What are senolytics?

Key takeaways

• When cells are impaired by cellular stressors, they enter a zombie-like state called senescence. 
• Senescent cells secrete pro-inflammatory molecules that can trigger neighboring healthy cells to age faster—like a moldy piece of fruit. 
• Senescent cells accumulate with age and contribute to age-related inflammation. Their accumulation is one of the hallmarks of aging.
• Senolytyics are compounds that selectively target senescent cells and are one of the most promising recent discoveries in aging research.

Related products

• Senolytic Complex: Based on leading institutional research in the field of cellular senescence, the Senolytic Complex contains senolytic compounds proven to clear human senescent cells in laboratory studies. The formulation includes fisetin and quercetin, two extensively researched flavonoids found in fruits and vegetables with potent senolytic activity; and powerful compounds derived from Chinese ginseng and chestnut rose extracts, shown in human clinical trials to accelerate senescent cell clearance, improve exercise recovery and endurance, and support muscle remodeling and cellular rejuvenation after strenuous exercise.

Vitamin D, omega-3, magnesium…and senolytics? Scientific discoveries in recent decades have changed what we can expect from our supplements. Instead of just taking a vitamin or mineral to replace what we’re missing (which can be important), we can now take supplements that target particular aspects of aging. This is where senolytics come into play: They clear the age-related accumulation of senescent cells, one of the hallmarks of aging. Whether this is a new curiosity or you’re already shopping for just the right senolytic supplement, this article provides a complete primer on cellular senescence and the specific senolytic compounds known to target and clear senescent cells.

What is cellular senescence?

Zooming way out for a second, what is aging? According to leading aging researchers, there are twelve hallmarks that drive aging [1]: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient-sensing, mitochondrial dysfunction, stem cell exhaustion, altered intercellular communication, chronic inflammation, dysbiosis, and cellular senescence.

In cellular senescence, cells enter a state of permanent cell cycle arrest while living on in a sort of zombie state—still metabolically active and viable, but no longer functioning in quite the same way. Cellular senescence is triggered by any number of stressors, including those that impair DNA and mitochondria, oxidative stress, telomere erosion, infections, mechanical stress, and much more. This isn’t all bad news: If a cell has a harmful mutation, senescence is a better outcome than that mutation replicating out of control. Senescent cells are normally cleared by our immune system within days to weeks.

And senescent cells aren’t all good or bad. Their particular senescence-associated secretory phenotype, or SASP, is what determines that. You can think of the SASP as a new personality and set of characteristics that this senescent cell now has; its composition is actually different, and so is the way it interacts with other cells, tissues, and the organism as a whole [2]. Components of the SASP, or molecules secreted by the senescent cells, include pro-inflammatory and pro-fibrotic molecules. Some senescent cells, especially those that are transient and quickly cleared by the immune system, are beneficial and can help orchestrate tissue remodeling and activate immune responses [3].

Other senescent cells have a SASP that’s problematic. In particular, when senescent cells aren’t cleared by the immune system and a threshold burden develops, they can impair neighboring and distant healthy cells—like a moldy piece of fruit—and contribute to “inflammaging” (age-related inflammation), immune decline, and even impact tissue function. As we age, our ability to clear senescent cells slows and senescent cells accumulate in multiple tissues throughout our body, and their rate of accumulation accelerates exponentially after age 60 [4].

Studies conducted in mice have found that cellular senescence is associated with or may cause disorders related to tissue inflammation, fibrosis and extracellular matrix degradation, adipose tissue insulin resistance, reduced muscle hypertrophy after resistance exercise, impaired fracture repair in older individuals, and even accelerated aging [3]. Further research is needed to confirm whether this finding can be extrapolated to humans

What are senolytics (and how do senolytics work)?

Senolytics are compounds that specifically target senescent cells with a problematic SASP; those that are destructive to tissue and cause inflammaging. Scientists discovered them by starting with a hypothesis that those particular cells would have pro-survival pathways—senescent cell antiapoptotic pathways, or SCAPs—that prevented their own destruction. They looked at proteomic and transcriptomic datasets to see if this was true and found that it was. Then they screened for compounds that could temporarily disable these pathways to allow some of the senescent cells to die off [3]. Clever, huh?

Scientists categorize senolytics into first generation senolytics and second generation senolytics. First generation senolytics, according to leading cellular senescence and senolytics researcher at Mayo Clinic, James Kirkland, Ph.D., were selected based on three important criteria: they target multiple pathways; they can be taken orally; and they are already known to be safe [5]. The ingredients in Elysium’s Senolytic Complex fall into this category. 

Note that some of the first generation senolytics—including all of those found in Elysium’s Senolytic Complex—are natural compounds that are safe and even offer additional health benefits. Here we’ll specifically focus on the ingredients you might find in senolytic supplements.

What are first generation senolytic supplements?

• Quercetin (Sophora japonica): A flavonoid found in fruits, vegetables, nuts, seeds, flowers, barks, and leaves [5]. Research has shown that quercetin induces apoptosis and clears certain senescent cells [6]. Additionally, a clinical trial of quercetin in combination with dasatinib showed that they reduced adipose tissue and skin epidermal senescent cells, while also reducing problematic SASP factors [7]. Quercetin is a key ingredient in Elysium’s Senolytic Complex.
• Fisetin (Rhus succedanea): A naturally occurring flavonoid found in fruits and vegetables such as strawberries, apples, persimmon, grapes, onions, and cucumbers. Research shows that fisetin also selectively eliminates senescent cells [8]. One study showed that fisetin reduced senescent cells in animal and human tissues, and that giving fisetin to mice late in their life “restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan” [9]. There’s no evidence to date that these animal studies can be extrapolated to humans. Fisetin is a key ingredient in Elysium’s Senolytic Complex.
• Chinese Ginseng (Panax notoginseng): Ginseng is a plant that’s been used in traditional Chinese medicine for thousands of years—with a variety of benefits, including clearing senescent cells [10]. Extracts from Panax notoginseng and Rosa roxburghii (chestnut rose) have been shown in human clinical trials [10-13] to accelerate senescent cell clearance, improve muscle recovery and exercise endurance, and support muscle remodeling and cellular rejuvenation after strenuous exercise. Chinese ginseng and chestnut rose extracts are key ingredients in Elysium’s Senolytic Complex.
• Piperlongumine (Piper longum): A natural compound found in the Indian long pepper plant. One study has shown that piperlongumine has senolytic properties [14]. More research is needed.
• Curcumin (Curcuma longa): A natural compound extracted from turmeric root. Curcumin is known to offer a variety of beneficial properties, including being anti-oxidant and anti-inflammatory. Preliminary evidence suggests curcumin has weak senolytic properties [9,15], but more research is needed.
• Luteolin (Reseda luteola): A compound derived from a weed not native to, but now found commonly in, North America. Preliminary evidence suggests that luteolin has weak senolytic properties [9], but more research is needed.

Second generation senolytics 

Second generation senolytics are currently being identified and studied [16]. These include cardiac glycosides, nanoparticles, prodrugs, senomorphics, CAR T cell therapies, and various drugs. We won’t cover these in detail here because they are still in early stages of study, aren’t available to customers, are not supplements, and aren’t yet proven to be either safe or effective in clinical studies.    

What are the benefits of senolytic supplements?

The ultimate goal of senolytic supplements is to help clear and manage senescent cells, one of the pillars of aging. A variety of studies in humans and animals suggest that there are many possible health benefits of clearing senescent cells with senolytic supplements and other senolytic compounds. Here’s what the research shows.

• Many preclinical models of aging and disease have found that senolytics play a role in improving issues related to type 2 diabetes, and bone, heart, kidney, liver, lung, muscle and neurological disorders, as well as in extending healthspan and lifespan [3]. Senolytics showed benefit in more than 40 conditions in preclinical studies [17]. Note that in many of these studies quercetin or fisetin are combined with other senolytic compounds that are not supplements—for instance, dasatinib and navitoclax. However, it is important to note that to date there is not yet evidence that these results can be extrapolated to humans, and further research is required to determine if these benefits can be extended to humans. 
• As mentioned previously, a clinical trial of quercetin in combination with dasatinib showed that they reduced adipose tissue and skin epidermal senescent cells, while also reducing harmful SASP factors [7].
• As referenced above, clinical trials [10-13] showed that administration of ginseng-chestnut rose extract prior to intense exercise accelerated senescent cell clearance, improved muscle recovery and exercise endurance, and supported muscle remodeling and cellular rejuvenation. Supplementation significantly accelerated the rate of glycogen accumulation in the skeletal muscle after the exercise challenge (which is important for recovery), mitigated the depletion of satellite cells in the muscle and upregulated markers of new muscle formation, significantly increased cycling time to exhaustion (a test of endurance performance), and supported a healthy inflammatory response. 

How often should you take senolytic supplements?

Senolytics have been called a “hit-and-run” approach [17] to clearing senescent cells. That’s because it takes weeks for senescent cells to accumulate, so senolytics can and should be used intermittently—which is how they are studied in preclinical and clinical trials. Elysium’s Senolytic Complex is designed to be taken intermittently on two consecutive days. Depending on your lifestyle and health goals, our Senolytic Complex can be easily personalized. For example, we recommend a once monthly 2-day dose to support healthy aging and general wellness; a twice-monthly approach to target senescent cell buildup and inflammaging for those who live a busy or somewhat stressful lifestyle; and a more frequent dosing schedule for athletes and individuals regularly engaging in intense exercise or high-stress occupations (e.g., weekly 2-day dose, preferably taken on the day prior to and the day of your most intense exercise). 

Are there other ways to clear senescent cells?

Scientists sometimes call exercise a “polypill” because it reliably improves health biomarkers and decreases the risk of virtually all health issues. Recent research suggests that it may also help with senescent cells: A study in 2021 found that a 12-week structured exercise program led to lower expression of key markers of cellular senescence [18]. Studies in animals also suggest that exercise may help delay the formation and accumulation of senescent cells. Calorie restriction is another intervention that’s commonly associated with healthy aging and has also been shown to delay the senescent cell program in animals [19]. Scientists are also considering combination strategies [3] that may be helpful in targeting root causes of aging, including exercise, calorie restriction, SASP inhibitors (including resveratrol), NAD+ precursors, and more.

What’s the future of senolytic supplements?

Cellular senescence and senolytics are important pillars of aging research, so you can expect to continue hearing about them as more research moves from preclinical research into human clinical trials. There are currently over 20 human clinical trials involving senolytics, studying COVID-19, osteoarthritis, neurodegenerative conditions, frailty, and more. Please note that Elysium's Senolytic Complex is not intended to screen, diagnose, treat, cure, or prevent any disease.

References

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