Senescence in Skin Aging — How Qualia Senolytic May Support Skin Youthfulness

What is Cellular Senescence?

Cellular senescence is a state of irreversible growth arrest that turns functional cells into “zombie cells”—cells that are unable to divide and proliferate, but also resistant to cell death. Senescence changes cells’ characteristics, functions, and the set of molecules they secrete. Molecules released by senescent cells are collectively known as the senescence-associated secretory phenotype (SASP) and include cytokines, chemokines, matrix metalloproteinases (MMPs), and growth factors, for example. These mediators can modulate the activity of surrounding cells and influence tissue function and health [1,2]. 

In normal conditions, senescent changes can be triggered in response to cellular stressors and have a beneficial role by preventing the proliferation of dysfunctional cells. There are many stress stimuli that can induce cellular senescence, such as exposure to environmental insults, mitochondrial dysfunction, persistent DNA damage, abnormal growth activation, oxidative stress, tissue damage signals, telomere shortening (a factor that limits DNA replication and cell division), among others [1]. 

The accumulation of senescent cells triggers a cascade of cellular dysfunction that disrupts tissue function and contributes to unhealthy aging.

Among other actions, SASP mediators help to recruit immune cells. The recruited immune cells should clear senescent cells from tissues to prevent their accumulation. This is part of the healthy function that promotes tissue repair and regeneration. But with aging, the immune system’s performance tends to change in predictable ways—this is called immunosenescence. One of the hallmarks of immunosenescence is that the immune system becomes less efficient in finding and eliminating senescent cells, which contributes to their accumulation in tissues. SASP factors are able to induce senescence in other cells (this is sometimes called the “bystander effect” and means that senescent cells can spread senescence to their neighbor cells). Senescent cells accumulate with aging, because of both immunosenescence and the bystander effect. This accumulation triggers a cascade of cellular dysfunction that disrupts tissue function and contributes to unhealthy aging [1,2]. In fact, cellular senescence is one of the hallmarks of aging [3].  

How Senescent Cells Contribute to Skin Aging

Senescence occurs in all types of tissues and organs: the skin is no exception. Age-related senescent changes in the skin cells are common. In normal conditions, what might be thought of as transient cellular senescence (i.e., senescent cells are removed shortly after they are created) in the skin has a protective role by promoting wound healing, protecting the skin from the detrimental effects of environmental insults, and preventing abnormal growth [4]. But with aging, senescent cells can linger, accumulating progressively in the skin, inducing senescence in neighboring cells [4,5], and creating a snowball effect of tissue degeneration and functional decline [6,7].  

The skin has different types of cells that can potentially become senescent. The accumulation of senescent keratinocytes in the epidermis and senescent fibroblasts in the dermis are probably the most significant; they contribute the most to the skin’s structural and functional decline. Not only are keratinocytes and fibroblasts the most abundant cell types of the epidermis and the dermis, respectively, they also have a central role in maintaining key characteristics associated with youthful skin, such as healthy barrier function, hydration, smoothness, elasticity, and firmness. Other skin-resident cell populations that may become senescent and contribute to skin aging include melanocytes, the cells that produce the pigment melanin that protects the skin from sunlight damage [8], and the different types of immune cells found in the skin [9].

The amount of senescent cells in the skin gradually increases with age as a result of intrinsic factors such as the ones mentioned above (mitochondrial dysfunction, DNA damage, oxidative stress, etc), but these internal factors are not the sole triggers of senescent changes. Extrinsic factors, such as environmental stressors, can cause a premature accumulation of senescent cells and, consequently, accelerate skin aging. Sunlight exposure and pollution are two of the major environmental triggers of cellular senescence [10,11]. Sunlight radiation, for example, can cause DNA damage, mitochondrial dysfunction, and oxidative stress in the skin, all of which are triggers for senescence [10]. Therefore, the skin is particularly susceptible to senescence. In vitro studies have shown that high-energy sunlight radiation induces senescence of keratinocytes [12], fibroblasts [13], and melanocytes [14]. 

One of the reasons senescent cells accumulate in the skin with aging is that the immune system is less effective at eliminating them [15]. The skin’s immune cells are themselves increasingly susceptible to senescence as we age and there is a decline in the immune mechanisms that eliminate senescent cells [16]. Furthermore, high-energy sunlight radiation also has immunosuppressive actions, further contributing to this loop of accumulation of senescent cells [17,18]. 

The skin’s immune cells are themselves increasingly susceptible to senescence as we age and there is a decline in the immune mechanisms that eliminate senescent cells.

Senescence of skin cells impairs their functionality and impacts the molecules they produce, which has a profound impact on skin physiology: it compromises skin barrier function, impairs protection from and resistance to environmental stressors, and disrupts the integrity of the dermal extracellular matrix; these effects manifest as loss of elasticity and firmness, thinning of the skin, wrinkling, loss of hydration, and many other changes commonly associated with skin aging [19–21]. 

How Skin Senescence May Influence Systemic Health

The relevance of the skin for our systemic (i.e., whole-body) health is highly undervalued. We don’t usually think of the skin as a vital organ, but we should. The skin is the largest organ of the human body. It has the essential role of simultaneously isolating the body from the outside world, protecting it from environmental aggressions, sensing the environment, and promoting physiological adaptations that maintain physiological homeostasis.

To carry out these functions, the skin combines within it three important physiological systems with whole-body (i.e., systemic) actions: the nervous, endocrine, and immune systems. Through the production of their signaling molecules—neurotransmitters, hormones, and immune signaling mediators—the skin is able to communicate with and influence other tissues and organs, including the brain, and thus the whole body [22–24]. 

The skin’s neuroendocrine system is in permanent crosstalk with the brain and the hypothalamic–pituitary–adrenal (HPA) axis (the central neuroendocrine signaling system that influences all sorts of body processes), through what is known as the skin-brain axis or brain-skin connection [24,25]. The hypothalamus not only has a central role in maintaining body homeostasis by integrating environmental and physiological signals [26], it is also involved in longevity and lifespan regulation and has a crucial role in systemic aging [27]. Therefore, by influencing hypothalamic signaling, the skin may indirectly influence whole-body signaling and play a part in systemic aging.

Supporting skin health and healthy skin senescence processes may therefore help to maintain or even promote the skin’s intrinsic capacity to resist environmental aggressions and to protect not only itself, but also the whole body from its aging-promoting effects.

Environmental stressors that accelerate skin aging can also influence neuroendocrine signaling in the skin. For example, through its action on the skin, sunlight radiation activates endocrine signaling via the HPA axis [28,29] (excessive sun exposure can be stressful). Many of the skin’s neuroendocrine signaling molecules are produced by cells that are susceptible to senescence and whose senescence is accelerated by those same environmental stressors [23,30]. Also, many SASP molecules produced by senescent cells have the capacity to influence neuroendocrine signaling [31]. In turn, through its crosstalk with the HPA axis, these molecules can influence neuroendocrine signaling at the systemic level. So by accelerating age-related changes in neuroendocrine signaling in the skin, environmental stressors may end up having similar effects at the systemic level. 

And it’s not just neuroendocrine signaling: sunlight radiation also influences immune system function [17,18]. Sunlight can have a suppressive effect on skin immunity whose manifestations include immunosenescence and changes in the production of immune mediators with systemic actions that also influence signaling pathways and other processes associated with aging [32].

Supporting skin health and healthy skin senescence processes may therefore help to maintain or even promote the skin’s intrinsic capacity to resist environmental aggressions and to protect not only itself, but also the whole body from its aging-promoting effects. 

Senolytics for Skin Aging

Compounds that support the management of senescent cells have the potential to help discourage age-related changes in skin structure and function driven by cellular senescence. By doing so, they may contribute to the maintenance of both healthy skin, and because skin health is so important to the health of other tissues and organs, to our overall health [33].* 

There are a few different approaches to the management of senescent cells:  

1. Senolytic Support: Senescent cells are experts at surviving, exploiting normal cellular prosurvival functions to linger. Compounds that have an affinity for finding cells that are using senescent cell prosurvival mechanisms, and then encouraging them to resume normal cellular functions that result in their removal from tissues are known as senolytics.*
2. Senomorphic Support: Senescent cells can spread senescence to neighboring cells because of the SASP they secrete (this is the bystander effect mentioned earlier). Compounds that dampen SASP, or change the characteristics or behaviors of senescent cells to be more like healthy cells are known as senomorphics (sometimes called senostatic).*
3. Immune System Support: One of the jobs of the immune system is to find senescent cells and remove them. When we are young, the immune system will typically be great at finding senescent cells. As we get older, the immune system tends to gradually become less proficient. Supporting a healthy immune system during aging, especially the immune cells that are critical in recognizing senescent cells, such as natural killer (NK) cells and T cells, is an important part of managing senescent cells.

Better management of senescent cells can support tissues in staying healthy [34]. In animal studies, this has been the case in a number of different tissues, including the skin. Several plant compounds may support skin health by influencing skin senescent cells. Qualia Senolytic contains these plant compounds—compounds that offer senolytic and/or senomophic support for skin health.*

Here are some examples of scientific studies that show how Qualia Senolytic may support the management of skin senescence:

Quercetin had a restoring effect on senescent dermal fibroblasts by supporting healthy cellular functions including senescence-associated genes and antioxidant enzyme genes [35].* 

Oleuropein and hydroxytyrosol, two polyphenolic compounds found in Olive Leaf Extract, supported the management of senescent cell numbers and influenced their secretory properties when administered to pre-senescent human dermal fibroblasts [36]. Hydroxytyrosol also supported resistance to the pro-aging effects of environmental stressors in human dermal fibroblasts by influencing the expression of molecules that contribute to the degeneration of the dermal extracellular matrix [37].* 

Genistein, one of the isoflavones found in Soybean extract, supported resistance to environmental stress-induced senescence in human dermal fibroblasts by supporting antioxidant enzyme activities and healthy mitochondrial function [38]*

Oligosaccharides purified from Panax notoginseng opposed fibroblast replicative senescence and promoted fibroblast cell proliferation [39].*

A number of Qualia Senolytic ingredients also offer support for the body’s normal signaling pathways associated with senescence induced by environmental stressors in keratinocytes and fibroblasts, including fisetin [40,41], quercetin [42], curcumin [43], genistein [44], and luteolin [45,46].*

You Might Wonder: Does Fasting Clear Senescent Cells?

Autophagy is a natural process in the body that helps to clean up and recycle cellular waste, providing a variety of health benefits. Natural autophagy has been linked to healthy cognitive function, optimal antioxidant function, and optimal overall health.

Fasting is a popular way to promote autophagy and for good reason. During periods of fasting, the body begins to break down and recycle its own cells. This helps to discourage detrimental immune signaling processes and support overall health. Studies have also found that fasting may have cognitive benefits. A 2022 study from the University of Southern California found that fasting could support memory and cognitive performance in mice.* To learn more about the benefits associated with fasting check out our podcast with Dave Asprey.

So why not just fast, instead of taking Qualia Senolytic? Ingredients in Qualia Senolytic support the body’s normal process of autophagy. That said, we'd think of supporting autophagy as a secondary benefit. 

The main intended benefit of Qualia Senolytic is managing senescent cells, which is not the same thing as autophagy. Autophagy and cellular senescence are two distinct cellular responses that can be activated by a variety of stresses and have to do with aging (so it's easy to confuse them). Both are needed to keep us healthy but they are different processes. 

Autophagy (literally meaning “self-eating”) is focused on degrading and recycling components inside cells and mitochondria (mostly damaged proteins and organelles). It helps maintain cellular homeostasis so that a cell does not become senescent (think of autophagy as an anti-senescence mechanism). 

Cellular senescence is about the whole cell and occurs when a cell has become so stressed and worn out that cleaning up some of the damage inside it is no longer sufficient. Instead of autophagy, a senescent cell needs to go through a "falling off" process (a healthy cellular function called apoptosis). Senolytics are focused on supporting the whole cell to promote the completion of this falling off process. This is the main goal of Qualia Senolytic.* Shop now. 

*These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, cure, or prevent any disease.

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