Q) were shown to effectively induce apoptosis in senescent cells. D is an inhibitor of multiple tyrosine kinases and is used for treating cancers, whereas Q is a flavonoid that targets BCL-2/BCL-XL, PI3K/AKT, and p53/ p21/serpine SCAPs. A recent study showed that transplantation of a small number of senescent cells was… Concluding remarks: Given its location, the skin is permanently exposed to environmental aggressors. Via its neuroendocrine system, the skin has a key role in sensing signals from the environment and orchestrating the appropriate responses to maintain organismal homeostasis. Skin senescence occurs with age or in response to exposure to environmental aggressors, such as UVR, and can impact systemic aging by spreading the aging phenotype via SAPS from skin to other tissues and organs…
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