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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.

The trouble with quercetin

Quercetin is a naturally occurring plant polyphenol, a category that often has poor water solubility, chemical instability, or poor bioavailability. 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.

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 have a significant senolytic effect, 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 [1]. 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, 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.

Conclusion

This study is a promising demonstration of how naturally occurring molecules 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.

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Literature

[1] 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.

About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic as well as attending various medical industry conferences. In 2019 he was listed in the top 100 journalists covering biomedicine and longevity research in the industry report – Top-100 Journalists covering advanced biomedicine and longevity created by the Aging Analytics Agency. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, and, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project. In 2015 he led the Major Mouse Testing Program (MMTP) for the International Longevity Alliance and in 2016 helped the team of the SENS Research Foundation to reach their goal for the OncoSENS campaign for cancer research.
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