There is no coincidence that cancer is more frequent as we age. And it is also no coincidence that many anti-aging therapies destined for rejuvenation could allow unleashed growth to take place and cause cancer. Hence my interest in those species which despite an abundant capability to regenerate their damaged tissues, show no increased rate of cancer.
Elephants are no masters of regeneration, but they know how to grow. Despite their huge number of cells and their 65-year old maximum lifespan in captivity, they rarely develop cancer. One way they do that is by having multiple copies of a gene manufacturing p53 (original studies here and here). Another way they could avoid cancer is by their sheer mass where metabolism gets slowed down to a pittance compared to our tiny frames.
But let’s get back to p53. When it was first discovered, this protein (hence the ‘p’ in its name) had a molecular mass of 53 kilodaltons, hence its name p53.
We have 2 copies of p53, one inherited from our mothers and one from our fathers. Some people have only one good copy of p53 – Li Fraumeni syndrome patients – and with only one ‘guardian of the genome’ instead of two, these unfortunate people develop cancer when young.
When first hearing that we only have 2 good copies of p53 (if we’re lucky to have even those 2!) and we have an approximate 1/3 chance of developing cancer through our lifespan and elephants having 20 copies of p53 and rarely developing cancer despite their mass, the temptation is that inserting additional copies of p53 in the human genome could become a safe way to prevent cancer from developing.
And for a moment, I considered this to be the future of oncology, but I was so wrong because I wasn’t seeing the big picture.
There is already a company in China being approved for genetic therapy in 2003 whereby they insert an additional copy of p53 with the help of an adenovirus in one type of cancer only. Now for diagnosed cases of cancer – or even for Li Fraumeni syndrome patients – that could work out very well. But for preventive purposes, I don’t think so.
When a cell is stressed, the level of p53 increases. When a cell is unstressed, its level of p53 decreases.
A cell often becomes malignant by turning p53 off. Because once a cell turns p53 on above a certain threshold, it has two possible fates:
-stop dividing forever – cellular senescence
-or committing programmed suicide – apoptosis
Which path a cell takes is still unclear – but probably if the level of p53 increases a lot, it commits suicide and if it increases moderately, it only stops dividing and the cell is still metabolically active [source].
I’m mentioning all this because three of the goals of defeating aging are:
-getting rid of senescent cells which poison the microenvironment around them
-preventing or at least curing cancer which is rampant with age
-replenishing the pool of young cells to allow for regeneration of damaged tissues to take place
By unknowingly playing with p53, you could have only two of the three above – let’s see how:
-you could turn p53 off to avoid a cell going senescent, but that cell could turn into a budding tumor
-you could turn p53 on at increased levels where even cancer cells could commit suicide, but that will leave you with fewer functional cells unless you’d replenish them. A consequence would be accelerated aging, fewer functional, differentiated cells, fewer healthy stem cells, all for avoiding cancer elephant-style 🙂
-you could turn p53 off to avoid a cell to commit suicide, but that could also increase the risk for cancer unless you have other mechanisms set in place to avoid that. Species capable of complete regeneration as adults with low cancer rates have these set in place – I don’t know how they do it, but if you’re interested in this direction, such species include aquatic invertebrates like hydras, corals, sea urchins, sea sponges etc (check ‘The aging gap between species’ book or this blog post for examples). Plants can also develop cancer even if they are modular organisms, but their tumors don’t metastasize because plant cells are not mobile like animal ones are.
Out of all possible evidence-based anti-aging therapies, senolytics could be the first reaching human patients. These are drugs administered to determine inflammation-inducing senescent cells to commit suicide. And it’s no wonder a couple of anti-cancer drugs already paved the way in this novel class of drugs. Chemotherapy includes a broad range of chemical substances from non-specific poisons to drugs targeting only a certain protein produced by a certain type of tumor. But when using such substances as senolytics, the same danger as in chemotherapy exists that you could also determine young cells to commit suicide and you don’t want that. So how can the two be distinguished?
Let me just mention first that there are two ways through which a cell ages or becomes senescent:
-first when a cell’s telomeres become short enough or when it reached its Hayflick’s limit, p53 will normally become activated and the cell will stop dividing. This is the physiological course a differentiated cell without telomerase – the enzyme that adds back to the length of telomeres – takes. This is the happy case of normal cell aging.
-and second when a cell’s DNA is damaged even if the cell’s telomeres are long enough, the cell will enter accelerated senescence through the same p53 mechanism. Anything that can damage DNA – radiation, genotoxins, viruses – can increase the number of senescent cells in a body.
Now in order to distinguish young cells from old ones, you could look through the microscope at a cell culture or a stained tissue microscope slide and you’d notice that :
-they look different: senescent cells are bigger, flatter and have more granules inside them than young cells
-they act differently: senescent cells often stain positive to a marker called senescence-associated beta-galactosidase which is nothing more than the common beta-galactosidase used by milk product manufacturers to make their products suitable for those of us who are lactose intolerant.
Here are two such images to notice the difference yourself – the first one includes young cells and the second one senescent ones that stained positive for beta-galactosidase:
Image by Y tambe (Y tambe’s file) [GFDL (http://www.gnu.org/copyleft/fdl.html), GFDL (http://www.gnu.org/copyleft/fdl.html), CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/) or CC BY-SA 2.5-2.0-1.0 (http://creativecommons.org/licenses/by-sa/2.5-2.0-1.0)], via Wikimedia Commons
Another biomarker of senescent cells could be p16, a protein whose levels increase when cells stop dividing if old and also a protein whose gene is turned off in many human cancers.
Coming back to our topic – designing senolytics that avoid the apoptosis of young, healthy cells – the ideal senolytic should accomplish two things:
-turn on p53 at increased levels to determine stubborn, senescent cells to commit suicide
-do that on senescent cells only
And in order to accomplish the second part, such a drug should be ‘programmed’ to only act on those cells where it recognizes senescence-associated biomarkers. There is no single biomarker today that stains positive or negative on all types of senescence cells, but increased levels of beta-galactosidase and p16 proteins could be a welcome start to identify old cells in vivo when designing such a drug.
If you have any comments or suggestions, I’d love to hear from you in the comment section below!
