The Formulator's View of the Qualia Senolytic Ingredients

The Formulator's View of the Qualia Senolytic Ingredients

What is Qualia Senolytic? What Does Qualia Senolytic do?

Qualia Senolytic contains a combination of nine vegan ingredients that were carefully selected to support healthy aging in an area called “cellular senescence.”* We’ll get to those nine ingredients in a moment, but before we do, let’s start by getting a better understanding of senescent cells and senolytics.

Aspects of cellular structure and function gradually shift in certain predictable ways as a normal part of the aging process. Scientists refer to nine of these gradual shifts as the Hallmarks of Aging—think of a hallmark in this case as meaning a distinguishing characteristic. Cellular senescence is one of the nine characteristics; it has to do with a special type of stressed or worn out cell called a senescent cell.

Senescent cells are created and removed from tissues constantly throughout life. They are formed as a routine part of normal healthy function. Muscle tissues, as an example, create senescent cells after intense exercise as part of recovery.

Senescent cells are also formed when a cell becomes so stressed or worn out that it’s not worth putting in cellular work to maintain or repair it (replacing it would be a better use of cellular resources).

As we get older, healthy creation and removal functions tend to shift in ways that result in gradual increases in the proportion of senescent cells in some, often many different tissues—removal functions fall behind. This occurs for two main reasons.

Senescent cells should proceed through a series of molecular steps in a biological process that got its name from the Greek word for “falling off,” in the sense of ripe fruit falling from trees, leaves falling from a plant, or petals falling from flowers.

Some senescent cells can get sidetracked on the journey to “falling off” (in this case from our tissues). These cells become experts at surviving, exploiting normal cellular prosurvival functions to linger, loitering and taking up space in tissues. This would be somewhat analogous to yellowing leaves that haven’t fallen off a plant yet.

Because it’s normal to have some senescent cells start, but not complete the “falling off” journey, tissues need a back up plan. The backup plan is the immune system. One of the jobs of the immune system is to find loitering senescent cells and remove them. When the immune system is adept at finding and removing these cells, the pace of removal maintains a healthy balance with creation. This is where aging enters the story.

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 in lots of different ways; one of these is with senescent cells—some senescent cells may get missed. Over time, this can result in gradual accumulation of senescent cells.

Senescent cells are often described as being “zombie cells.” This is because, not unlike the undead zombies in movies, a senescent cell can get stuck in a kind of limbo. It has one more thing in common with movie zombies: senescent cells can change the behaviors of otherwise healthy cells near them, which may reinforce and spread cellular senescence.

But why is the accumulation of senescent cells important? It comes down to a fundamental principle—the health of tissues depends on the health of the cells in those tissues. What do you think might happen if space that should be filled with healthy cells is being taken up by loitering senescent cells instead? The answer is very similar to what occurs if a plant has a growing number of yellowing leaves taking up space on its branches. 

There are a few main reasons gardeners prune leaves: (1) pruning allows resources and nutrients to be used in healthy, vibrant leaves rather than being poorly invested in less healthy ones; (2) pruning encourages new growth; and (3) pruning promotes the overall health and appearance of a plant. This is where senolytics come in; they can be thought of as a way to support the pruning away of the equivalent of yellowing leaves in our tissues.* 

The word “senolytic” is derived from the Latin words senex (=old) and lytic (=destroying). They are aptly named. Senolytics show an affinity for finding cells that are using senescent cell prosurvival mechanisms, and then convincing them to finish the journey to “falling off” instead.*

Now let’s answer the original question—What is Qualia Senolytic? It is a dietary supplement formulated to help bring the creation and removal of senescent cells back into a healthy balance. It does this by, figuratively speaking, promoting the pruning away of senescent cells. Its goals are similar to those of pruning a plant: support efficient use of cellular resources, encourage growth of more youthful cells by making “room” in tissues for them, and ultimately to support tissue health and appearance—promoting whole-body rejuvenation.*

Now that we have the “what is it” and “how does it work” covered, I want to share a bit about each of the ingredients in Qualia Senolytic.

Quercefit® Quercetin Phytosome

In March, 2015, Scripps and Mayo Clinic scientists reported that they’d identified two compounds that seemed to have an affinity for finding senescent cells and convincing them to finish the journey to “falling off.”* The scientists coined the term “senolytics” to describe this newly discovered functional area. One of these compounds was a flavonoid type polyphenol called quercetin (1). Since then, quercetin has been on the very short list of most studied senolytic compounds. But what’s quercetin? And why Quercefit®?

Quercetin is a yellow plant pigment. Its name is derived from a Latin word (quercetum) for a group of oak trees, because quercetin was originally identified in oaks. Some ingredients—quercetin is one of them—are poorly absorbed. This creates an obstacle, of sorts, for getting enough of the ingredient into the body. We opted for Quercefit®, because this unique and patented Phytosome® formulation of quercetin was created to overcome the bioavailability obstacle. By creating a quercetin phytosome complex using sunflower lecithin, the bioavailability is dramatically enhanced (2).* The result, as the maker of Quercefit® (a company named Indena) likes to say, is “Quercetin, made better.” 

We chose our recommended dose of Quercefit® taking into account several different factors. The primary factor was how quercetin in general, and Quercefit® specifically, are being dosed as a senolytic in clinical research. An example of this dosing is a planned clinical trial (ClinicalTrials.gov identifier NCT04313634) which is using a similar intermittent dosing protocol to what’s recommended for Qualia Senolytic. The trial is dosing Quercefit® at 1000 mg daily for several days. Our recommended dose selection also took into account that Qualia Senolytic contains several other ingredients which share some functional overlap with quercetin. We opted for a slightly lower recommended daily dose of Quercefit® (750 mg per dose) to account for the contributions being made by these other ingredients (especially one we’ll mention in a moment that’s structurally almost identical to quercetin).*

Quercefit® is a registered trademark of Indena S.p.A.

Fisetin

Like quercetin, fisetin is a yellow plant pigment. In fact, its name originates from a German word (fisetholz) for a traditional yellow dye called “young fustic.” Polyphenols, like fisetin (and quercetin), play important roles in the plant kingdom. One of these roles is protecting plants from environmental stress. Because of this, fisetin is found in many plants, with strawberries, apples, persimmon, grapes, onions, and cucumbers, as examples, containing low amounts. So fisetin has a role in dealing with stress in plants; might it also have a role in supporting cells that are under stress in us?

Shortly after quercetin was identified as a senolytic, a search began to find out whether any other plant compounds might be. This search turned up fisetin—the results suggested it may have even more potential than quercetin (3). In this initial research, fisetin supported the reemergence of some aspects of healthy tissue structure and function in older animals (3).* The word senolytic is used to describe compounds that support senescent cells journey to “falling off.” A different word, senomorphic, is used to describe healthy shifts in the phenotype of senescent cells (phenotype has to do with structural and functional characteristics). Fisetin (as well as quercetin) are thought to have both senolytic and senomorphic potential (4). We included fisetin in Qualia Senolytic because of this potential, and because some experts we’ve communicated with feel it may be the most promising natural compound.*

We chose our recommended dose of fisetin based on how it is most commonly being dosed in clinical research to support management of senescent cells. As an example, in several ongoing studies fisetin is being dosed at 20 mg per kg body weight daily, orally for 2 consecutive days (ClinicalTrials.gov identifier NCT03675724, NCT03430037, NCT04476953, NCT04771611, NCT03325322). The 1400 mg fisetin recommended daily dose in Qualia Senolytic would correspond to the dose being used in these studies for a person weighing approximately 155 pounds (70 kg). Our recommended dose selection also took into account that Qualia Senolytic contains several other ingredients which would be expected to complement fisetin.* 

Luteolin

Luteolin is the ingredient we hinted at in the Quercefit® section. The chemical structure of luteolin and quercetin are very similar; luteolin is missing an OH (this combination of oxygen and hydrogen is called a hydroxyl group), otherwise they are identical (5). Luteolin is a yellow plant pigment—it has this in common with both quercetin and fisetin. And like fisetin, it was used for centuries as a yellow dye and its name originates from this yellow color—the Latin name for yellow is luteus. Luteolin is found in many plants, primarily in leaves and flowering buds. Some of the vegetables and herbs that are sources of luteolin include celery, artichoke, broccoli, oregano, parsley, peppermint, thyme, and chamomile.

The search that led to fisetin, also uncovered two other polyphenols with potential for helping to manage senescent cells. One of these was luteolin. While luteolin was not as potent as fisetin, it was senolytic at a dose where quercetin was not (3).* Senescent cells are an example of complexity science; they commonly rely on networks—complex systems seem to love network architecture—of cellular pathways (usually abbreviated as SCAPs) to linger. It’s helping to restore these SCAPs networks to healthy function where quercetin, fisetin are believed to act to support pruning of senescent cells. Luteolin supports some of the same SCAPs mechanisms (6–10).*

Note: SCAPS include networks and pathways related to the BCL-2 family, PI3K-AKT-mTOR signaling, serpines, dependence receptors, tyrosine kinases, genome guardians, and HIF-1α, as examples.

We included luteolin in Qualia Senolytic because a guiding principle in complexity science is the idea of redundancy, which when translated to creating a formulation means we like to include more than one ingredient that share some similar functions in the formulation. We chose our 150 mg recommended dose of luteolin expecting it to be complementary with both fisetin (11, 12) and quercetin (13) in convincing senescent cells to complete the journey to “falling off” (think of the luteolin dose as replacing some of the mg that could otherwise have been used by Quercefit®). While luteolin and quercetin are almost identical chemically, they have similar but not identical biological actions, so we believe a combination is a more robust choice than relying on only one.*

Longvida Optimized Curcumin® Extract

The search that led to the identification of fisetin and luteolin as potential senolytic compounds also identified one more, curcumin (3). Other research has also suggested curcumin’s potential for helping to manage senescent cells (14–16).* Curcumin has been one of the most studied polyphenols over the past 2 decades. It comes from turmeric (Curcuma longa roots), is the pigment that gives turmeric its characteristic yellow-orange color, and is why turmeric is sometimes referred to as “yellow root” or “golden spice” (17). In addition to the senolytic potential it has on its own, we expect curcumin to complement other ingredients in Qualia Senolytic, especially quercetin (18–23) and milk thistle seed extract (24–30).*  

While senolytics are an emerging scientific field, one of the findings, dating back to the initial study that identified quercetin as a senolytic, has been that senolytic compounds should not be assumed to be equally active in helping to manage senescent cells in all tissues—combining senolytics with different tissue affinities appeared to be a better strategy than just using one (1). Quercetin, as an example, was better for helping to manage senescent cells when the cells came from bone marrow; it was not nearly as good when senescent cells were from fat tissue (1). Fisetin, on the other hand, has supported management of senescent cells from fat tissue (3). And, curcumin appears to have senolytic potential in intervertebral disc cells (14). Part of the reason that Qualia Senolytic has nine ingredients is because we wanted to make sure to include support for different tissues, covering more bases, so to speak.*  

Similar to what was mentioned for quercetin, curcumin is known for its relatively poor bioavailability. Longvida® was developed by university neuroscientists to address and overcome the poor bioavailability of curcumin (31) and is trademarked as “the Cognitive Curcumin of Choice®” and as “Longvida Optimized Curcumin®.” It has been used in human studies in areas including cognitive function, mood, exercise recovery, and joint health. We chose it as the source of curcumin because it was designed to deliver free curcumin to target tissues, including the brain (as Neurohackers we always think the brain merits some support). We selected our recommended dose (400 mg) to match what’s been used in cognitive studies, which we expect to be complementary with other ingredients in Qualia Senolytic.*

Longvida® is a registered trademark of Verdure Sciences®.

Piperlongumine (from Piper longum Root Extract)

Fisetin is the second senolytic compound (in order) that we mention in this blog. And, with the possible exception of quercetin, fisetin has been the most embraced natural compound in both the research and longevity communities (look no further than the list of ClinicalTrials.gov identifiers we mention in the fisetin section, which are only a partial listing of ongoing studies). But fisetin was not the next natural compound with senolytic potential identified after quercetin …that would be piperlongumine (32).*  

Piperlongumine is an alkaloid found in several species of pepper plants, most notably long pepper (Piper longum) from which it got its name. Long pepper is a close relative of one of the most widely used spices in the world, black pepper (Piper nigrum). In Ayurveda, long pepper is considered a rasayana (rejuvenator). It is frequently combined with both black pepper and ginger—collectively called Trikatu (“three pungent spices”). Long pepper has a taste similar to, but hotter and more complex than black pepper, and has often been used somewhat interchangeably as a spice: the word “pepper” is actually derived from the Sanskrit word for long pepper (pippali) not black pepper. Piperlongumine is one of the compounds that produce this stronger and more complex taste.

We included a Piper longum extract, standardized to supply our recommended dose of 50 mg of piperlongumine, in Qualia Senolytic for a few reasons. Piperlongumine has shown senolytic potential in several studies (32–34). The initial research suggested piperlongumine also may complement other senolytic compounds (32). Piperlongumine is currently the only natural compound that supports a novel mechanism to help manage senescent cells (something called oxidation resistance 1 or OXR1 for short) (33). Lastly, piperlongumine may support the immune system, natural killer cells specifically, in being functionally more adept in managing stressed cells (35).*

Senactiv®

As we get older, the way our muscles respond to exercise changes. One of the changes has been called “anabolic resistance” (36). Anabolic resistance has to do with muscle plasticity. It means that the signals to build up muscle, to literally convince them to get bigger and stronger through strength training as an example, tend to be muted in older adults. Put another way, gains in muscle growth and mass tend to be less following the same amount and intensity of exercise in older compared to younger adults. One of the reasons for anabolic resistance may be related to senescent cells (37).

Senescent cells are created and removed from muscle tissue as a routine part of regeneration functions following intense exercise (37–40). It's normal (and healthy) for some senescent cells to emerge after exercise, but they should be fairly quickly pruned away after they’ve done their jobs. New research suggests this is exactly what occurs in young mice …but not in older mice (37). While both old and young mice had an increase in muscle senescent cells after exercise, a week or two later more senescent cells had lingered in muscle tissue from the older mice, which contributed to impaired muscle regenerative responses. But, in the same study, giving a senolytic cocktail to old mice—the cocktail included quercetin—supported muscle growth and healthier muscle fibers (37).* 

We included SenActiv® in Qualia Senolytic, because the research emphasis of this extract has been on exercise performance and recovery, including supporting the management of senescent cells after exercise (41, 42).* Senactiv® (previously called ActiGin) is a patented combination of two adaptogenic extracts—notoginseng root (Panax notoginseng) and sweet chestnut rose (Rosa roxburghii). It is the result of more than 10 years of research and development. In human and animal research studies, rather than seeing SenActive® mentioned by name, you’ll see Rg1 supplied by NuLiv Science, Inc., Brea, CA, USA. The dose of Rg1 used in the human studies has been 5 mg (41–45), while we are recommending a 50 mg dose of SenActive®. This can be a bit confusing. The key point is that we are using the extract from these studies at the studied dose, with 50 mg of SenActiv® providing the 5 mg ginsenoside Rg1 mentioned in the studies. 

SenActiv® is a registered trademark of NuLiv Science USA Inc.

Olive Leaf Extract

Olives are one of the foods found in the Mediterranean diet. It’s been hypothesized that some of the health-promoting properties of both the Mediterranean diet (46, 47), and of olives (48–52), may be related to their polyphenols.* Olive oils, fruits, and leaves are all sources of polyphenols, but differ in the relative amounts of certain ones. Oleuropein (a secoiridoid polyphenol) is found in higher amounts in leaf extracts, while another type of polyphenol, hydroxytyrosol, is in higher amounts in fruit extracts. 

We included a recommended dose of 250 mg olive leaf extract, standardized for 40% oleuropein (i.e., 100 mg of oleuropein per dose), in Qualia Senolytic for two reasons. In a 2020 study, oleuropein supported the management of senescent chondrocytes—chondrocytes are the cells that create cartilage, so support healthy joints (53).* Joints tend to be an area where many people experience the effects of aging, so we wanted to supply some support for managing senescent cells in this tissue.* This is the first reason. The second reason has to do with a word we introduced when discussing fisetin, senomorphic. Let’s discuss this term in more detail.

Senescent cells have a functional characteristic that scientists refer to as senescence-associated secretory phenotype or SASP for short—phenotype is an observable characteristic. SASP means that senescent cells secrete a complex mix of substances into the environment near them. Earlier in this blog post, when we were describing why senescent cells are sometimes referred to as zombie cells, we wrote, “...senescent cells can change the behaviors of otherwise healthy cells near them…” SASP is how they change these behaviors; it's a major reason why lingering senescent cells cause stress to healthy cells (54, 55). Scientists have proposed that dampening SASP signals—compounds that do this are referred to as senomorphics—may be complementary with senolytics to manage senescent cells (56–58). Existing evidence suggests that oleuropein may support this area; it has senomorphic potential (53, 59),* which is the second reason we felt an olive leaf extract standardized for oleuropein was a good fit with the other ingredients in Qualia Senolytic.

Milk Thistle Seed Extract

The seed-like fruits from milk thistle (Silybum marianum) have been used for more than 2,000 years in Europe and countries bordering the Mediterranean sea. Milk thistle has been one of, if not the most studied liver tonic herbs.* The main active substance in milk thistle is silymarin, which is a complex mixture of flavonolignan compounds including silybin (often called silibinin in scientific studies). Silybin has been proposed as worth exploring for helping to manage senescent cells (60, 61), but we would not consider it as a senolytic compound (it hasn’t been studied for that yet). Instead, we choose to include it expecting it to complement other senolytic ingredients we’ve discussed.*

Senescent cells rely on prosurvival SCAPs networks to linger. Because of this, most of the initial research on potential senolytics focused on identifying compounds that may support different healthy cellular functions related to restoring SCAPs networks to healthy function (62). We took a similar approach during our development of Qualia Senolytic, researching ingredients with an eye to understanding how different compounds had been reported to play structure and function roles within aspects of SCAPs networks. This led us to milk thistle seed extract, which supports several cellular functions related to the healthy function of SCAPs networks (Src-Kinase, e-cadherin (63, 64), and Hsp90 (65, 66) as examples). We also included it because we expect milk thistle seed extract to complement the stressed cell support from curcumin (from Longvida®) (24–30).*

Milk thistle is most commonly dosed based on its silymarin content. We are using an extract standardized to 58% silymarin by HPLC, which corresponds to 80% silymarin by spectrophotometry (HPLC and spectrophotometry are different types of tests—HPLC is the more accurate). Many studies, especially older ones, give an amount of silymarin that was not based on HPLC, which means the amount they used would look higher than it really would have been. The key thing to understand is that the milk thistle extract we are using is from the company that produced the 1st standardized European milk thistle extract in 1971 (silymarin was only identified in 1968), and produced the extract used in a number of the human studies. Our recommended dose of 125 mg of milk thistle seed extract supplies 72.5 mg silymarin by HPLC (this would be equivalent to 100 mg of silymarin by spectrophotometry). This dose was chosen to supply an amount of silymarin we expect to play a complementary role with other ingredients in Qualia Senolytic.* 

Soybean Seed Extract

Soybean is native to East Asia, where it is used to make a variety of fermented foods, such as soy sauce, tofu, tempeh, and miso. Most legumes, and some nuts and seeds, contain a type of bioflavonoid called isoflavones. Soybeans are the most common source of isoflavones in human food; the major isoflavones in soybean are genistein, daidzein, and glycitein. Because of this, cuisines that consistently consume fermented soybean foods have much higher isoflavone intake than Western diets. Average daily intake of soy isoflavones in the Japanese diet is 25-50 mg, for example. In the USA and Europe, average intake is less than 3 mg and often less than 1 mg a day (67). 

We included a soybean seed extract standardized for 40% isoflavones in Qualia Senolytic, because we expect this extract to play a complementary role in the overall formulation. Daidzein, as an example, was one of the top 4 compounds identified as a possible candidate for helping to manage some types of senescent cells based on their structure and function characteristics (68). Similar to milk thistle seed extract, soy isoflavone have been proposed as candidates worth exploring for supporting the management of senescent cells (60, 61).* And, also, similar to milk thistle seed extract, our attempts to better understand the cellular mechanics underlying SCAPs networks led us to soy isoflavones.

Senescent cells are often talked about as if every senescent cell is the same. This is an oversimplification. They share much in common; they are also diverse. We believe that a robust approach to dealing with this diversity entails supplying a diverse group of ingredients that have both overlapping and different structure function-supporting roles within an overall formulation. For soy isoflavones these included cellular functions related to histone deacetylase (69, 70), serpines (71), Src-kinases (72, 73), and tyrosine kinases (73), as examples. The recommended dose of soybean seed extract in Qualia Senolytic supplies 80 mg of soy isoflavones. We chose the dose to complement other ingredients in Qualia Senolytic.*

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

References

1. Y. Zhu et al., Aging Cell. 14, 644–658 (2015).
2. A. Riva, M. Ronchi, G. Petrangolini, S. Bosisio, P. Allegrini, Eur. J. Drug Metab. Pharmacokinet. 44, 169–177 (2019).
3. M. J. Yousefzadeh et al., EBioMedicine. 36, 18–28 (2018).
4. S. Romashkan, H. Chang, E. C. Hadley, J. Gerontol. A Biol. Sci. Med. Sci. 76, 1144–1152 (2021).
5. H. M. Awad et al., Chem. Res. Toxicol. 14, 398–408 (2001).
6. Q. Jiang et al., Curr. Pharm. Biotechnol. 19, 428–437 (2018).
7. X. Lu, Y. Li, X. Li, H. A. Aisa, Oncol. Lett. 14, 1993–2000 (2017).
8. S. Verma et al., J. Recept. Signal Transduct. Res. 37, 391–400 (2017).
9. S. Dirimanov, P. Högger, Biomolecules. 9 (2019), doi:10.3390/biom9060219.
10. J. Fu et al., PLoS One. 7, e49194 (2012).
11. A. Kim, J.-M. Yun, J. Med. Food. 20, 782–789 (2017).
12. M. Hytti et al., J. Nutr. Biochem. 42, 37–42 (2017).
13. K. Sak, K. Kasemaa, H. Everaus, Food Funct. 7, 3815–3824 (2016).
14. H. Cherif et al., J. Clin. Med. Res. 8 (2019), doi:10.3390/jcm8040433.
15. S. Pirmoradi, E. Fathi, R. Farahzadi, Y. Pilehvar-Soltanahmadi, N. Zarghami, Drug Res. . 68, 213–221 (2018).
16. H. Jin et al., Cell. Signal. 33, 79–85 (2017).
17. S. Prasad, B. B. Aggarwal, in Herbal Medicine: Biomolecular and Clinical Aspects, I. F. F. Benzie, S. Wachtel-Galor, Eds. (CRC Press/Taylor & Francis, Boca Raton (FL), 2012; https://www.ncbi.nlm.nih.gov/pubmed/22593922).
18. E. Mutlu Altundağ et al., Nutr. Cancer. 73, 703–712 (2021).
19. N. S. Srivastava, R. A. K. Srivastava, Phytomedicine. 52, 117–128 (2019).
20. M. M. Abdel-Diam et al., Environ. Sci. Pollut. Res. Int. 26, 3659–3665 (2019).
21. S. Kundur et al., J. Cell. Physiol. 234, 11103–11118 (2019).
22. E. Mutlu Altundağ, A. M. Yılmaz, S. Koçtürk, Y. Taga, A. S. Yalçın, Nutr. Cancer. 70, 97–108 (2018).
23. G. H. Heeba, M. E. Mahmoud, A. A. El Hanafy, Toxicol. Ind. Health. 30, 551–560 (2014).
24. A. Montgomery, T. Adeyeni, K. San, R. M. Heuertz, U. R. Ezekiel, J. Cancer. 7, 1250–1257 (2016).
25. V. Alfonso-Moreno, A. López-Serrano, E. Moreno-Osset, Rev. Esp. Enferm. Dig. 109, 875 (2017).
26. S. Dalimi-Asl, H. Babaahmadi-Rezaei, G. Mohammadzadeh, Iran. J. Med. Sci. 45, 477–484 (2020).
27. S. O. Ali, H. A. Darwish, N. A. Ismail, Basic Clin. Pharmacol. Toxicol. 118, 369–380 (2016).
28. M. Nasiri et al., Asian Pac. J. Cancer Prev. 14, 3449–3453 (2013).
29. N. Abdel-Magied, A. A. Elkady, Exp. Mol. Pathol. 111, 104299 (2019).
30. H. Avci et al., Exp. Toxicol. Pathol. 69, 317–327 (2017).
31. V. S. Gota et al., J. Agric. Food Chem. 58, 2095–2099 (2010).
32. Y. Wang et al., Aging . 8, 2915–2926 (2016).
33. X. Zhang et al., Aging Cell. 17, e12780 (2018).
34. X. Liu et al., Bioorg. Med. Chem. 26, 3925–3938 (2018).
35. L. O. Afolabi, J. Bi, L. Chen, X. Wan, Int. Immunopharmacol. 96, 107658 (2021).
36. R. W. Morton, D. A. Traylor, P. J. M. Weijs, S. M. Phillips, Curr. Opin. Crit. Care. 24, 124–130 (2018).
37. C. M. Dungan et al., Geroscience (2022), doi:10.1007/s11357-022-00542-2.
38. Y. Saito, T. S. Chikenji, T. Matsumura, M. Nakano, M. Fujimiya, Nat. Commun. 11, 889 (2020).
39. C. Yang et al., Aging . 10, 1356–1365 (2018).
40. Y. Saito, T. S. Chikenji, Front. Pharmacol. 12, 739510 (2021).
41. T. X. Y. Lee et al., Aging . 13, 16567–16576 (2021).
42. J. Wu et al., J. Ginseng Res. 43, 580–588 (2019).
43. C.-W. Hou et al., PLoS One. 10, e0116387 (2015).
44. J. Wu et al., J. Funct. Foods. 58, 27–33 (2019).
45. J. Wu et al., Aging . 12, 20226–20234 (2020).
46. C. Petrella et al., Curr. Med. Chem. 28, 7595–7613 (2021).
47. A. Medina-Remón et al., Br. J. Clin. Pharmacol. 83, 114–128 (2017).
48. M. Finicelli, T. Squillaro, U. Galderisi, G. Peluso, Nutrients. 13 (2021), doi:10.3390/nu13113831.
49. A. Mehmood, M. Usman, P. Patil, L. Zhao, C. Wang, Food Sci Nutr. 8, 4639–4655 (2020).
50. A. Romani et al., Nutrients. 11 (2019), doi:10.3390/nu11081776.
51. B. Barbaro et al., Int. J. Mol. Sci. 15, 18508–18524 (2014).
52. B. Klimova, M. Novotný, K. Kuca, M. Valis, Neuropsychiatr. Dis. Treat. 15, 3033–3040 (2019).
53. M. Varela-Eirín et al., Aging . 12, 15882–15905 (2020).
54. H. Thoppil, K. Riabowol, Front Cell Dev Biol. 7, 367 (2019).
55. M. Amaya-Montoya, A. Pérez-Londoño, V. Guatibonza-García, A. Vargas-Villanueva, C. O. Mendivil, Adv. Ther. 37, 1407–1424 (2020).
56. C. Kang, Mol. Cells. 42, 821–827 (2019).
57. J. Birch, J. Gil, Genes Dev. 34, 1565–1576 (2020).
58. L. Zhang, L. E. Pitcher, V. Prahalad, L. J. Niedernhofer, P. D. Robbins, FEBS J. (2022), doi:10.1111/febs.16350.
59. B. Menicacci, C. Cipriani, F. Margheri, A. Mocali, L. Giovannelli, Int. J. Mol. Sci. 18 (2017), doi:10.3390/ijms18112275.
60. M. Malavolta et al., Mediators Inflamm. 2018, 4159013 (2018).
61. A. Al Mamun et al., Eur. J. Pharmacol., 174991 (2022).
62. L. J. Hickson et al., EBioMedicine. 47, 446–456 (2019).
63. S. M. Woo, K.-J. Min, I. G. Chae, K.-S. Chun, T. K. Kwon, Mol. Carcinog. 54, 216–228 (2015).
64. G. Deep, S. C. Gangar, C. Agarwal, R. Agarwal, Cancer Prev. Res. . 4, 1222–1232 (2011).
65. H. Zhao, G. E. Brandt, L. Galam, R. L. Matts, B. S. J. Blagg, Bioorg. Med. Chem. Lett. 21, 2659–2664 (2011).
66. E. Cuyàs et al., Food Chem. Toxicol. 132, 110645 (2019).
67. G. Rizzo, L. Baroni, Nutrients. 10 (2018), doi:10.3390/nu10010043.
68. D. Kusumoto et al., Nat. Commun. 12, 257 (2021).
69. M. K. Sundaram et al., Anticancer Agents Med. Chem. 18, 412–421 (2018).
70. I. A. M. Groh, C. Chen, C. Lüske, A. T. Cartus, M. Esselen, J. Nutr. Metab. 2013, 821082 (2013).
71. E. P. Feener, J. M. Northrup, L. P. Aiello, G. L. King, J. Clin. Invest. 95, 1353–1362 (1995).
72. J. Lee, J. Ju, S. Park, S. J. Hong, S. Yoon, Nutr. Cancer. 64, 153–162 (2012).
73. G. Xie et al., J. Invest. Dermatol. 137, 1731–1739 (2017).

No Comments Yet

Sign in or Register to Comment