How Close Are We To Winning The Fight Against ‘Zombie Cells’?

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As we age, our tissues contain an increasing number of senescent cells. We wrote a full, in-depth article about senescent cells that you can find here. In short, senescent cells are cells that have stopped dividing, either because they have reached their replication limit (known as the Hayflick limit), or because they have sustained severe damage to their DNA. Senescence is a good thing when you are young – it shuts down division of damaged cells so that they will not pass genetic mutations on to their offspring, keeps the population of cells healthy and reduces the risk of cancer.

Senescent cells are supposed to be destroyed by the immune system, but with increasing age, senescent cells accumulate faster and the immune system gets worse at removing them. It’s in large numbers that senescent cells begin to become a problem. They are sometimes described as ‘zombie cells’ because they don’t really contribute to the function of the tissue they are part of. In fact, they are actively harmful, as the signals they release to call for their removal by the immune system cause inflammation and can even contribute to cancer when they are present in large numbers.

Many longevity researchers hope that we might be able to slow or even reverse ageing by removing senescent cells from the body. Is this a realistic prospect? What are our best methods for doing this currently, and what are the biggest problems we need to overcome? A recent review published in the peer-reviewed journal Biomedicines discusses these questions.

What We Know

Firstly, let’s summarise what we know about senescent cells, their role in ageing, and how they can be removed.

• Cells become senescent as time passes, and the rate at which senescent cells appear increases with age.
• Senescent cells function differently to normal cells, and this eventually contributes to almost all age-related diseases.
• Senescent cells differ from healthy cells in ways that allow them to be targeted by drugs.
• Interventions that prevent the formation of senescent cells or remove them after they have formed have been shown to protect against age-related diseases in animal models.
• We currently know of multiple natural compounds and drugs, some of which have been approved for the treatment of specific diseases, that are able to reduce senescent cell numbers.

How To Kill A Zombie

Compounds for tackling senescence can be divided into two broad categories:

Senolytics:

Senolytics is the name given to the group of compounds that can destroy senescent cells while leaving normal cells intact. Many senolytics are natural compounds that were found to destroy senescent cells, while others are repurposed drugs. Here are some prominent examples:

Quercetin is a type of plant compound called a flavonoid that was shown to be beneficial in the treatment of several diseases including diabetes and heart disease. When studied as a senolytic, it is often combined with the drug dasatinib, and this combination (abbreviated to D+Q) is one of the most well known senolytic treatments. D+Q delays many age-related diseases in mice, and has entered several human clinical trials.

Fisetin is another flavonoid with senolytic properties. It has been shown to extend lifespan in mice, and is currently being trialled in humans.

Curcumin has been shown to clear certain human senescent cells. Researchers have also been able to synthesise a compound similar to curcumin that is better at removing senescent cells. Curcumin appears to extend lifespan in mice and reduce symptoms in some age-related diseases in humans.

Navitoclax is a drug belonging to a group of compounds called BCL-2 inhibitors. BCL-2 proteins control ‘cell suicide’ (apoptosis), and targeting the correct BCL-2 proteins can cause senescent cells to self-destruct. Navitoclax and other BCL-2 inhibitors can protect against age-related diseases in mice. Navitoclax is being trialled in humans to treat several types of cancer, but for now its side effects make in unsuitable for the treatment of general ageing.

HSP90 inhibitors are a group of drugs that inhibit heat shock protein 90, a protein that helps senescent cells to survive by reducing self-destruct signals. HSP90 inhibitors protect mice against age-related diseases, but safer versions are likely to be needed to make them viable in humans.

p53-targeting drugs target a pathway that is important in the regulation of senescence. These drugs showed promise in mice but a phase 2 clinical trial in knee osteoarthritis in humans failed. More effective and less toxic versions of these drugs may still be valuable.

Senomorphics:

Senomorphics take a different approach to senolytics. Instead of destroying senescent cells, senomorphics either make senescent cells behave more like younger cells, or prevent the formation of senescent cells in the first place:

Rapamycin is one of our most promising potential anti-ageing drugs and deserves it’s own dedicated article. It is thought to delay the onset of age-related diseases and extend lifespan in multiple ways, including by inhibiting both the onset and the release of harmful factors from senescent cells. Rapamycin is already a clinically approved drug, so we understand its safety in humans well. Clinical trials are still investigating the effects of rapamycin in human ageing.

Metformin is another promising drug that was found to inhibit senescence and the release of harmful factors from senescent cells. Metformin has been used to treat type II diabetes for over 60 years and slows age-related deterioration in animals. There are some indications that these effects carry over to humans, with one study famously finding that diabetics taking metformin lived longer on average than unmedicated non-diabetics. The effects of metformin in non-diabetics are still being investigated.

Resveratrol is a natural plant compound that activates an enzyme called SIRT1, part of a group of enzymes called sirtuins thought to be protective against ageing. Resveratrol, alongside other sirtuin activators, can reduce senescence and extend lifespan in mice. One of these sirtuin activators has entered clinical trials in humans.

Other senomorphics exist and mostly work by targeting various molecular pathways involved in senescence. However, these are not currently being trialled in humans.

The Limits Of Targeting Senescence:

There’s good reason to be hopeful about these compounds. Senescence seems to be an important driver of most age-related diseases, which means that we might be able simultaneously reduce the risk of many debilitating conditions with a single drug. However, progress towards such a treatment is likely to be quite slow. Thorough clinical trials take a long time. What’s more, most clinical trials involving these compounds are looking at the effects in elderly people who already have one or more diseases of ageing. This means that they are usually taking other drugs, which could interact with the senescence-targeting drugs and make the results of the trial harder to interpret.

While senescence certainly seems to be important in many diseases, it isn’t one of the primary hallmarks of ageing – that is to say that suppressing or eliminating senescent cells won’t fix the underlying causes of senescence like telomere shortening. Senolytics aren’t going to be the silver bullet against ageing, but they are one of the most promising lines of investigation in human longevity research.