What Are Senolytics? The Science and Benefits

Senolytics: Enhancing Health and Longevity

Imagine a world where aging is no longer an inevitable decline but a process we can actively influence. This isn't science fiction; it's the science of senolytics. These groundbreaking compounds target and eliminate senescent cells – the aging cells in our bodies that no longer divide but still cause harm. With the potential to revolutionize our approach to aging and health, senolytics represent a new dawn in medical science, offering hope for a healthier, more vibrant life as we age. This article will explore the exciting possibilities of senolytics, shedding light on how these small molecules might pave the way for a new era in health and wellness.

What Are Senolytics?

Senescence is a cellular state in which cells stop dividing but don’t die, remaining in permanent cell cycle arrest. Cellular senescence occurs in response to stress and is part of healthy tissue function. In normal conditions, senescence is a protective response to cellular stress and senescent cells are quickly eliminated by the immune system. But with aging, immune clearance becomes less effective, allowing senescent cells to linger indefinitely in tissues, gradually accumulate, and promote tissue dysfunction and health decline through the action of chemical mediators they produce [1,2]. 

Cellular senescence was first described in 1961 by Hayflick and Moorhead who reported that in vitro cell cultures of human fibroblasts had a limited capacity for replication and eventually entered a state of irreversible growth arrest [3]. What they observed was a type of cellular senescence called replicative senescence, which is triggered by telomere shortening. Telomeres are DNA sequences at the ends of chromosomes that shorten slightly each time a cell divides. Once telomeres reach a critical length, cell division stops. This process is one of the hallmarks of aging [4] and happens in all healthy cells except for stem cells, which have unlimited capacity for division. This replication limit became known as the "Hayflick limit" [5].

We now know that telomere shortening is just one of the many possible causes of cellular senescence. Cells can also become senescent in response to other sources of cellular stress, such as mitochondrial dysfunction, oxidative stress, DNA damage, or abnormal growth activation, among others [6,7]. 

As research on cellular senescence advanced, it became clear that the accumulation of senescent cells can have a tremendous negative impact on physiology and accelerate age-related deterioration of health [8]. Cellular senescence is also now regarded as one of the twelve hallmarks of aging [4]. 

As research on cellular senescence advanced, it became clear that the accumulation of senescent cells can have a tremendous negative impact on physiology and accelerate age-related deterioration of health.

This growing awareness of the importance of cellular senescence stimulated a new area of research aiming to find interventions that could mitigate the accumulation of senescent cells. But it wasn’t until 2015 that two compounds were identified that seemed to have an affinity for finding senescent cells and driving them into apoptosis. Apoptosis is the normal cellular process our body uses to get rid of unwanted or unrepairable cells. Senescent cells should go through apoptosis, but the senescent cells that accumulate with aging do not; they resist it. Scientists looked for compounds that could help senescent cells to overcome this resistance. This is when the term “senolytics” was coined to describe compounds that selectively eliminate senescent cells [9]. Since then, research on senolytics has grown steadily and many other senolytic compounds have been revealed, along with several different mechanisms of action underlying senolytic activity.

Figure 1. Cellular senescence. Source: US National Institute on Aging

A Closer Look at How Senolytics Work

Senescent cells that resist going through apoptosis and evade immune clearance can linger indefinitely in tissues. They resist apoptosis by downregulating pro-apoptotic pathways that would lead them to death and upregulating pro-survival mechanisms, known as senescent cell anti-apoptotic pathways (SCAPs) [6–8]. Senescent cells secrete hundreds of chemical mediators collectively called senescence-associated secretory phenotype (SASP) mediators that can influence immune signaling and tissue function, including cytokines, chemokines, matrix metalloproteinases, and other bioactive molecules. When senescent cells accumulate in tissues in sufficient numbers, these mediators can actively drive a cascade of senescence build-up, and interfere with immune signaling and tissue repair and regeneration [2,10]. 

Senolytics have the important action of helping to keep senescent cells in check and prevent their accumulation. Senolytics selectively find senescent cells and disable their pro-survival SCAP networks [11]. By doing so, senolytics push senescent cells towards completing the process of cell death (apoptosis) that lingering senescent cells have been escaping.

Senolytics push senescent cells towards completing the process of cell death (apoptosis) that lingering senescent cells have been escaping.

Senolytics are one of three main approaches to the management of senescence. Another strategy is SASP neutralization using senomorphics, which are compounds that suppress the activity or prevent the production of SASP mediators [12]. This approach is more complex because it requires continuous intervention with senomorphics to block new SASP mediators senescent cells keep producing. Senolytics, on the other hand, have the advantage of abolishing the production of SASP molecules by permanently eliminating the senescent cells that secrete them, requiring only intermittent administration [11]. 

Another strategy to support the elimination of senescent cells is to promote the efficiency of immune-mediated clearance. This helps to support the body’s natural processes of senescent cell elimination and to restore the balance between senescent cell generation and clearance [12].

The permanent elimination of senescent cells with senolytics is important because it helps to block the cascade of tissue dysfunction that senescence can trigger. Lingering senescent cells and their SASP mediators form a secretory network that reinforces and propagates senescence to neighboring cells, thereby creating a ripple effect of senescence build-up that gradually disrupts tissue function [13–15]. 

Cellular senescence burden in tissues and organs has been associated with poor physical health in aged individuals [16]. In animals, transplantation of only a relatively small number of senescent cells into healthy young mice was sufficient to propagate cellular senescence to host tissues and promote physical dysfunction akin to that of aged animals [17].

Preclinical studies have shown that the selective elimination of senescent cells with senolytics can restore healthy function in different tissues and organs [17–23]. Studies in aged mice have also demonstrated that senescent cell elimination can ameliorate age-associated conditions and delay health decline during aging [24–26], highlighting the potential of senolytics for supporting healthy aging.

Figure 2. Senolytics and senomorphics. Adapted from Thoppil & Riabowol. Front Cell Dev Biol, 2019. License CC BY 4.0

The Benefits of Senolytics: Impacts on Healthy Aging

Cellular senescence is both a consequence and a cause of aging. It’s a consequence because, as we age, not only does the immune system become less apt at finding and clearing senescent cells, but there is also an increase in cellular stressors that induce senescence, which potentiates the accumulation of senescent cells. It’s a cause because SASP molecules secreted by senescent cells promote persistent changes in immune signaling and tissue repair and regeneration that drive tissue dysfunction and functional decline [2,10]. Cumulative senescence can promote poorer physical function and other detrimental physiological changes that accelerate the aging process and contribute to poorer health as we age [14–16,27].

Senescence has been linked to age-related dysfunctions in several tissues and organs, including the heart [28], blood vessels [29], liver [30], kidney [31], pancreas [32], lungs [33], muscle [34], and joints [35]. Senescence has also been associated with several conditions that tend to develop as we age, such as a decline in cognitive function [36], cardiovascular health [37], pulmonary health [38], kidney function [39], gastrointestinal function [40], muscle and bone strength [41,42], endocrine health [43], and skin aging [44].

Alleviating cellular senescence burden with senolytics may help to delay functional decline as we age. It’s important to highlight that, ideally, senescent cell management should not aim at totally eliminating senescent cells, but rather at promoting balanced senescence. Although lingering senescent cells can have nefarious actions, transient cellular senescence is a healthy protective response that suppresses the proliferation of dysfunctional cells, promotes tissue repair and regeneration, and contributes to tissue homeostasis [6,45]. 

Senescent cells’ actions are necessary but meant to be restricted; it’s when their clearance fails that senescence becomes detrimental. By helping to keep senescence transient, senolytics may help to prevent dysfunctions caused by unchecked cellular senescence and to prevent the acceleration of age-related dysfunction caused by their accumulation.

Preclinical research has given ample support to the healthy aging benefits of senolytics. Studies in animals have demonstrated the ability of senolytics to mitigate age-related dysfunctions in the liver [30], support heart and kidney tissue repair after injury [20,21], counter age-related bone loss [19], promote healthy metabolic function [46], and support cognitive function in animal models of brain aging [22,23], among other beneficial actions. In addition to these tissue-specific effects, studies have also shown that the selective elimination of senescent cells with senolytics can enhance healthspan and longevity in animals [17,18,24,25].

Senolytic Potential: Advancements in Aging Research

Senolytic supplements are a relatively new area of research. Since the identification of the first senolytic compounds in 2015 [9], research on senolytics has grown steadily. Many senolytic compounds have been revealed, along with several different mechanisms of action underlying senolytic activity. 

Because this is a relatively new area of research, human studies with senolytics are still limited. Most research on the potential of senolytics in mitigating the burden of senescent cell accumulation and promoting healthy aging and longevity has been on animal models. Nevertheless, the first human trials with senolytics have shown promising results: a combination of senolytics that included the flavonoid 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 randomized, double-blind, placebo-controlled trials assessing the benefits of senolytics are currently underway. Although clinical studies conducted so far have indicated that the senolytic compounds used have good tolerability, the range of side effects of senolytics in humans is not yet fully known. Most ongoing clinical trials are focusing on individuals with age-related health conditions [11], but a few studies with healthy older individuals are also underway.  

For example, one clinical study (NCT05653258) will assess the effects of a combination of two senolytic compounds (one of which is quercetin) on senescent cell levels in adipose tissue, metabolic parameters, physical performance, and health-related quality of life in older overweight individuals. Another clinical study (NCT06133634) will assess the effects of the senolytic compound fisetin on vascular function in older adults and determine the potential mechanisms by which fisetin may support vascular function. 

Qualia's Role in Senolytic Advancement

The accumulation of senescent cells contributes substantially to age-related health deterioration. Interventions aimed at mitigating the accumulation of senescent cells have the potential to counter one of the main drivers of the aging process and support a more youthful physiology.

We developed Qualia Senolytic with the purpose of offering a product that would support healthy aging by helping to bring the creation and clearance of senescent cells back to a healthy balance, promote the growth of more youthful cells by eliminating senescent cells, support healthy tissue function, and revitalize aging tissues, promoting whole-body rejuvenation.*

A key point we kept in mind while developing Qualia Senolytic was that senescent cells are highly heterogeneous in their biochemistry and physiological function: their properties and SASP differ based on which tissue they’re found at and senescent cells from different tissues are driven into apoptosis through distinct mechanisms [2]. 

We were aware that to target cellular senescence comprehensively, we had to consider their different mechanisms of survival and different tissue specificities. 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; some senolytics even act through more than one mechanism.* 

We believe that a more comprehensive intervention to support balanced senescence may be achieved by combining different senolytic compounds targeting different types of senescent cells. This is supported by research that indicated that combining senolytics with different tissue affinities may be a better strategy than using a single senolytic [9]. This is why Qualia Senolytic combines a selection of senolytic ingredients with different tissue affinities.* 

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, or by supporting mechanisms that help correct the apoptosis resistance rely upon.* Some of the ingredients in Qualia Senolytic are being studied in ongoing clinical trials, namely fisetin and quercetin. 

The selective elimination of senescent cells with senolytics has emerged as a promising strategy for addressing age-related complexities and promoting youthfulness. At Qualia, we’re keeping track of the latest developments in senolytic research and applying that knowledge to develop solutions that may help you live a long, healthy life.  

Learn more about Qualia Senolytic in The Formulator's View of the Qualia Senolytic Ingredients.

Frequently Asked Questions

What is the most potent senolytic? 

In a preclinical study that screened 10 flavonoid polyphenols for senolytic activity using senescent fibroblasts from humans and mice, fisetin was the most potent senolytic, even surpassing the clinically studied senolytic compound quercetin. There are many ongoing clinical studies sponsored by the Mayo Clinic to assess the senolytic action of fisetin in humans.* Learn more about fisetin's bioavailability. 

What foods are high in senolytics?

Fruits such as strawberries, apples, and red grapes are all rich in senolytic compounds. Red onions, cucumbers, and black tea are high in senolytic compounds, too. But to get the necessary amounts from food alone would require excessive amounts of the foods mentioned. To get the studied amounts of senolytic compounds is only through senolytic supplements such as Qualia Senolytic. Senolytic supplements supply senolytic compounds in amounts that are out of reach through diet alone.

What are examples of natural senolytics?

Many biological actions of natural compounds are dose-dependent, meaning they only occur above specific amounts. That’s the case with the senolytic compounds studied so far: the amounts found in foods are not sufficient to attain the dose threshold for a senolytic action. Quercetin, fisetin, luteolin, and curcumin are all examples of natural senolytic compounds found in Qualia Senolytic.

*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.

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