November 03, 2011
Killing Senescent Cells Delays Age-Related Diseases In Mice
When cells get old some of them die. But unfortunately other cells live on what's called a senescent state in which they produce toxins that harm neighboring cells and the whole body. Got some aches and pains? You can probably at least partially blame them on senescent cells. Mayo Clinic researchers working with genetically engineered mice showed that by killing off senescent cells they delayed the development of age-related diseases such as muscle loss and cataracts. Killing off bad cells enabled the good cells in muscles to function better. I want this treatment in a human-usable form. The sooner the better.
ROCHESTER, Minn. — Researchers at Mayo Clinic have shown that eliminating cells that accumulate with age could prevent or delay the onset of age-related disorders and disabilities. The study, performed in mouse models, provides the first evidence that these "deadbeat" cells could contribute to aging and suggests a way to help people stay healthier as they age. The findings appear in the journal Nature, along with an independent commentary on the discovery.
These mice were genetically engineered to make their senescent cells more vulnerable. For us adults perhaps gene therapy could add the genetic mechanism needed to kill off our old cells. But it will be a big challenge to get genes delivered into all the cells in the body.
It is hard to selectively kill off just certain types of cells as cancer treatment side effects and failures have shown. Though in some ways killing senescent cells is easier than killing cancers. First off, to cure cancer the dead rate of cancer cells has to be near 100%. By contrast, the killing of just half of all senescent cells would cut the toxin load to the body in half and leave room for healthier cells to divide and take the place of sicker cells. Second, since a single course of treatment doesn't have to kill all senescent cells there's a lot more time in which to do successive waves of treatments to kill off the surviving senescent cells.
A co-author of this study talks in terms of potential benefits in terms that begin to approach the radical rhetoric of biogerontologist Aubrey de Grey. Aubrey advocates the outright defeat of aging (reversal of aging with youth lasting thousands of years). One of the major planks in Aubrey's platform for aging defeat is the killing off of senescent cells.
"By attacking these cells and what they produce, one day we may be able to break the link between aging mechanisms and predisposition to diseases like heart disease, stroke, cancers and dementia," says co-author James Kirkland, M.D., Ph.D., head of Mayo's Robert and Arlene Kogod Center on Aging and the Noaber Foundation Professor of Aging Research. "There is potential for a fundamental change in the way we provide treatment for chronic diseases in older people."
Human bodies become more inflamed as they get old in large part due to senescent cells.
Five decades ago, scientists discovered that cells undergo a limited number of divisions before they stop dividing. At that point the cells reach a state of limbo — called cellular senescence — where they neither die nor continue to multiply. They produce factors that damage adjacent cells and cause tissue inflammation. This alternative cell fate is believed to be a mechanism to prevent runaway cell growth and the spread of cancer. The immune system sweeps out these dysfunctional cells on a regular basis, but over time becomes less effective at "keeping house."
Note the point about the immune system becoming less able to sweep away dysfunctional cells. Immune system rejuvenation would reduce the incidence of cancer. If we can kill off both cancer cells and senescent cells we could add decades to our life expectancies.
The scientists genetically engineered the mice to cause their senescent cells to die in the presence of a compound that is non-toxic to normal cells.
Dr. van Deursen and colleagues genetically engineered mice so their senescent cells harbored a molecule called caspase 8 that was only turned on in the presence of a drug that has no effect on normal cells. When the transgenic mice were exposed to this drug, caspase 8 was activated in the senescent cells, drilling holes in the cell membrane to specifically kill the senescent cells.
The great result: killing off senescent cells delayed the onset of age-related diseases.
The researchers found that lifelong elimination of senescent cells delayed the onset of age-related disorders such as cataracts and muscle loss and weakness. Perhaps even more importantly, they showed that removing these cells later in life could slow the progression of already established age-related disorders.
The findings support a role of senescent cells in the aging process and indicate that chemicals secreted by these cells contribute to age-related tissue dysfunction and disease.
This is a very exciting report.
This report reminds me of work done by Thomas Rando and Irina Conboy at Stanford (and Conboy later elsewhere) showing that blood from old mice suppresses cell growth in young mice. This suggests that stem cell therapies would work far better if senescent cells were killed off since they are probably (I am guessing) the source of the growth-suppressing blood chemicals in the old. Other work earlier this year by Tony Wyss-Coray at Stanford found a chemokine secreted by cells was at least partially responsible for suppressing neurogenesis (the creation of new neurons).
Blood cells from one mouse cannot travel into the brain of the other because of the blood-brain barrier, so the team concluded that free-floating molecules in the blood, capable of passing through, must be responsible for the effects. By comparing more than 60 chemokines—chemical messengers secreted by cells that circulate in the blood—the researchers identified several associated with the detrimental effect of old blood. Administering one of these chemicals, called CCL11, to young mice dampened neurogenesis and impaired learning and memory.
The ability to kill off senescent cells will probably boost brain function as well as other parts of the body. Gotta love that.
Update: Nicholas Wade looks at the benefits and harm from cells becoming senescent.
And despite being termed senescent, the cells are very active: They convert themselves into factories that churn out 100 different kinds of growth factors, along with cytokines, the inflammatory agents that stimulate the immune system. The evolutionary reason for this activity may be to provoke the immune system to attack patches of premalignant and malignant cells.
It is not certain that wiping out senescent cells will provide an unalloyed blessing. Killing them might up cancer risk. Effective cures for cancer would therefore reduce the risk of treatments that kill senescent cells.
This seems very, very promising indeed!
Perhaps this could be programed to kill off cells manufacturing those cellular signals?
Full text article: "Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders"
The paper closes with:
"...both life-long and late-life clearance of the p16Ink4a expressing
senescent cells selectively delayed age-related pathologies
in tissues that accumulate these cells. Furthermore, our data indicate
that acquisition of the senescence-associated secretory phenotype
(SASP), which enables cells to secrete a variety of growth factors,
cytokines and proteases, contributes to age-related tissue dysfunction.
There were no overt side effects of senescent cell clearance in our
model, even though it has been postulated that senescent cells enhance
certain types of tissue repair. Our proof-of-principle experiments
demonstrate that therapeutic interventions to clear senescent cells or
block their effects may represent an avenue for treating or delaying
age-related diseases and improving healthy human lifespan."
Could slowing the genetic program that drives cells toward senescence work also?
One of these days, when humans learn how to control apoptosis, the rich will look better and live longer than the rest of us.
In our envy, we proles will turn on them. They will make fine eating.
I think H.G. Wells had something to say about that.
You didn't fill in the href.
[EDIT: I fixed it]
You point out a potential future conflict that would be a good movie theme.
If such treatments become available, but only to the rich, conflict is inevitable.
Might be like a high-tech version of the movie "Titanic".
Yes, I think this is a very good candidate for the death clock. I can't see any other explanation besides a death clock for the 10x difference in lifespan between a mouse and bat.
Frustrating that it took some 50 years to go from discovering the Hayflick limit for cells to identifying the mechanism for transferring that limit to the overall biological system. But, better late than never.
According to the following paper -
"Restoration of senescent human diploid fibroblasts by modulation of the extracellular matrix"
- senescent cells are largely rejuvenated when transplanted into a more youthful extracellular matrix (ECM).
Maybe removing senescent cells also locally clears compromised ECM allowing other cells to revert to a younger phenotype?
If it's an actual "death clock", which is to say, an active mechanism for killing off the aged organism, rather than just a degenerative process, you'd want some sort of non-linearity in the mechanism. Like perhaps senescent cells somehow keeping track of the number of cells in their neighborhood which are also senescent, and switching to a "kill mode" when it passes some threshold.
So, suppose that when a cell determines, somehow, (How?) that it is senescent, (Can't divide any further.) it starts secreting signaling compounds at a low level, while still devoting some energy to doing whatever its role is in the body.
It monitors the level of those compounds, in order to assess the population density of cells in a similar state.
When the level goes over some threshold, the cell switches to killer mode, and devotes all it's flagging energy to secreting the signaling compounds, which then put the organism into a downward spiral.
Transplanting a senescent cell into a tissue with few other senescent cells would expose it to a lowered level of signaling compounds, and might switch it out of it's killer state.
The obvious approach is to attempt to block reception of the relevant chemokines, so that senescent cells 'think' they're exceptions residing in youthful organisms, and don't switch on their killer mode.
In the paper I cited, the cells transplanted to the young ECM were all senescent.
So the only factor that caused the rejuvenation was the ECM.
The formerly growth arrested senescent cells suddenly recovered their growth potential and became "morphologically indistinguishable from young cells" (article). BTW, young cells transported to old ECM grew sluggishly.
It would be very interesting to know if the transplanted cells included some young cells whether the senescent cells could achieve even more population doublings.
I am going to see that movie.
Lou, that's an interesting bit of research. Looks like the young ECM actually did rejuvenate the senescent cells to some extent, including telomere restoration. Now we need a way to make old extra-cellular matrix look more like young extra-cellular matrix. Is it something the young cells excrete? Something the old cells excrete that's not to be found around young cells? Or maybe something that the young cells secrete ties up or eliminates a product of old cells.
It's a promising line of research, that's for sure.
As far as keeping the ECM in good shape, there are two approaches I saw in the literature -
The first is inhibiting the enzymes that become too aggressive in disassembling the ECM with age. I believe some flavonoids, NSAIDs and tetracycline derivatives are candidates. I am not sure whether the side effects outweigh the benefits or what the correct doses are. The other approach is to slow or stop nonenzymatic glycation of the ECM, or to break the bonds after they have formed. It would interesting to know all the ways young vs. old ECM differ.
Just posted on the Fight Aging! website -
SENS Foundation on Clearance of Senescent Cells
"... How might the results of this intervention be translated for human rejuvenation therapies? ... SENS Foundation is currently funding work by Dr. Kevin Perrot in Campisi's laboratory, screening compounds for their effectiveness in eliminating cells exhibiting the classical senescence-associated secretory phenotype."
BTW, it's worth noting that dermabrasion, which disproportionately clears both senescent cells and old collagen, appears to rejuvenate skin.
Yeah your right damaging cells provokes a repair/partal/rejuvinate responce. The reason why the old cells rejuvinate in the younger ECM is all about cell signaling from various compounds emited by the younger type cells, it would also work the other way round and make young cells old if the surrounding ECM was older than lesser numbered younger cells, you only got to look at what we do to try and cure cancer to work that out, we don't cut out the cancer but the surrounding tissue also because there is a risk that healthy tissue removed will behave like the cancer cells that have been removed as they have been under the influence from signaling factors from the cancer cells.
This article has incorrectly interpreted information from the van Deursen study by cutting out little snippits and hailing them as the cure all for old age. First and foremost, senescent cells are not "bad" cells. They do produce cytokines and the like that cause inflammation in the surrounding tissue, much like the cytokine "storms" that are produced in some microbial infections. However, senescent cells, which are essentially cells that irreversably stop dividing my mitosis are important (along with apoptosis) in the suppression of cancer formation. Ironically senescent cells can also aid in the formation of cancer, but that's a story for another day. These paradoxical effects of senescent cells makes our understanding of the aging process all the more difficult. Some have hypothesized that senescent cells evolved to give an adaptation that promoted the survival of the younger organism, but because in the older days life-span was often shorten due to environmental reasons (famine, war, etc.) evolution did not select for senescent cells that did not cause detrimental effects in the older populations (note that the older population can not reproduce as much as their younger counterparts and so pass on advantageous genes that would keep them alive longer).
Anyways, I digress. If you read carefully the van Deursen study you would note that the life-span of the animal models did not differ significantly from the control models. That is because the biological maker (p16) that was used to eliminate the senescent cells is not produced in great quantities in all tissues of the body. That is, not all tissues accumulate a lot of senescent cells in their tissues over time. For example, not much affect was found in cardiac tissue, and the experimenters guessed that the mice in the study probably died of cardiac failure.
As far as brain function goes, the laboratory that I currently work at has actually taken a look at the morphology of the brains from the same animal models that were used in the van Deursen study. No significant changes were found at all between the group with senescent cells and the group without senescent cells. We also looked so far at three areas of the brain (striatum, hippocampus, parietal cortex) and none of these regions showed any significant differences. This is not conclusive, as there may be another region of the brain that is significantly affected But it could also be said that senescent cells are not prevalent, or their products (cytokines) do not affect the brain directly. Further research will have to be conducted. But I can say that brain function will more than likely not be improved by removing these cells, although dysfunction could be delayed.