The Link Between Your Metabolism and Aged ‘Zombie’ Cells

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Introducing The ‘Zombie Cells’: What Is Senescence, Why Does It Happen and Why Is It Bad In The Long Run?

If you take cells from human tissue and culture them in the lab, they will eventually stop dividing. An average human cell can divide between 40 and 60 times before it it can no longer replicate itself. At this point, it will either self-destruct (a process known as apoptosis), or it will enter a state called senescence in which it cannot divide further. Cells can also enter senescence when they sustain irreparable damage to their DNA or cellular organs (organelles).

Senescence is important because it helps protect us against cancer, as it imposes an upper limit on the number of cellular replications that can occur. Once a cell becomes senescent, it sends out signals (including inflammatory molecules) to tell the immune system to come and destroy it. Unfortunately, with ageing, senescent cells start to accumulate faster and the immune system gets worse at removing them, which means that senescent cells accumulate in larger and larger numbers.

Senescent cells are ‘zombie cells’ because they won’t die when they are supposed to, but they also don’t really contribute to the function of the tissue that they are part of – in fact, they are actively harmful. Those same molecules that senescent cells use to signal to the immune system become very damaging when released en masse, and can promote diseases of ageing including, ironically, cancer. (To learn more about senescent cells and what can be done about them, check out this article.)

What Is Metabolism and What’s The Link With Senescence?

In this paper, researchers reviewed the relationship between senescence and the metabolism, which is defined as the sum of the chemical reactions occurring within our cells and our bodies as a whole. They wanted to take a closer look at how metabolic changes during ageing can lead to cells becoming senescent. In turn, they asked the question ‘what is the impact of senescent cells on the metabolism, and how might we address these problems therapeutically?’

First, the researchers highlighted the main metabolic changes that can drive senescence:

• Mitochondrial dysfunction: The mitochondria (the power plants of the cell, responsible for producing the cellular fuel called ATP) become less efficient. This not only leaves less energy available to the cell, but also depletes important molecules (see NAD depletion below) and results in the production of harmful molecules called free radicals, which cause damage to the cell that may trigger senescence.
• NAD+ depletion: Production of ATP requires a molecule called NAD+ (nicotinamide adenine dinucleotide). The job of NAD+ is to pick up electrons that come from the breakdown of nutrients from our food, and to hand them over to proteins that use them to produce ATP. When mitochondria become less efficient, they need more NAD+ to produce the same amount of ATP, which depletes levels of NAD+ from the cell (see this article for a more detailed explanation.) NAD+ is necessary for the correct functioning of certain other molecules, including those that suppress genes associated with senescence and those that protect the DNA against damage (which as mentioned earlier, can trigger senescence).
• Oxygen: Although we need it to survive, oxygen is ultimately poisonous to our cells. This is because oxygen can react with other molecules to form reactive oxygen species (ROS), which have the ability to damage other molecules like our DNA and cause them to break apart. This might be particularly relevant in cancers, which often have increased blood (and therefore oxygen) supplies. Cancers tend to promote senescence in the surrounding non-cancerous cells, which in turn helps the cancer to grow by providing molecules that benefit the cancer cells. Inversely, lower levels of oxygen activate damage-resistance and repair mechanisms that protect cells against senescence.
• High blood sugar: Blood sugar (glucose) tends to increase with age due to reduced production and reduced sensitivity to the hormone insulin, which acts to keep blood sugar low. We don’t fully understand how glucose promotes senescence, and mechanisms vary for different cell types. Most seem to involve the promotion of cellular damage. Glucose can also react with proteins and lipids to form advanced glycation end products (AGEs), which are molecules that bind to other proteins and prevent them from functioning correctly, which can promote senescence.
• Disrupted autophagy: Autophagy, which literally means ‘self eating’, is the cell’s waste disposal mechanism. Its function is to digest and destroy damaged cellular components like the dysfunctional mitochondria discussed earlier. With age, autophagy becomes less effective, which reduces the cell’s ability to recover from damage and may force it to enter senescence instead.
• Metals: Though our understanding is currently limited, the accumulation of metals within cells (such as iron, copper and zinc) can promote senescence by enabling the formation of reactive oxygen species and free radicals, and by altering protein production.

The accumulation of senescent cells within tissues in turn has negative consequences for the metabolism:

• Changes to fat metabolism: Senescent cells synthesise more fatty acids, and produce more enzymes that oxidise and saturate fatty acids, among other changes. This promotes many chronic diseases including atherosclerosis, fatty liver disease and insulin resistance.
• Dysfunction of metabolic organs: Senescence of insulin-producing cells in the pancreas (beta cells) results in a decline in insulin production, making it harder to control blood sugar levels. Senescence also disrupts the function of other organs that are important to the metabolism, like the liver and skeletal muscle (in which senescence contributes to sarcopenia – the progressive loss of muscle mass and strength with age). Muscle is an important metabolic organ because it stores protein, glucose and fatty acids, and thereby influences their levels in the circulation.
• NAD+ depletion: Just as the depletion of NAD+ promotes senescence, senescence appears to further promote NAD+ depletion in other cells by releasing factors that attract white blood cells called macrophages. These macrophages release an enzyme that breaks down NAD+.

You may be able to see that the senescence and metabolic changes form a vicious cycle, with senescent cells disrupting the metabolism in ways that are likely to cause more senescence. Are there any ways we might be able to break this cycle to both improve metabolic health and potentially slow down the ageing process overall?

Interventions Targeting Senescence and The Metabolism

Given the link between senescence and the metabolism, targeting one of them with therapeutic interventions might have beneficial effects on the other. In the paper, researchers lay out some possible strategies:

• Senolytic drugs: Senolytic drugs or senolytics are a class of drug that are able to destroy senescent cells, which should theoretically improve metabolic health and might be used to treat metabolic diseases. Obvious targets are type 1 and type 2 diabetes, as senescent cells are known to play a role in both and some evidence has shown beneficial effects for senolytics in mouse models. The effects of senolytics in humans is still an area of ongoing research with uncertainty over their eventual effectiveness.
• Calorie restriction: Calorie restriction diets have beneficial effects on both the metabolism (such as improving control of blood sugar, LDL and fatty acids) and on senescence, with evidence suggesting that it can supress senescence in animal models and in humans.
• Targeting blood sugar: Since elevated blood sugar appears to promote senescence, interventions that lower blood sugar should reduce the accumulation of senescent cells. We already have many safe and effective interventions that do this in the form of antidiabetic drugs like acarbose, which reduces glucose uptake in the gut, and metformin, which reduces blood sugar through many mechanisms. Metformin in particular has been shown to supress senescence and extend lifespan in mice. Ongoing clinical trials of metformin may be able to tell us more about its benefits in humans.
• Statins: Statins are another class of widely used drug that have senescence-suppressing effects on human cells, both through their effects on cholesterol and through other independent mechanisms.
• Exercise: Mouse models suggest that exercise may suppress senescent cells and the inflammatory factors that they release. There’s also human evidence that low levels of exercise correlate with reduced senescence, though many other factors could be at play as well. Overall, though, there’s a good argument to be made that exercise probably suppresses senescence and certainly improves metabolic health.

At the moment, our best bet for mitigating senescence in humans is to limit the development of senescent cells in the first place, since the other two methods (suppressing the activity of senescent cells or removing them entirely) are still emerging areas of research. Senescent cells are known players in many diseases of ageing, and quite possibly unknown players in many other conditions in which their role has not yet been studied. Understanding their relationship with the metabolism will lead to new methods of targeting them, and this will – we hope – improve our ability to treat a wide range of age-related chronic diseases.

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