Researchers have demonstrated that nanoparticles coated with quercetin molecules can selectively target and eliminate harmful senescent cells.
What are senescent cells?
As you age, increasing numbers of your cells enter into a state known as senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals that encourage nearby healthy cells to enter the same senescent state. Their presence causes many problems: they reduce tissue repair, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related diseases.
Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.
By the time people reach old age, significant numbers of these senescent cells have built up, causing chronic inflammation and damage to surrounding cells and tissue. These senescent cells are a key process in the progression of aging.
Senescent cells only make up a small number of total cells in the body, but they secrete pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP. The SASP is thought to significantly contribute to aging and cancer; thus, targeting senescent cells and removing them has been suggested as a potential solution to this problem, such therapies are known as senolytics.
The trouble with quercetin
Quercetin is a naturally occurring plant flavonol from the flavonoid group of polyphenols. Like many flavonols it has poor water solubility, chemical instability, and poor bioavailability, meaning high doses are typically required to have a significant effect. These confounding factors could be muddling its effectiveness and making it unreliable as a senolytic therapy. This likely explains why different senolytic studies using quercetin have yielded conflicting results: there are simply too many processes that can influence these natural molecules for them to be reliable.
That said, these issues have not held back its popularity and quercetin supplement is readily available and cheap. It is commonly sold and used as a method of reducing inflammation and as an antioxidant, although some studies suggest it is a weak pro-oxidant that provokes an antioxidant response from the cell. However, while many people simply assume that oxidants are bad and antioxidants and reducing free radicals are good, this is a simplification of a far more complex situation and one which is beyond the scope of this article.
We have seen in past mouse studies and recent Mayo Clinic human trials that quercetin, when used in combination with the cancer drug dasatinib, can be the basis for an effective therapy for eliminating senescent cells. Unfortunately, on its own, quercetin does not appear to have a significant senolytic effect, if any, which is possibly due to its limitations as a polyphenol.
However, there are ways to overcome these issues with quercetin and other similar polyphenols, and that is by using special delivery systems that make the molecules more effective and controllable. Polymer nanoparticles, lipid-based carriers, inclusion complexes, micelles, and conjugate-based delivery systems are all examples of approaches that can deliver molecules more effectively.
Nanoparticles make quercetin more effective
The researchers of this study opted to use a nanoparticle-based delivery system to carry quercetin molecules to senescent cells in order to destroy them . They created magnetite nanoparticles and coated their surface with quercetin molecules, then examined the senolytic action of this approach.
They found that the nanoparticles were effective at attenuating inflammatory signals, such as interleukin 8 and interferon beta, which are secreted by senescent cells. They also found that cells forced into early senescence via stress were destroyed by the nanoparticles and that the secretion of inflammatory signals was reduced.
Doing this also led to an elevated activity of AMP-activated protein kinase (AMPK). This is a critical nutrient and energy sensing enzyme that is present in all mammalian cells and maintains energy homeostasis. When activated, it facilitates energy-generating processes, such as glucose uptake and fatty acid oxidation, and decreases energy-consuming processes, such as protein and lipid synthesis. AMPK is one of the four pathways that control our metabolism, and its deregulation is a proposed reason why we age and develop metabolic conditions such as type 2 diabetes.
Cellular senescence may contribute to aging and age-related diseases and senolytic drugs that selectively kill senescent cells may delay aging and promote healthspan. More recently, several categories of senolytics have been established, namely HSP90 inhibitors, Bcl-2 family inhibitors and natural compounds such as quercetin and fisetin. However, the senolytic and senostatic potential of nanoparticles and surface-modified nanoparticles has never been addressed.
In the present study, quercetin surface functionalized Fe3O4 nanoparticles (MNPQ) were synthesized and their senolytic and senostatic activity was evaluated during oxidative stress-induced senescence in human fibroblasts in vitro. MNPQ promoted AMPK activity that was accompanied by non-apoptotic cell death and decreased number of stress-induced senescent cells (senolytic action) and the suppression of senescence-associated proinflammatory response (decreased levels of secreted IL-8 and IFN-ß, senostatic action). In summary, we have shown for the first time that MNPQ may be considered as promising candidates for senolytic- and senostatic-based anti-aging therapies.
This study is a promising demonstration of how naturally occurring molecules such as quercetin can be enhanced to be more bioavailable, effective, and reliable. Fisetin, apigenin and similar polyphenols are all potential candidates for this approach and could open the door to new and cost-effective senolytic therapies. There has also been interest in quercetin in the context of cancer prevention, improving its effectiveness may also present new opportunities in this area too.
 Lewinska, A., Adamczyk-Grochala, J., Bloniarz, D., Olszowka, J., Kulpa-Greszta, M., Litwinienko, G., … & Pazik, R. (2019). AMPK-mediated senolytic and senostatic activity of quercetin surface functionalized Fe3O4 nanoparticles during oxidant-induced senescence in human fibroblasts. Redox Biology, 101337.