The Achilles’ heel of senescent cells: from transcriptome to senolytic drug. (1)
Cellular senescence is an underlying contributor to accelerated aging and disease.2
Aging, or “senile,” cells stop dividing to produce new cells and lose their ability to die off, which causes them to build up in the body. These accumulated cells pour out harmful, pro-inflammatory chemicals and other signaling molecules that contribute to aging and increase the risk of most age-related diseases—including cancer.3-5
Ridding the body of these aging cells to make way for fresh new cells is an important target for slowing aging and reducing disease risk.6 This is the goal of pharmaceutical researchers as they develop new drugs to purge senile cells from aging bodies.
But senescence is a double-edged sword. While it is harmful in healthy cells, senescence is desirable in tumor cells because it halts their out-of-control replication. By definition, cancer cells have become “immortal,” and continue to replicate without forming useful structures. By “turning back on” the senescence process, cancer cells can be made “mortal” again and eventually die off. In fact, deliberately triggering senescence in malignant cells represents a new approach to fighting cancer.6
The idea that we can use natural substances to selectively target cellular senescence has opened a promising new door in the fight against cancer and aging.6
Studies have used drugs and synthetic biological products capable of clearing away accumulated aging cells in aging tissues. In animals, these compounds have produced dramatic results, such as delaying the onset of aging, slowing existing age-related changes, and even extending lifespans.7-9 But in their current state of development, these drugs and other synthetic products are impractical, dangerous, or both, making them entirely unsuitable for use in humans to prevent either aging or cancer.
Researchers have found that two natural compounds, when combined, successfully remove aging cells from the body without harmful side effects.
Tocotrienols, the less well-known members of the vitamin E family, are emerging as the ideal senolytic nutrient. Studies show that tocotrienols have dual and complementary actions: In cancer cells, tocotrienols can stimulate cellular senescence, shutting down their malignant potential. 6. In healthy tissue, tocotrienols can slow aging changes, promote normal cell division and specialization, and prevent cells from reaching their damaging final aging state.10-14
Studies have shown the benefits of combining tocotrienols with quercetin, a flavonol found in many fruits and vegetables. Quercetin also has dual and complementary actions with regards to aging cells. Like tocotrienols, quercetin can induce senescence and promote cell death in numerous types of cancer cells.6,15
And, like tocotrienols, quercetin has the opposite effect in healthy cells, delaying senescence in younger cells and rejuvenating older cells to rid them of their abnormal, age-promoting function.1,6
Together, these two nutrients sweep the body clear of aging cells, while promoting natural termination of cancer cells.
Combined Anti-Aging and Anti-Cancer Effects
Several studies have now been performed on the combination of tocotrienols and quercetin in slowing, delaying, or even reversing the consequences of senescence—particularly the excessive inflammatory signals that aging cells produce.16-18
A key reason why aging cells are so closely tied to aging and disease is because they pour out substances that generate inflammation throughout the body.3,19
In fact, aging cells are now recognized as an important source of the chronic inflammation that is known to produce age-related diseases.16
Growing evidence from animal models shows that the combination of tocotrienols plus quercetin sharply reduces blood levels of pro-inflammatory molecules.16
By suppressing these damaging factors, tocotrienols and quercetin reduce systemic inflammation in the body.17,18 Reducing inflammation has the beneficial effect of reducing the overall risk of aging and disease.
Cellular senescence is a natural process by which cells lose their ability to continue to divide. This process is essential for the prevention of cancer because it puts an upper limit on normal cell replications. It is also essential in tissue remodeling which occurs during development of embryos and during wound healing.9
In both of these special cases, rapid cell replication must be balanced by appropriate growth arrest so that normal structures form.
But aging cells remain alive, surviving in tissues without contributing much to the overall health of the organism over time.9 Worse, aging cells disrupt tissue structures and alter tissue function because of certain molecules that they secrete.7 Chief among these deleterious signaling molecules are mediators of inflammation (cytokines and other pro-inflammatory molecules).3,19
These inflammatory changes spread to other cells in the area, hastening their own decline into an aging state, and further accelerating the overall aging of the organism.3,19 Conversely, when cells lose their ability to age, they continue to grow far past their natural limits.
Thus, gaining precise control over the process of cellular senescence would represent a huge breakthrough in our ability to slow aging (by preventing aging changes and/or clearing away aging cells), and in our capacity to fight cancer (by deliberately inducing aging changes in malignant cells to stop their growth).
New Approach to Fighting Cancer
As we’ve seen, cancer cells are essentially “immortal” in part because they have lost the ability to enter senescence, and hence, to stop their out-of-control replication. That means that deliberately inducing senescence in cancer cells is a potentially effective method of slowing or stopping a tumor from continuing to grow—or even from developing in the first place.
Mounting evidence has demonstrated that treating malignant cells with tocotrienols has several anti-tumor effects, including:
- Inducing mitochondrial damage, which starves cancer cells of energy, and
- Inducing apoptosis, the normal cell death program that cancer cells lose.20-24
What is so remarkable is that these cell-damaging effects are not seen in healthy, non-malignant cells, which means that tocotrienols selectively target cancer cells.21
Tocotrienols, the less well-known members of the vitamin E family, are of great interest to researchers. Recent studies show that tocotrienols have the ability to slow cellular aging in normal tissues, while reducing inflammation. At the same time, in what seems to be a remarkable fashion, tocotrienols may accelerate the destruction of cancer cells.
Tocotrienols, particularly in combination with quercetin, appear capable of removing many aging cells.
Tocotrienols have other anti-aging effects that are proving beneficial in our fight against diabetes, metabolic syndrome, and neuro-degeneration.42,47-53
- Zhu Y, Tchkonia T, Pirtskhalava T, et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell. 2015;14(4):644-58.
- Bhatia-Dey N, Kanherkar RR, Stair SE, et al. Cellular Senescence as the Causal Nexus of Aging. Frontiers in Genetics. 2016;7:13.
- Lasry A, Ben-Neriah Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 2015;36(4):217-28.
- Chinta SJ, Woods G, Rane A, et al. Cellular senescence and the aging brain. Exp Gerontol. 2015;68:3-7.
- Sikora E, Bielak-Zmijewska A, Mosieniak G. Cellular senescence in ageing, age-related disease and longevity. Curr Vasc Pharmacol. 2014;12(5):698-706.
- Malavolta M, Pierpaoli E, Giacconi R, et al. Pleiotropic Effects of Tocotrienols and Quercetin on Cellular Senescence: Introducing the Perspective of Senolytic Effects of Phytochemicals. Curr Drug Targets. 2016;17(4):447-59.
- Baker DJ, Wijshake T, Tchkonia T, et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-6.
- Xu M, Tchkonia T, Kirkland JL. Perspective: Targeting the JAK/STAT pathway to fight age-related dysfunction. Pharmacol Res. 2016;111:152-4.
- Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature. 2016;530(7589):184-9.
- Khor SC, Razak AM, Wan Ngah WZ, et al. The Tocotrienol-Rich Fraction Is Superior to Tocopherol in Promoting Myogenic Differentiation in the Prevention of Replicative Senescence of Myoblasts. PLoS One. 2016;11(2):e0149265.
- Khor SC, Mohd Yusof YA, Wan Ngah WZ, et al. Tocotrienol-rich fraction prevents cellular aging by modulating cell proliferation signaling pathways. Clin Ter. 2015;166(2):e81-90.
- Durani LW, Jaafar F, Tan JK, et al. Targeting genes in insulin-associated signalling pathway, DNA damage, cell proliferation and cell differentiation pathways by tocotrienol-rich fraction in preventing cellular senescence of human diploid fibroblasts. Clin Ter. 2015;166(6):e365-73.
- Khee SG, Yusof YA, Makpol S. Expression of senescence-associated microRNAs and target genes in cellular aging and modulation by tocotrienol-rich fraction. Oxid Med Cell Longev. 2014;2014:725929.
- Makpol S, Zainuddin A, Chua KH, et al. Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts. Clinics (Sao Paulo). 2012;67(2):135-43.
- Zhao JL, Zhao J, Jiao HJ. Synergistic growth-suppressive effects of quercetin and cisplatin on HepG2 human hepatocellular carcinoma cells. Appl Biochem Biotechnol. 2014;172(2):784-91.
- Qureshi AA, Rei
- Qureshi AA, Reis JC, Qureshi N, et al. delta-Tocotrienol and quercetin reduce serum levels of nitric oxide and lipid parameters in female chickens. Lipids Health Dis. 2011;10:39.
- Qureshi AA, Tan X, Reis JC, et al. Inhibition of nitric oxide in LPS-stimulated macrophages of young and senescent mice by delta-tocotrienol and quercetin. Lipids Health Dis. 2011;10:239.
- Qureshi AA, Tan X, Reis JC, et al. Suppression of nitric oxide induction and pro-inflammatory cytokines by novel proteasome inhibitors in various experimental models. Lipids Health Dis. 2011;10:177.
- Burton DG, Faragher RG. Cellular senescence: from growth arrest to immunogenic conversion. Age (Dordr). 2015;37(2):27.
- Viola V, Pilolli F, Piroddi M, et al. Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E. Genes Nutr. 2012;7(1):29-41.
- Tiwari RV, Parajuli P, Sylvester PW. gamma-Tocotrienol-induced autophagy in malignant mammary cancer cells. Exp Biol Med (Maywood). 2014;239(1):33-44.
- Parajuli P, Tiwari RV, Sylvester PW. Anti-proliferative effects of gamma-tocotrienol are associated with suppression of c-Myc expression in mammary tumour cells. Cell Prolif. 2015;48(4):421-35.