Scientists hunt zombie cells: ‘The grand challenge’

Smoking, poor diet, obesity can create cell types implicated in many old-age diseases

Younger looking mice: elderly rodents that either have their zombie cells (left) or have been treated since midlife to remove these cells (right).

Younger looking mice: elderly rodents that either have their zombie cells (left) or have been treated since midlife to remove these cells (right).

 

Smoking ages people prematurely because it damages DNA, but scientists have discovered that it also creates zombie-like cells. These cells are implicated in many diseases typical of old age.

Radiation and chemotherapy, or anything that damages DNA, will also zombify cells. “Smoking induces a high burden of senescent cells in the lungs, but also a poor diet and obesity encourages senescence,” says Prof Judy Campisi, a biologist who pioneered studies into these cells at the Buck Institute for Research on Ageing in California.

Zombie cells, labelled “senescent” by scientists because of their sleep-like state, are very resistant to dying. In a lab dish, they slumber for years under conditions that would kill ordinary cells within hours. They have been linked to diabetes, heart disease, osteoarthritis, lung fibrosis and Alzheimer’s.

“The more zombie cells you have the more we seem to age. If we were able to remove these cells, it may offer a way of staying younger,” says Prof Emma Teeling at University College Dublin, who investigates the biology of ageing using long-lived bats. She believes bats rarely accumulate senescent cells.

Prof Campisi helped reveal that zombies secrete proteins that can encourage chronic inflammation. Worse still, like the zombie hordes in Game of Thrones, senescence cells turn others into troublesome, near-immortal cells. They even zombify cells in distant parts of the body, without coming near to them, via their secretions.

The more senescent cells you accumulate, it seems the faster your biological clock ticks. Suspiciously, these zombie-like cells turn up at the sites of many chronic diseases, including in fat tissue and the pancreas of diabetics. Also, scientists find them in the brain of people with Alzheimer’s, in lesions that result in heart attacks and stroke, and lungs of patients with chronic obstructive pulmonary disease.

It is not all dark tidings. Researchers have unearthed means to destroy the zombies. What doesn’t work is hitting them directly with drugs to kill them. Instead, subtlety is required. Interfering with proteins zombie cells use to shield themselves from self-destruction, and so “find ways to make these old cells commit suicide by reversing their anti-suicide capabilities”, is the favoured strategy, says Prof Teeling. Cell suicide is a trigger the body frequently squeezes to stop cells turning rogue and cancerous.

Destroy the zombies

In efforts to destroy the zombies, scientists at the prestigious Mayo Clinic in the US first transplanted a small number of senescent cells into the knee joint of mice. This triggered osteoarthritis. Putting them into their abdomen caused mice to become frail and to even die early. When the scientists gave the mice either an anti-cancer drug (Dasatinib) or a natural flavonoid found in apple skin (quercetin), zombie cells numbers fell and the mice stopped suffering prematurely from age-related diseases.

Clinicians at the Mayo Clinic then delivered this two-drug combo to patients with a chronic lung disease (idiopathic pulmonary fibrosis), which is relentlessly progressive and fatal. In January, they reported that this first-in-human trial with so-called “senolytic” agents proved safe in 14 patients. Promisingly, five days after treatment ended, some physical improvements in patients were noted. Larger patient trials are planned. Optimism about senolytics, however, is tempered by zombie cells being a natural anti-cancer mechanism (see below).

If senolytics are proven safe, they could cure or ward off many debilitating conditions that we now think of as normal in old age. More than a dozen start-ups as well as big pharma are seizing the opportunity to investigate their potential against various diseases. The great hope is that senolytics could offer a path to us living into a healthier, more active old age. “What we need to look at is not living longer, but living healthier longer,” says Prof Teeling. “That is the grand challenge.”

Anti-cancer strategy

Our cells can be pushed into a zombie-like state that later in life is tied to age-related diseases, but scientists must tread carefully when it comes to deploying drugs against these zombies.

The zombification evolved to shield us from a fatal threat. “It protects against cancer,” says Prof Judy Campisi. “One reason is that senescence cells stop dividing. Cells that cannot divide cannot form a tumour.” The success of this strategy is partly evident in the fact that young people rarely get cancer.

It makes evolutionary sense. The body turns to zombification to stymie cancer and keep us alive when we are younger, so we can reproduce and pass on our genes. The downside is that zombie cells amass as we get older, something that once mattered little. “For most of our evolutionary history, there was no ageing or cancer. People died of starvation and predation, accidents and infections,” says Prof Campisi.

Now though, the protective mechanism leaves us in old age with a harmful accumulation of zombie cells. Scientists like Prof Campisi, who co-founded the leading company in this area, Unity Biotech, believes that by carefully targeting senescent cells for elimination, we can treat diseases of old age such as osteoarthritis. Out of safety concerns, only patients with severe conditions will be able to volunteer for initial drug trials.