Longevity Briefs: A Chink In The Armour Of ‘Zombie Cells’ That Drive Ageing

Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

The accumulation of senescent cells (often called zombie cells) throughout life is believed to be an important driver of ageing. Senescent cells are cells that can no longer function properly or divide, either because they have reached their replication limit or because they have been heavily damaged. Such cells are supposed to either self destruct or be eliminated by the immune system, however with advancing age, these mechanisms increasingly fail and senescent cells accumulate.

Even in old age, senescent cells are relatively few in number, but are believed to have a significant impact on health via a cocktail of signalling molecules collectively known as the senescence-associated secretory phenotype (SASP). SASP factors promote inflammation, trigger senescence in other cells, and are thought to play an important role in promoting and sustaining age related diseases like cancer and atherosclerosis. For this reason, drugs that either suppress the SASP or remove senescent cells altogether might be able to treat or prevent age-related diseases. Of course, it is important that drugs that kill senescent cells (senolytics) do not also kill healthy cells, which means they need a target that is exclusively found in senescent cells. Most existing senolytics target the mechanisms that allow senescent cells to resist self-destruction. In this study, researchers discover a new method for singling out senescent cells by targeting their unique glucose (sugar) metabolism.

The discovery:

Compared to healthy cells, senescent cells are known to rely more on glycolysis – a process that allows glucose to be broken down for ‘fuel’ in an inefficient way, but with the advantage of not consuming any oxygen. However, senescent cells rely on glycolysis even when oxygen is available. This behaviour is known as the pseudo-Warburg effect (the classic Warburg effect refers to the same phenomenon when it occurs in cancer cells).

Researchers wanted to see if they could target glycolysis in senescent cells to selectively kill them. Using a technique in which two proteins can be tagged such that they produce bioluminescence when interacting with each other, researchers were able to identify an aberrant interaction between two proteins called PGAM1 and Chk1 kinase within human cells in which senescence was induced. They found that PGAM1-Chk1 interactions were enhanced in senescent cells and correlated with increased glycolysis. They also found that Nutlin 3b, a molecule that interferes with this PGAM1-Chk1 interaction, could suppress glycolysis in senescent cells and led to their death, while having no significant effect on non-senescent cells.

Researchers then investigated the effects of Nutlin 3b in animals, first in aged (20 month-old) mice. 6 mice were treated with Nutlin 3b via weekly injections for 12 weeks, while another 6 received control injections. They found that Nutlin 3b was correlated with significant improvements in muscle strength without affecting body weight, as well as reductions in markers of inflammation.

Researchers then tested the effects of Nutlin 3b treatment in a mouse model of pulmonary fibrosis (lung scarring) and found that Nutlin 3b was associated with significant reductions in scarring compared to control mice (5 per group).

The implications:

Switching to glycolysis helps to protect senescent cells against DNA damage because unlike aerobic respiration, glycolysis does not produce reactive oxygen species – metabolic byproducts that can damage DNA. In this study, researchers also identified downstream mechanisms of PGAM1-Chk1 that enhanced DNA repair.

This research demonstrates that targeting the PGAM1-Chk1 interaction in senescent cells can inhibit glycolysis and kill senescent cells selectively, seemingly by enhancing DNA damage. This led to improvements in physiological functions during ageing and a reduction in lung fibrosis in mice, suggesting that this strategy could have the potential to treat age-related disease.