Chemotherapy is usually effective against cancer, but recurrence/resistance can occur. Senescence – stopping of cell cycle and cell growth – is typically considered good for malignant cancer cells, stop them from dividing as a therapy. But here we see that chemotherapy-induced senescence changes cancer cells so that if they are released from senescence and re-enter cell cycle growth, they are more dangerous than before – with more stem cell like properties and more aggressive growth. This needs to be addressed. Abstract:
Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16INK4a, p21CIP1 and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells
The small, freshwater hydrozoan animal Hydra appears to be truly immortal.
In ancient Greek myth, the Hydra was a multi-headed monster that grew two more heads for every one that it lost. As it turns out, the real-life animal named after this mythical beast may be even more tenacious.
A new study finds that hydra — spindly, freshwater polyps — can live seemingly forever, without aging.
Unlike most multicellular species, hydra don't show any signs of deteriorating with age, according to the new research, published Dec. 7 in the journal Proceedings of the National Academy of Sciences
Over eight years, the researchers found no evidence of senescence in their coddled hydra. Death rates held constant at one per 167 hydras per year, no matter their age. (The "oldest" animals studied were clones of hydras that had been around for 41 years — though individuals were only studied for eight years, some were biologically older because they were genetic clones.) Likewise, fertility remained constant for 80 percent of the individual hydras over time. The other 20 percent fluctuated up and down, likely because of laboratory conditions.
"I do believe that an individual hydra can live forever under the right circumstances," Martinez said.
In the wild, disease, predators and water contamination kill off hydras before they can achieve immortality. But the findings fly in the face of old models that assumed that all animals must decline with age, Martinez said. And that means that studying hydra could help scientists unravel the mystery of why most animals do age.
"I’m hoping this work helps sparks another scientist to take a deeper look at immortality," Martinez said, "perhaps in some other organism that helps bring more light to the mysteries of aging.”
The actual paper is here.
Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility.
Obviously, the mechanisms of immortality (or as scientists would call it “nonsenescence”) for Hydra are not directly applicable to interventions designed to retard the human aging process. However, the benefit of basic science research such as this is that it can lead to novel, sometimes, unexpected, directions, can promote work in other species, and can lead to innovative discovered that may, eventually, directly or indirectly affect human health. So, no, humans cannot have “a high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and…[a] germ line is not segregated from the soma;” nevertheless, further investigation into the Hydra and other relevant mechanism may someday help unlock the key to inhibition of senescence in humans, leading to longer and healthier lives.
Some interesting work suggests that clearing the body of senescent cells can increase lifespan and enhance health:
Mice were much healthier and lived about 25 percent longer when scientists killed off a certain kind of cell that accumulates in the body with age.
What's more, the mice didn't seem to suffer any ill effects from losing their so-called senescent cells.
These are cells that have stopped dividing, though not necessarily because the cells themselves are old. "It's a normal cell that experienced an unusual amount of stress, and it decided to stop dividing," says Jan van Deursen, who studies senescent cells at the Mayo Clinic College of Medicine in Rochester, Minn.
Older creatures have a lot more of these cells than young 'uns. And even though the cells aren't dividing, they do keep busy — they secrete a mixture of chemicals that can trigger inflammation, which seems to be involved in just about every major age-related disease.
So van Deursen and his colleagues wanted to know: What would happen if you simply got rid of senescent cells? That's tough to do in humans, but possible in mice.
The researchers created mice that were genetically altered so that giving them a drug would trigger senescent cells to kill themselves. Then they waited until the mice reached middle age, and gave some of them the drug.
At first, wiping out the senescent cells didn't seem to make much difference. But as the mice got older, the research team could see that the treated mice looked healthier.
"And then when we started to record the life span of the animals, we saw that there was about a 25 percent extension in life span of animals that had their senescent cells removed from 1 year of age on," says van Deursen.
What's more, the treated mice had fewer cataracts, hearts with better stress tolerance, and improved kidney function. And losing the cells didn't seem to cause them any problems, the researchers report Wednesday in the journal Nature.
The bottom line, says van Deursen, is that "it seems like we're accumulating a cell type that we really don't need for anything and that makes us more unhealthy and reduces the length of our healthy lives."
Needless to say, the hunt is already on for drugs that could eliminate these cells in people. That's not going to happen tomorrow, of course, and useful drugs might never materialize. But the findings in mice provide researchers with a new place to look.
Van Deursen himself is working with a new company, Unity Biotechnology in San Francisco, that has some promising candidates.
A scientist named Judith Campisi, who studies senescent cells at the independent Buck Institute for Research on Aging, also works with Unity. She thinks the findings of the latest study are significant. "The impressive thing is those mice not only lived longer but they lived healthier," says Campisi.
But she cautions that removing these cells isn't going to be a magic bullet against aging.
"Obviously, even in the Nature paper, those mice got old and died," she points out.
And some research shows that these cells may have a useful role to play in our bodies. For example, there's evidence that senescent cells aid wound healing and that cellular senescence helps protect against cancer.
"One needs to move forward with care about trying to just kill off senescent cells with the anticipation that things will be wholly beneficial," says Dominic Withers, a researcher at the MRC Clinical Sciences Centre, Imperial College London.
He says it looks like these cells do contribute to aging, but it's too soon to say what to do with them.
"I think it's early days at the moment," Withers says. "There's still quite a lot to learn about whether you would want to try and kill senescent cells or do something to the senescent cells that exist, such as stop them secreting this cocktail of potentially bad molecules.
