Senescence: What Are Senolytics

Senescence is a term that derives from the Latin word senex, meaning senior or of old age. The word senescence is often used to refer to biological aging and the deterioration that comes with getting older. It takes this meaning when it is used to refer to a whole organism—organismal senescence. But senescence is also a process that occurs at the cellular level. 

Cellular senescence is a physiological process through which, in response to stress, cells stop dividing but don’t die. Instead, senescent cells linger indefinitely, interfering with normal tissue function. Cellular senescence is one of the main contributors to the aging process and has a significant impact on healthspan—the period of life during which one is in good health.

Cellular senescence is one of the main contributors to the aging process and has a significant impact on healthspan—the period of life during which one is in good health.

To combat the impact of cellular senescence, scientists are studying compounds they refer to as senolytics, which are intended to support the natural cellular processes that remove senescent cells. In this article, we will delve deeper into the concept of cellular senescence and the evolving field of senolytics.

Understanding Senescence 

Senescence is a cellular stress response characterized by a permanent state of growth arrest (i.e., cells stop dividing) and the production of chemical mediators that influence tissue function and immune responses. These chemical mediators are collectively known as senescence-associated secretory profile (SASP). SASP includes cytokines, chemokines, matrix metalloproteinases, and other bioactive molecules [1,2]. 

Cells become senescent in response to different types of stress, such as mitochondrial dysfunction, oxidative stress, DNA damage, abnormal growth activation, or telomere shortening, among others. Stressed cells, of all types, should be removed from the body by a cellular process called apoptosis (think of this as being an orchestrated and intentional form of cellular death) and the immune system. Lingering senescent cells are an exception. Despite accumulating damage, these cells don’t die. Instead, they linger by upregulating pro-survival mechanisms called senescent cell anti-apoptotic pathways (SCAPs) and downregulating pro-apoptotic pathways, allowing them to remain in tissues indefinitely [3–5]. Because they refuse to die, senescent cells are commonly referred to as zombie cells. 

Because they refuse to die, senescent cells are commonly referred to as zombie cells.

Senescence occurs as part of healthy tissue function and can have beneficial effects [4,6]. Transient senescence is beneficial because it’s part of a protective response to stress that suppresses the proliferation of dysfunctional cells [7]. Transient senescent cells can promote cellular stemness (i.e., the capacity for self-renewal and differentiation) and enhance regenerative potential, promote tissue repair and remodeling, contribute to tissue homeostasis, and recruit immune cells that remove dysfunctional cells [3]. 

Senescent cells can be beneficial as long as they are promptly removed by the immune system. In normal conditions, senescent cells restrict their own actions by producing SASP mediators that recruit immune cells to eliminate them. But when immune clearance fails, either due to inefficiency of the immune system or to the ability of senescent cells to evade detection, senescent cells can linger in tissues and gradually accumulate. In this context (i.e., lingering or non-removed senescent cells), senescence becomes detrimental and promotes tissue dysfunction and immune signaling dysregulation, both locally and systemically [1–3]. 

Implications of Cellular Senescence

Lingering senescent cells continue to secrete SASP molecules whose actions were meant to be restricted [1–3]. The same SASP molecules that contribute to tissue remodeling and repair in the short-term, can contribute to tissue dysfunction in the long-term. Senescent cells secrete hundreds of factors that, if left unchecked, can influence physiological signaling pathways that disrupt immune function and promote tissue health deterioration [1–3]. 

Furthermore, factors secreted by senescent cells can activate a self-amplifying secretory network that reinforces senescence [8]. SASP mediators can induce senescence in neighboring cells through paracrine signaling (i.e., signaling that induces changes in nearby cells) [9]. This is sometimes referred to as a bystander effect because otherwise healthy cells are being impacted by neighboring senescent cells. This reinforcement and propagation of senescence creates a snowball effect of senescence build-up that contributes to tissue degeneration and functional decline, and that may explain some of the detrimental changes associated with aging [10,11]. 

Senescence and Aging

Senescent cells build up in tissues as we age as a result of several factors: 1) several cellular stressors that induce senescence increase with aging; 2) the immune system becomes less efficient at finding and clearing senescent cells with aging, allowing growing numbers of transient senescent cells to evade elimination and linger; and 3) SASP factors released by lingering senescent cells promote senescence in neighboring cells [5,12]. These processes can perpetuate a feed-forward cycle of senescent cell accumulation with a mounting impact on tissue function.

The accumulation of senescent cells in tissues and organs correlates strongly with age‐related dysfunction [13] and cellular senescence burden has been associated with poor physical function in aged individuals [14]. In animals, transplantation of a relatively small number of senescent cells into healthy young mice was sufficient to spread cellular senescence to host tissues and cause persistent physical dysfunction similar to that of aged animals [15].

Senescence plays such an important part in the aging process that it is regarded as one of the hallmarks of aging [16]. It is also linked to many of the other hallmarks of aging. For example, senescence can be triggered as a stress response to mitochondrial dysfunction, genomic instability, epigenetic alterations, and telomere attrition, and is one of the causes of stem cell exhaustion that occurs with age [11].

Senescence can be triggered as a stress response to mitochondrial dysfunction, genomic instability, epigenetic alterations, and telomere attrition, and is one of the causes of stem cell exhaustion that occurs with age.

The SASP is thought to be partially responsible for persistent immune signaling changes that contribute to multiple age-related conditions. When senescent cells accumulate in tissues in sufficient numbers, the SASP mediators they secrete may actively drive a cascade of senescence build-up, interfere with tissue repair and regeneration, and contribute to aging and poorer health as we age [17,18]. All cell types can undergo senescence during aging, even those in non-proliferating or slowly proliferating tissues, such as the brain or the heart [19–21]. 

Senescence has been linked to age-related dysfunctions in several tissues and organs, including the kidney [22], pancreas [23], lungs [24], liver [25], heart [26], blood vessels [27], joints [28], and muscle [29]. Senescence has also been associated with many conditions that tend to develop as we age, such as the decline in cognitive function [30], cardiovascular health [31], pulmonary health [32], gastrointestinal function [33], muscle and bone strength [34,35], kidney function [36], endocrine health [37], as well as skin aging [38].

Studies in mice with accelerated aging and naturally aged have demonstrated that the elimination or disruption of senescent cells can ameliorate several age-associated conditions and delay health decline during aging [39–41].

Senolytics: A Potential Solution

What Are Senolytics? The accumulation of senescent cells can have a tremendous negative impact on performance and accelerate age-related deterioration of health. Interventions aimed at mitigating the accumulation of senescent cells and bringing senescence back into a healthy balance may have the capacity to counter the detrimental effects of senescence, support a more youthful physiology, and counter one of the main drivers of the aging process. One of the ways to do so is with senolytics.

Senolytic supplements are substances that preferentially target senescent cells and support the body in protecting itself against senescent cell burden. Senolytics have an affinity for finding senescent cells, counteracting their pro-survival and anti-apoptotic mechanisms, and convincing them to finally undergo the cellular removal process  (apoptosis) that transient senescent cells naturally go through, but lingering senescent cells have been avoiding. 

Selective elimination with senolytics is one of the main ways senescent cells can be managed. Another approach is SASP neutralization using senomorphics [42]. Senomorphics neutralize or prevent the production of SASP molecules by blocking signaling cascades within senescent cells, disrupting secretion of the SASP, or inhibiting the activity of individual SASP mediators. However, senescent cells of different origins secrete different SASP factors and drive tissue dysfunction through varying mechanisms, making this approach more complex [42]. Senolytics can also abolish the production of SASP molecules as a consequence of targeting and eliminating the senescent cells that secrete them, which has the advantage of being a more permanent approach [43].

Another strategy to support the management of cellular senescence is the enhancement of immune-mediated senescent cell clearance [42]. Promoting immune health and the efficiency of immune clearance of senescent cells helps to support the body’s natural processes of senescent cell elimination and to restore the balance between senescent cell generation and clearance [42].

The Latest Research on Senolytics

Senolytics are still a relatively new area of research. The term “senolytics” was coined in 2015 when two compounds were identified that seemed to have an affinity for finding senescent cells and driving them into apoptosis. One of these compounds was the flavonoid quercetin [44]. This stimulated the search for other plant compounds with senolytic action, revealing early on piperlongumine, fisetin, luteolin, and curcumin as senolytics [45,46]. Fisetin was a particularly promising finding: in a study that screened a panel of 10 flavonoid polyphenols for senolytic activity using senescent murine and human fibroblasts, it was found that fisetin was the most potent senolytic, even surpassing quercetin [46]. In the meantime, research on senolytics has grown steadily and many other senolytic compounds have been revealed, along with several different mechanisms of action underlying senolytic activity.

The term “senolytics” was coined in 2015 when two compounds were identified that seemed to have an affinity for finding senescent cells and driving them into apoptosis

The first human trials with senolytics have shown promising results: a combination of senolytics that included quercetin reduced markers of senescence in blood, skin, and adipose tissue in individuals with metabolic and kidney dysfunction [47] and supported physical function in a small group of individuals with lung dysfunction [48]. Several clinical trials assessing the use of senolytics for age-related conditions are underway, but for now, most published research on senolytics has been carried out in animals. 

Preclinical research has shown that the selective elimination of senescent cells with senolytics can enhance healthspan and longevity in animals [15,39,40,49]. Studies in animals have also shown that senolytics are able to mitigate age-related bone loss [50] and liver dysfunction [25], support kidney and heart tissue repair following injury [51,52], promote metabolic function [53], and support cognitive performance in models of cognitive decline [54,55]. 

The Potential of Senolytics

Senescent cells are highly heterogeneous in their biochemistry and physiological function, which adds complexity to the management of senescent cells. Their properties differ depending on which tissue they’re found, as do the SASP mediators they produce. Senescent cells from different tissues are also driven into apoptosis through distinct senolytic mechanisms [2]. 

Fortunately, senolytics are also heterogeneous in their actions. Different senolytics can target senescent cells from different tissues and drive them into apoptosis through different mechanisms. Quercetin, for example, was better at managing senescent human endothelial cells than senescent cells from fat tissue [44], whereas fisetin was able to support the management of senescent cells from fat tissue [46]. Curcumin showed senolytic potential in intervertebral disc cells [56], oleuropein from olive leaf extract supported the management of senescent chondrocytes (the cells that create cartilage and support healthy joints) [57], and SenActiv® (a patented combination of two adaptogenic extracts—notoginseng root [Panax notoginseng] and sweet chestnut rose [Rosa roxburghii]) supported the management of senescent cells after exercise [58,59].* 

Some senolytic compounds even act through more than one mechanism. For example, fisetin, quercetin, and oleuropein are thought to have both senolytic and senomorphic action [57,60,61].* 

Senescent cells rely on prosurvival senescent cell anti-apoptotic pathways (SCAPs) to linger. Compounds that support cellular functions related to restoring SCAP networks to healthy function may be an additional help to promote balanced senescence [62]. Milk thistle fruit extract [63–66] and soy isoflavones [67–70] are two examples of compounds that support several cellular functions related to the healthy function of SCAP networks. 

Therefore, a more comprehensive intervention to support the management of cellular senescence may be achieved by combining different senolytics targeting different types of senescent cells with different SASPs and SCAPs. Research has supported this view and indicated that combining senolytics with different tissue affinities may be a better strategy than just using one [44].

Listen to our science team discuss Senolytics: The Latest Breakthrough in Aging and Longevity Science (transcript here).

How Can Qualia Senolytic Help?

Biological aging can be accelerated by the existence of persistent age-related conditions driven by cellular senescence, but alleviating cellular senescence may help mitigate functional decline as we age. Ideally, strategies aimed at senescent cell management should preserve beneficial transient senescence while eliminating detrimental lingering senescent cells—the goal is to promote balanced senescence.

Senolytics are a promising strategy to do so.

Qualia Senolytic was developed with the goal of supporting healthy aging by helping to bring the creation and clearance of senescent cells back into a healthy balance. Qualia Senolytic was also designed to support the efficient use of cellular resources, promote the growth of more youthful cells by eliminating senescent cells, support healthy tissue function, and revitalize aging tissues, promoting whole-body rejuvenation.*

Qualia Senolytic combines a selection of senolytic ingredients with different tissue affinities that provide a more comprehensive approach to senescent cell management.* All nine ingredients in Qualia Senolytic have shown senolytic potential in preclinical research by promoting the elimination of senescent cells by apoptosis or immune clearance.* Some of the ingredients in Qualia Senolytic are being studied in ongoing clinical trials, namely fisetin and quercetin. 

Learn more about Qualia supplements here. 

*Disclaimer: These statements have not been evaluated by the Food and Drug Administration.  This product is not intended to diagnose, treat, cure, or prevent any disease. These statements are not intended as general medical advice. This product is not a replacement for prescription medication. Please consult your physician before taking any dietary supplements. This article is not a guarantee, promise, or reflection of other users’ results.  

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