Cellular Senescence Offers Vital Clues for Healthy Aging

In the rapidly evolving field of longevity, emerging research on cellular senescence—a state of stable cell cycle arrest in which cells cease to replicate—offers vital clues for healthy aging. Though they stop multiplying, senescent cells linger and remain metabolically active, secreting chemicals that fuel inflammation and harm normal neighboring cells. While senescent cells play an important role in inhibiting abnormal cell growth, preventing neoplastic transformation and other biological processes, excessive accumulation of senescent cells has been implicated in a range of age-related diseases, including cancer, cardiovascular disease, diabetes and neurodegenerative disorders.^1,2

“Under normal conditions, old or damaged cells are eliminated through apoptosis, a programmed cell death process,” says Samuel Fortin, PhD, Chief Scientist and co-founder of Evidence Based Supplements. “However, when this mechanism fails, cells become senescent and resist apoptosis, leading to their accumulation within tissues and contributing to inflammation, tissue dysfunction and age-related diseases. Addressing cellular senescence is of paramount importance for healthy aging and longevity.”

Cellular senescence can be triggered by a variety of internal and external factors, including telomere shortening, DNA damage, high levels of reactive oxygen species (ROS), epigenetic alterations, mitochondrial dysfunction, radiation exposure, environmental toxins, chronic inflammation, and other influences. While the exact mechanisms are not fully understood, emerging research hints at effective strategies for addressing these triggers and modulating cellular senescence. A number of compelling studies suggest dietary supplements can address senescence through various actions, including selectively targeting and eliminating senescent cells, regulating metabolic and mitochondrial function, protecting against oxidative stress, taming inflammation and enhancing cellular detoxification.^3,4,5

 

Telomeres, specialized structures at the ends of chromosomes, are essential in preserving the stability of the genetic material during cell division. Telomeres shorten with each cell division and eventually reach a critical length, leading to cellular senescence or apoptosis. Short telomeres have been associated with numerous age-related diseases and poor health outcomes.

 

“Detoxification is vital for healthy aging and longevity,” says Nayan Patel, PharmD, author of The Glutathione Revolution (Hachette Books, 2020). “Detoxification processes help maintain cellular and tissue homeostasis by eliminating harmful substances and metabolic waste products that contribute to cellular dysfunction and senescence.”

 

Reactive oxygen species (ROS) damage cellular components and accelerate senescence. ROS  accumulation can inhibit autophagy; reducing ROS relieves this inhibition and promotes autophagic activity.

 

As compelling research on the link between senescent cells and longevity continues, supplements with proven potential for regulating cellular senescence should play a starring role in any healthy aging regimen.

“Our bodies face an inordinate amount of new, foreign toxins, both externally and internally,” says Adam Killpartrick, DC, CNS, CFMP. “The body’s response to this onslaught includes altered physiology, heightened levels of inflammation and increased oxidation that negatively impact the key elements associated with aging and cellular senescence. Given this consistent assault, science-backed supplements have become a necessity, not just an option, to set the stage for healthy aging and longevity.”

And because the process of aging is highly individual, supplements backed by up-to-date research allow practitioners to craft a customized protocol, tailoring interventions to individual needs. Here, nine research-backed compounds with promising results, and how they inform a personalized therapeutic approach.

• NMN (nicotinamide mononucleotide), a derivative of vitamin B3 naturally produced in the body, shows great potential for regulating cellular senescence. NMN is known to influence autophagy—the process of removing damaged cellular components and maintaining cellular health—and protect cells under hypoxic conditions. Studies show NMN boosts levels of NAD+ (nicotinamide adenine dinucleotide), promoting DNA repair and supporting cellular metabolism. Normal age-related decreases in NAD+ levels are thought to contribute to cellular senescence, so increasing NAD+ production may have the ability to slow senescence and enhancing overall cellular function and health. In research, NMN appears to counteract some effects of cellular senescence, and studies suggest NMN treatment may reduce the number of senescent cells in the body, improve the function of tissues affected by cellular senescence and possibly extend lifespan.^6,7,8
• Resveratrol, a stilbenoid polyphenol found in grapes, red wine, peanuts and other foods, has been extensively studied for its role in healthy aging. Recent research specifically points to its ability to combat cellular senescence through various mechanisms, including activating autophagy and influencing metabolic and mitochondrial function. Resveratrol shows potential in reducing cellular senescence by inhibiting senescence-associated markers, protecting against oxidative stress-induced DNA damage, preventing premature telomere shortening and influencing epigenetic changes that can affect telomere length and telomerase regulation. Studies also suggest resveratrol supplementation activates the SIRT1 protein, involved in telomere maintenance and other cellular processes. SIRT1 activation has been linked with improved telomere function and longevity.^9,10,11
• Luteolin, a flavonoid compound found in carrots, peppers, celery, cabbage and other fruits and vegetables, is known for its ability to reduce inflammation and oxidative stress, blunting the activity of certain inflammatory molecules and lessening the production of ROS that can damage cellular components and accelerate senescence. Luteolin specifically shows promise in mitigating cellular senescence by inhibiting senescence-associated markers and inducing autophagy. Recent research suggests luteolin triggers key signaling pathways involved in autophagy regulation, such as the AMP-activated protein kinase (AMPK) pathway and the mammalian target of rapamycin (mTOR) pathway. Luteolin has also demonstrated protective effects on mitochondrial function by preserving mitochondrial membrane potential and reducing oxidative stress.^12,13,14

 

AMP-activated protein kinase (AMPK), an energy-sensing enzyme plays a crucial role in regulating autophagy. AMPK activation can induce autophagy by phosphorylating downstream targets involved in autophagy initiation.

 

Some supplements are reported to inhibit the mammalian target of rapamycin (mTOR) pathway, a key regulator of autophagy. Inhibition of mTOR and activation of AMPK can promote autophagy.

 

• Quercetin, a flavonoid compound in apples, onions, green tea and other fruits and vegetables, has proven senolytic properties, combatting senescent cells and promoting their elimination. Quercetin has garnered attention for its effects on autophagy and senescent cell formation. In one study, quercetin treatment induced autophagy in human leukemia cells through activation of the AMPK pathway and subsequent inhibition of mTOR signaling. Other research found quercetin selectively induced cell death in senescent cells while sparing non-senescent cells. Quercetin also reduced the expression of senescence-associated markers and alleviated senescence-associated secretory phenotype (SASP) factors. Additional studies point to quercetin’s anti-inflammatory and antioxidant effects that contribute to its role in mitigating senescence and supporting healthy aging.^15,16,17,18
• Fisetin, like quercetin, is a flavonoid found in a variety of plant sources, including strawberries, apples, mangoes, grapes, tomatoes and onions. Fisetin has demonstrated powerful anti-inflammatory, antioxidant and senolytic properties, selectively targeting senescent cells and promoting their elimination. Other research highlights fisetin’s effects on autophagy and senescent cell formation. In one study, fisetin treatment reduced the number of senescent cells in various tissues, including adipose tissue, liver and kidney. In another study, fisetin significantly decreased inflammation, improved age-related health issues, enhanced physical function and extended lifespan in mice by reducing senescent cells. Research also points to fisetin’s potential as an autophagy-inducing compound. In one study, fisetin treatment induced autophagy in human lung cancer cells, linked with the inhibition of the mTOR pathway.^19,20,21
• Pterostilbene, a polyphenol abundant in blueberries and a natural analog of resveratrol, is recognized for its potent antioxidant and anti-inflammatory properties and has been extensively studied for its role in healthy aging. Pterostilbene downregulates NLRP3 inflammasome activation, preventing inflammation-related conditions. Research also suggests its ability to mitigate cellular senescence via autophagy. While the exact mechanisms of pterostilbene-induced autophagy are not yet known, several possible pathways have been proposed. Studies show pterostilbene regulates autophagy through mTOR pathway inhibition, AMPK activation and SIRT1 activation. Pterostilbene’s antioxidant properties also minimize ROS levels in cells, preventing ROS accumulation that can inhibit autophagy. Some research suggests pterostilbene may selectively target and eliminate senescent cells, reduce the total number of senescent cells, improve physical function and extend lifespan.^22,23,24
• Omega-3 fatty acids, found in fatty fish and some plant sources, are well-known for their antioxidant and anti-inflammatory benefits. Current evidence shows they also play an important part in age-related diseases and cellular senescence. Omega-3s modulate inflammation, known to contribute to cellular senescence, and blunt the production of ROS that can accelerate senescence. Studies also suggest omega-3s influence senescence by activating autophagy in various cell types, including brain cells and immune cells. Because conventional omega-3 supplements pose significant bioavailability and absorption challenges, their beneficial effects may be lessened. MAG-O3 Monoglyceride EPA, a patented form that delivers omega-3 fatty acids in a novel monoglyceride format, has been shown to dramatically improve bioavailability and absorption. Research suggests MAG-O3 induces apoptosis in damaged cells, enhances mitochondrial function, and reduces ROS. MAG-O3 also maximizes the utilization of EPA and DHA and optimizes the Omega-3 Index and AA:EPA ratio for better inflammation management.^{325,26,27,28,29}
• Curcumin, a polyphenolic compound isolated from turmeric root, is recognized for its multiple health benefits, including anti-aging properties. Curcumin is a powerful antioxidant and anti-inflammatory, and recent research points specifically to its role in managing cellular senescence. Curcumin is shown to activate cellular pathways that influence senescence, including the AMPK pathway and sirtuins, and trigger autophagy. Other research suggests curcumin has a positive impact on telomere length and function. In studies, curcumin supplementation improved telomerase activity, reducing telomere shortening and increasing telomere length. Like omega-3 fatty acids, curcumin is poorly absorbed, with low bioavailability. Tetrahydrocurcumin (4HC), the major bioactive metabolite of curcumin, is significantly more soluble, exhibiting a longer half-life in the body, better absorption and dramatically increased bioavailability. In studies, 4HC demonstrated superior antioxidant properties compared to curcumin. Additional research shows 4HC alleviates acute inflammation by mitigating the production of pro-inflammatory mediators and is more effective at attenuating inflammation compared to curcumin, at less than half the dose.^{30,31,32,33,34}
• Glutathione, a tripeptide molecule composed of cysteine, glutamate and glycine, is a potent antioxidant that’s essential for detoxification, minimizing chronic inflammation, neutralizing ROS, eliminating metabolic waste and enhancing excretion of toxins. Recent research also highlights glutathione’s specific role in cellular senescence. Age-related decreases in glutathione levels are linked with increased oxidative stress and cellular damage, and studies suggest glutathione depletion is associated with markers of senescence and heightened cellular senescence. Other research shows boosting glutathione levels can lessen oxidative stress, improve mitochondrial function and delay age-related decline and cellular senescence. As with omega-3 fatty acids and curcumin, the delivery system is critical. Conventional glutathione supplements are broken down by the body into various amino acids, which are then absorbed and used as building blocks to reproduce glutathione—a highly inefficient method of glutathione supplementation. Transdermal glutathione products and sprays that utilize sub-nano technology circumvent the potential for the tripeptide to be broken down during delivery, significantly enhancing potency and allowing higher doses to be readily absorbed.^35,36,37,38

 

References:

1. Roger L et al. Mechanisms and regulation of cellular senescence. Int J Mol Sci. 2021 Dec; 22(23): 13173.
2. Gasek NS et al. Strategies for targeting senescent cells in human disease. Nat Aging. 2021; 1, 870–879.
3. Dodig S et al. Hallmarks of senescence and aging. Biochem Med (Zagreb). 2019 Oct 15; 29(3): 030501.
4. Di Micco R et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nat Rev Mol Cell Biol. 2021 Feb; 22(2): 75–95.
5. SenNet Consortium. NIH SenNet Consortium to map senescent cells throughout the human lifespan to understand physiological health. Nat Aging. 2022; 2, 1090–1100.
6. Yoshino J et al. NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018 Mar 6; 27(3):513-528.
7. Mills KF et al. Long-term administration of Nicotinamide Mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016 Dec 13; 24(6):795-806.  .
8. Gomes AP et al. Declining NAD+ induces a pseudohypoxic state disrupting nuclear-mitochondrial communication during aging. Cell. 2013; 155(7):1624-1638.
9. Tian Y et al. Resveratrol as a natural regulator of autophagy for prevention and treatment of cancer. Onco Targets Ther. 2019 Oct 17; 12:8601-8609.
10. Kou X et al. Resveratrol as a natural autophagy regulator for prevention and treatment of Alzheimer’s Disease. Nutrients. 2017 Aug 24; 9(9):927.
11. Miki H et al. Resveratrol induces apoptosis via ROS-triggered autophagy in human colon cancer cells. Int J Oncol. 2012 Apr; 40(4):1020-8.
12. Ashrafizadeh M et al. Autophagy regulation using luteolin: new insight into its anti-tumor activity. Cancer Cell Int. 2020 Nov 4; 20(1):537.
13. Lee Y et al. Regulation of apoptosis and autophagy by luteolin in human hepatocellular cancer Hep3B cells. Biochem Biophys Res Commun. 2019 Oct 1; 517(4):617-622.
14. Liao Y et al. Luteolin induces apoptosis and autophagy in mouse macrophage ANA-1 cells via the Bcl-2 Pathway. J Immunol Res. 2018 Aug 30; 2018:4623919.
15. Yoon SJ et al. Quercetin induces mitochondrial-mediated apoptosis and protective autophagy in human retinal pigment epithelial cells against hydrogen peroxide-induced oxidative stress through the PI3K/Akt/mTOR signaling pathway. Journal of Medicinal Food. 2019; 22(10), 1019-1028.
16. Zhu Y et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell, 2015, 16(4), 644-658.
17. Chondrogianni N et al. Anti-ageing and rejuvenating effects of quercetin. Exp Gerontol. 2010 Oct; 45(10):763-71.
18. Zoico E et al. Senolytic effects of quercetin in an in vitro model of pre-adipocytes and adipocytes induced senescence. Sci Rep. 2021 Dec 1;11(1):23237.
19. Park JH et al. Fisetin regulates astrocyte migration and proliferation in vitro. Korean Journal of Physiology & Pharmacology. 2018; 22(6), 633-644.
20. Yousefzadeh MJ et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018, 36, 18-28.
21. Zhu, 2015.
22. Chakraborty A et al. Long-term induction by pterostilbene results in autophagy and cellular differentiation in MCF-7 cells via ROS dependent pathway. Mol Cell Endocrinol. 2012 May 15;355(1):25-40.
23. Wang Y et al. Pterostilbene simultaneously induces apoptosis, cell cycle arrest and cyto-protective autophagy in breast cancer cells. Am J Transl Res. 2012;4(1):44-51. Epub 2012 Jan 5.
24. Zhang L et al. Pterostilbene, a natural small-molecular compound, promotes cytoprotective macroautophagy in vascular endothelial cells. J Nutr Biochem. 2013 May;24(5):903-11.
25. Morin C et al. Potential application of Eicosapentaenoic Acid Monoacylglyceride in the management of colorectal cancer. Mar Drugs. 2017 Sep 4;15(9):283.
26. Morin C et al. Anti-cancer effects of a new docosahexaenoic acid monoacylglyceride in lung adenocarcinoma. Recent Pat Anticancer Drug Discov. 2013 Sep;8(3):319-34.
27. Morin C et al. Docosahexaenoic Acid Monoglyceride increases carboplatin activity in lung cancer models by targeting EGFR. Anticancer Res. 2017 Nov;37(11):6015-6023.
28. Gevariya N et al. Omega-3 Eicosapentaenoic Acid reduces prostate tumor vascularity. Mol Cancer Res. 2021 Mar;19(3):516-527.
29. Champigny CM et al. Omega-3 Monoacylglyceride effects on longevity, mitochondrial metabolism and oxidative stress: insights from Drosophila melanogaster. Mar Drugs. 2018, 16, 453.
30. Zia A et al. The role of curcumin in aging and senescence: Molecular mechanisms. Biomed Pharmacother. 2021 Feb;134:111119.
31. Zhu S et al. Curcumin activates autophagy via the PI3K/Akt/mTOR signaling pathway in non-small cell lung cancer cells. Eur J Pharmacol. 2019;852:55-63
32. Sarker MR et al. Curcumin increases telomerase activity in HepG2 cells via hTERT mRNA transcriptional regulation. Mol Cell Biochem. 2016;416(1-2):1-11.
33. Pari L et al. Effect of tetrahydrocurcumin on blood glucose, plasma insulin and hepatic key enzymes in streptozotocin induced diabetic rats. J Basic Clin Physiol Pharmacol. 2005;16(4):257-74.
34. Zhang ZB et al. Curcumin’s metabolites, Tetrahydrocurcumin and Octahydrocurcumin, possess superior anti-inflammatory effects in vivo through suppression of TAK1-NF-κB pathway. Front Pharmacol. 2018 Oct 17;9:1181.
35. Rahman I et al. Glutathione, oxidative stress and aging. Aging and Disease. 2016; 7(6), 81-91.
36. Liu D et al. Glutathione depletion induces senescence-like growth inhibition through the crosstalk between the Keap1-Nrf2 and p53-p21 pathways in human diploid fibroblasts. Journal of Gerontology Series A: Biological Sciences and Medical Sciences. 2013; 68(9), 1059-1072.
37. Li Y et al. Glutathione depletion triggers TGF-β1-induced senescence of human umbilical vein endothelial cells. Aging Cell. 2018; 17(3), e12765.
38. Jang YC et al. Mitochondrial dysfunction and activation of iNOS are responsible for the palmitate-induced decrease in adiponectin synthesis in 3T3-L1 adipocytes. Aging Cell. 2018; 17(2), e12693.