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Why Senescent “Zombie” Cells Should be on Your Radar and How to Kill Them

How to kill senescent zombie cells

All the cells in your body will become senescent at some point in your life, with the exception of cancer cells. But what are senescent cells and why do people sometimes call them zombie cells? In simple terms, a senescent cell is one that can no longer divide. It is a cell at the end of its life. As with many things here at Gene Food, though, cellular senescence is far from straight forward. So, in this article, I’ll look at why these ‘zombie’ cells should be on your radar and how to kill them.

What are senescent cells?

Cellular senescence was first outlined in the early 1960s by researchers Leonard Hayflick and Paul Moorhead. These scientists found that a certain kind of fetal cell (fibroblasts) became senescent after replicating itself a maximum of around 50 times. After this point, cells no longer divide. This process became known as replicative senescence and the Hayflick limit (no word on what Moorhead thought about that!).

Fibroblasts are a type of cell found in connective tissue. Other types of cells, including keratinocytes, endothelial cells, lymphocytes, chondrocytes and vascular smooth muscle cells have also demonstrated replicative senescence, although the number of cellular divisions shows some variability for cell types and in different species of animal. Additionally, people with progeroid syndromes (such as Werner syndrome) have far fewer average cell divisions compared to cells from people without such syndromes. 1

In humans, the only cells that buck this trend for replicative senescence are cancer cells. This is why researchers often use cancer cell lines, such as HeLa cells, in laboratory studies (see The Immortal Life of Henrietta Lacks, an amazing book!). Some types of rat cells and some cells from mice have also demonstrated ‘immortality’ under certain conditions in laboratory cultures. 2 3

Cellular senescence has long been seen as an irreversible mechanism that helps protect us against cancer. In recent years, however, medical scientists have come to realize that cellular senescence isn’t like flipping a switch and senescence may even promote tumor growth in some cases. In such cases, the immortality of these cells is downright scary, which is why they’ve earned the zombie cell moniker.

Cells go through a multi-step process as they become senescent. True senescence occurs at the point when cell-cycle arrest is irreversible, i.e. when growth factors cannot stimulate the cells to divide further. Senescent cells’ growth is arrested in the transition phase G1 to phase S of the cell cycle, but this arrest does not mean the cell dies. Indeed, senescent cells can still be metabolically active for a long time, even when we don’t want them to be.

Nowadays, cellular senescence is understood as a series of phenotypically diverse cellular states that occur after a cell’s growth is first curtailed. These steps include significant changes in chromatin and secretome, as well as the activation of tumor-suppressive genes. Yes, cellular senescence can be a safeguard against cancer, but it is also far more than that. Cellular senescence plays a role in embryonic development, the healing of wounds, tissue repair, and ageing.

How do cells become senescent?

Replicative senescence happens when a cell’s DNA is damaged. This damage results from the progressive shortening of telomeres with each division of a cell, hence the Hayflick limit of around 50 divisions. For a quick primer on telomeres and cellular senescence, check the biology dictionary online.

Cells can also become senescent, however, long before the typical Hayflick limit. That’s because a cell’s DNA may become damaged due to high levels of reactive oxygen species (ROS), cell to cell fusion, or the activation of oncogenes. As we age, these processes become more likely, meaning we have more and more senescent cells in our body’s tissues.

Interestingly, the Hayflick limit was established under laboratory conditions using human fetal fibroblast cells at around 20% oxygen. A level of 3% oxygen, which is closer to normal physiological conditions, appears to allow for an additional 20 divisions in human cells. However, at 50% oxygen, conditions become cytotoxic. Subcytotoxic conditions that don’t immediately kill cells can accelerate senescence, with scientists referring to this as stress-induced premature senescence or SIPS. 45

Why should you care about cellular senescence?

Why should you care about these zombie cells? In short, because understanding senescent cells could lead us to develop new ways to prevent and treat diseases and age-related health issues. Cellular senescence is involved in growth and development, tissue repair, ageing, and diseases and disorders related to ageing. Indeed, cellular senescence has been linked to the shortening of telomeres, leading to instability in chromosomes and tumor promotion.

While senescent cells are no longer able to divide, they do remain metabolically active. What’s more, zombie cells develop some pretty undesirable metabolic tendencies, including a pro-inflammatory secretome, up-regulation of immune ligands, abnormal gene expression, and other issues. To cellular biologists, this is downright blood-curdling.

In senescent cells, we typically see reorganized chromatin, enlarged cytoplasm (the contents of a cell, outside the nucleus), and an abnormally shaped nucleus. Senescent cells tend to be larger than non-senescent cells and also secrete certain molecules or different amounts of these molecules than other cells, with a variety of impacts on health. Certain genes are overexpressed in senescent cells, including those for inflammatory regulators such as interleukin-1-beta. Senescent cells also contribute to increased activity of metalloproteinases, which can damage other cells and tissues.

Even a small number of senescent cells can disrupt tissue homeostasis and function and senescent cells are now thought to contribute to age-related pathologies such as osteoarthritis, skin aging, and other health issues. 678

Senescence Associated Secretory Phenotype (SASP)

An accumulation of senescent cells is characterized by what’s called a Senescence Associated Secretory Phenotype (SASP), which consists of altered levels of inflammatory cytokines, growth factors, and proteases. SASP is mainly associated with inflammation and proliferation and changes in the extracellular matrix, i.e. the stuff between our cells. This can have a negative effect on nearby cells, inducing senescence in those cells as well, and creating a positive feedback loop where senescent cells lead to more senescent cells, and so on. 9

Senescent cells can also develop a resistance to apoptosis (programmed cell death), meaning they don’t die when we might want them to (like in every good horror movie). In some cases, senescent cells do self-destruct and are cleared away by the immune system. But, unfortunately, things can go awry as we age, with more senescent cells sticking around and the immune system becoming less able to clear the cells. As senescent cells start to build up in the body, the likelihood of tissue damage and age-related diseases increases.

Indeed, SASP is associated with a number of age-related diseases. These include type 2 diabetes and atherosclerosis. Senescent cells increase in many tissues as we age, and these cells also occur at a higher level in those with certain chronic diseases and after radiation or chemotherapy.

And here’s where things start to get even more complicated. The SASP is associated with the development of cancer and can occur after treatment for cancer, but cellular senescence can also help protect against cancer. As such, broad eradication of senescent cells isn’t a sure-fire way to prevent cancer. Still, the race is on to develop drugs that clear senescent cells, in the hope that this can combat ageing and restore good health.

The potential benefits of senolytics

In recent years, researchers have been hard at work investigating the possibility of selectively clearing or ‘killing’ senescent cells to enhance healthy lifespan. This area of science is still relatively fresh, with new insights occurring regularly. Drugs or treatments intended to kill senescent cells are called senolytics.

One of the most promising areas of senolytics research is that looking at STACs, or sirtuin-activating compounds. Sirtuins are genes that help silence other genes, with Sirtuin2 associated with alterations in cellular senescence in yeast. STACs include plant polyphenols such as resveratrol and fisetin, and some animal studies note that resveratrol in particular appears to extend lifespan. Further research also showed that resveratrol increased sirtuin levels in yeast, flies, and worms, with corresponding increases in lifespan of some 10-20%.1011

Other studies, again in mice, have found that clearing senescent cells could help delay age-related disorders.1213 This only appears to help in some tissues, however, with possible protection against cancer after clearing senescent cells.

In one study from 2018, researchers began by injecting senescent cells into young mice.14  They observed a loss of health and function, which they reversed by treating the mice with a combination of two drugs: dasatinib and quercetin. These drugs selectively killed senescent cells and slowed physical deterioration. They also extended both lifespan and health span in naturally aging mice.

The combination of these two agents was seen to prevent cell damage, delay physical dysfunction, and, when used in naturally aging mice, extend lifespan. In contrast, injecting young mice with even a small number of senescent cells led to impairments in walking speed, muscle strength, endurance, daily activity, food intake, and body weight, with changes seen after just two weeks. Furthermore, the mice were found to have higher numbers of senescent cells, beyond those injected, suggesting the cells promoted senescence in neighboring cells.

In older mice also injected with senescent cells, the combination of senolytics alleviated normal age-related physical dysfunction, leading to increased walking speed and endurance, better grip strength, and improvements in daily activity. In much older mice, biweekly treatment with dasatinib and quercetin improved post-treatment lifespan by 36%.

The researchers involved in this study noted that the combination of drugs may be helpful not only for older people, but for those who survive cancer after treatment with senescence-inducing radiation or chemotherapy. Dasatinib itself is a chemotherapeutic drug used to treat certain kinds of leukemia, and commonly causes a raft of side effects in more than 30% of those treated with the drug. As such, this is not a drug to use lightly.

Rapamycin has also been investigated for its potential impact on cellular senescence. This drug is an immunosuppressant and is used to prevent rejection of organs after transplant. It has also been found to extend the lifespan of middle-aged mice by 9-14% or by 10-18% in younger mice.1516 And, in elderly humans, rapamycin lessened the degree of immunosenescence.17

Rapamycin has serious side effects, however, making it unsuitable as an anti-ageing agent. But, because we know that rapamycin works by inhibiting a metabolic pathway known as TOR (Target of Rapamycin), researchers are now looking at developing other drugs that target other parts of that same pathway, without the same severity of side effects.

In another study, researchers investigated two approaches to clear senescent cardiac muscle cells from the hearts of mice.18 One treatment involved giving a signaling agent to mice with a specific type of genetic programming so as to trigger senescent cells to self-destruct. The other approach was to give naturally aged mice the cancer drug navitoclax. Both treatments helped to restore heart health, alleviating myocardial hypertrophy and fibrosis.

The senolytic drug ABT263 (navitoclax) reduced telomere dysfunction in cardiomyocytes without affecting telomere length. Both the genetic clearance approach and navitoclax essentially reversed the damage that aging causes to the heart.

Previous studies have also looked at the use of navitoclax as a senolytic. The results suggest that, like dasatinib and quercetin, navitoclax is a selective senolytic, helping to clear some, but not all, types of senescent cells. Specifically, navitoclax reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and mouse embryonic fibroblasts (MEFs), but not human primary preadipocytes. Another drug, called TW-37, does not appear to have much senolytic activity. 19

What about telomeres? Aren’t there already supplements you can take that prevent cellular senescence by extending telomeres? Indeed, there are! But these telomerase supplements are by no means problem-free and haven’t been found to have an anti-ageing effect or any real health benefits. Indeed, animals with more telomerase do not live longer; telomerase won’t do much for the brain, given that this organ is mostly made up of non-proliferating cells; and telomerase favors the development of tumors, which isn’t at all what we want.

The takeaway

So, where does this leave us? In short, we’re just beginning to get to grips with a number of senolytic agents. Researchers are starting to figure out which drugs are effective for clearing particular types of senescent cells and the potential health benefits of doing so. As yet, there are no drugs approved as senolytics and no approved treatment protocols for what amounts to an anti-ageing therapy. Instead, individuals invested in the study of gerontology often experiment upon themselves, for better or worse.

Interestingly, health care and health research bureaucracy means that few studies are carried out that address the broader process of aging and cellular senescence as a contributing factor. Funding is, instead, largely focused on treating specific diseases and disorders. This leaves researchers scrambling to cobble together the bigger picture when it comes to treating cellular senescence more broadly.

Two senolytic drugs, dasatinib and quercetin, are, for instance, U.S. FDA-approved for other indications but not specifically for eliminating senescent cells. As such, options are limited if you’re looking for a way to kill and clear senescent cells right now. The best option, then, appears to be to try to limit the occurrence of stress-induced prematurely senescent cells by reducing oxidative stress and the production and impact of reactive oxygen species (ROS).

There are three key ways to reduce oxidative stress: limiting exposure to environmental pollutants with oxidizing properties; increasing levels of endogenous and exogenous antioxidants; stabilizing mitochondrial energy production and efficiency. These approaches encompass a two-prong approach comprising the prevention of ROS formation and quenching ROS with antioxidants. You can read more about ROS and ways to reduce oxidative stress here.

And, as always, we’d love to hear from you via our contact form if you have questions or comments about cellular senescence, or if you have some killer photos of your zombie cell costume for Halloween.

Leigh Matthews

Leigh Matthews, BA Hons, H.Dip. NT, is a health and wellness writer for Gene Food specializing in plant-based nutrition. Read her full bio here.

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