Wait! Don’t run away! This is actually super cool. It’s a long post, but you’ll be super smart by the end ;)
Yesterday, an extremely exciting academic study from the Netherlands Cancer Institute in Amsterdam described tremendously exciting leaps in anti-aging drugs, often thought to be a holy grail of biological science. These results are so cool I wanted to break them down into layman’s terms for people who aren’t necessarily interested in hardcore microbiology (if you are, the original paper can be found in Cell (paywalled; reduced but public version is here)). By the end, you’ll know enough to perfectly understand the title! I’ve taken some scientific liberties in breaking it down into easily explainable terms, but for the most part, everything here is pretty much accurate, if a bit simplified.
Cells in your body have a pretty standard life cycle — they’re created when a single cell divides into two (called mitosis), they perform their function, and, when they’re damaged or reach the end of their life span, they die. However, cells don’t just wink out of existence; they need to be destroyed by something as soon as they’ve reached the end of their usefulness. If they’re not destroyed quickly, degraded or malfunctioning cells can turn into things like cancer or cause inflammation.
To ensure that they die when they need to, cells undergo something called apoptosis, or programmed cell death. This is where the cell, after detecting that it’s time to die, releases chemicals that shred itself and destroy the cell — it pretty much commits suicide. Apoptosis is vital for us to survive; our cells are tremendous self regulating systems so knowing when it’s time to die is important to keep things running.
However, sometimes cells don’t die when they should. If they don’t, they enter into a phase called senescence. Senescence occurs when the cell is too damaged to continue dividing into more cells, but is stopped from completing apoptosis for some reason. Cells drop into senescence in increasing amounts as we age, and it’s one of the leading theories on why humans grow old and die — eventually, the number of cells that are dividing and renewing the body drop in proportion to the number of cells in senescence, leading to higher and higher numbers of dysfunctional cells (that can cause cancer or inflammation), and the human body degrades until it can no longer function and we die.
(As a side note, one way that cells can enter senescence is by telomere shortening. This is tremendously interesting, but not super relevant to understanding the article. I dive into it a bit below this parenthetical, but if you’re not interested or want to come back later, keep reading at the “TELOMERE DISCUSSION ENDS HERE” marker :)
To understand telomere shortening, first we need to talk about how DNA works — cells in your body are constantly dividing to refresh the tissues that they make up. Some divide faster than others — for example, cells in your hair follicles and stomach divide much faster than brain cells (as a note on that, most cancer is caused by cells that begin dividing too rapidly/uncontrollably, so chemotherapy often targets and kills cells that divide quickly. Because of this, chemotherapy causes your hair to fall out and GI distress — those cells divide more quickly and are thus killed by the chemotherapy drugs. We’ll talk more about that later).
Every cell in your body has a copy of your DNA (the cell usually just references the pertinent segments to its operation, but it still has the whole copy), so part of cell division is making a copy of your DNA (yeah, all of it — it’s a lot to copy!) so that at the end, the cells (the existing and new one) both have a full copy of your DNA. Copying your DNA is performed by an enzyme (a name for any biological agent that facilitates a chemical reaction — think of them as molecular machines) called DNA polymerase. When DNA polymerase makes a copy of your DNA, it crawls down the entire length of your DNA and spits out a copy as it goes. When it gets to the end of a strand, it’s not a perfect fit on the end (the mechanics of this is a little complicated) and needs a bit of “scratch” DNA at the end of the strand to successfully complete the DNA replication. This “scratch” DNA is called a telomere and, at birth, consists of around 11,000 copies of a certain DNA sequence. Each time DNA divides, one of these copies is destroyed as the DNA polymerase completes the copy — this is why it’s important to have lots of copies! Your body does replenish the telomere with new copies over time, but as you age, they gradually get shorter and shorter as your body’s genetic replication outpaces its ability to repair the telomeres — by old age, you have around 4,000 copies left per DNA strand. (Fun fact: men consume telomeres faster than women, and science isn’t sure why.)
The shortening telomeres is hypothesized to be connected with aging — studies show that people with longer telomeres live longer than those with shorter telomeres.
As mentioned above, one of the ways that cells can enter senescence is when their telomeres are shortened beyond usefulness — the cell may (or may not) still be working well, but it has lost the ability to divide. Lots of studies about longevity center around trying to lengthen the telomeres or slow down the rate that they decay.
And now back to our originally scheduled programming.
—- TELOMERE DISCUSSION ENDS HERE —-
Welcome back! If you read the big chunk on telomeres, here’s a reminder of where we’re at: cells that don’t divide any more but haven’t managed to kill themselves (which is something we want them to do) enter senescence, which is generally a Bad Thing™ and is a leading theory on why we age. Senescent cells usually leak lots of nasty chemicals that cause inflammation and damage in our bodies and can also develop into tumors.
So, how do we fix senescence? Well, ideally, we want senescent cells to successfully kill themselves (kinda dark, I know, but it’s what keeps your body healthy!). Scientists just figured out (the paper was released on March 23, 2017) how to do this in mice (and very probably in humans)! Here’s how it works:
The scientists looked at senescent cells and expected to find one of two things stopping apoptosis: either a lack of the proteins that cause apoptosis, or a high number of proteins that inhibit apoptosis. Instead, they found just the levels of both that they expected! Huh? They figured that something was blocking apoptosis from happening further down the line rather than a systemic cellular reason that the cells weren’t undergoing apoptosis.
To figure out what was blocking it, they looked for proteins that were being generated in higher numbers than normal in the cell that might be jamming up the works of the apoptosis mechanisms. One that they found was called FOXO4 (proteins don’t have tremendously friendly names), one of a family of proteins (the FOXO family) that perform various functions in the cell. FOXO4 had already been studied and found to be associated with aging… Hmmmmmm… seems like we’re onto something here.
They started looking at what FOXO4 actually does in senescent cells, and one important thing was that it liked to grab on (bind) to a protein called p53. p53 is nicknamed “the guardian of the genome” because it is a tumor supressor — when it detects mutation in the cell’s DNA (which can turn the cell into cancer), it causes apoptosis (in fact, lots of cancers are associated with genetic mutations that switch off p53, meaning that p53 stops working and can’t kill the cell before it forms a tumor and possibly becomes cancerous). (Not so) fun fact, most people have a suprisingly huge number of cells that can become tumorous in their lifetime, but our cells are so good at self regulation that they nip it in the bud with p53 before it can hurt us. Go cells! (and GO P53!!!).
An important part of this is that FOXO4 lives in the nucleus of the cell and p53 does its work at the mitochondria — two different parts of the cell. When p53 was bound to FOXO4, p53 got stuck in the nucleus with the FOXO4 and never made it out the mitochondria where it could start apoptosis. So, the scientists wanted to find a way to get FOXO4 and p53 unstuck from each other — maybe then the p53 could do its job and the senescent cell would die. To do this, they created a sort of evil FOXO4 twin called a FOXO4-DRI peptide — it looked and acted like FOXO4 from a chemical perspective (in fact, p53 liked to bind with FOXO4-DRI even more than regular FOXO4, which is important because of some complicated chemistry), but FOXO4-DRI didn’t only live in the nucleus — it could exist anywhere in the cell.
When FOXO4-DRI is introduced into the senescent cells, the p53 breaks away from FOXO4 and binds to the FOXO4-DRI. Now free from the FOXO4 that’s stuck in the nucleus, the p53 and FOXO4-DRI combo could drift to the mitochondria where p53 could do its work and the cell would undergo apoptosis — senescent cells could finally die!
The outcome of this in mice was incredible. One set of mice was given high doses of doxorubicin (sold as Adriamycin), which is a chemotherapy drug that is known to cause damage to the liver (if you read the section on telomerases, this is another rapidly dividing tissue that is often damaged during chemotherapy; this destruction of tissues other than the cancer is called off-target toxicity). Because of the damage doxorubicin does, it creates large numbers of senescent cells. In the mice, the senescent cells damaged by doxorubicin successfully died off when FOXO4-DRI was introduced. They reversed a substantial part of the damage done by the chemotherapy!
But it doesn’t end there. In another set of rats that were genetically modified to age quickly, FOXO4-DRI caused hair that was lost due to age to grow back. Perhaps most amazingly, the mice’s behavior changed, too — frail mice seemed to grow younger and began to explore, exercise, and respond to physical stimuli just like healthy young mice did. They also saw kidney dysfunction due to age reversed as kidneys grew more healthy (with the senescent cells killed off, healthy cells could flourish).
While these are amazing results, the real kicker is the naturally aged mice — lots of studies limit themselves to genetically modified mice, which introduces other variables that might affect the outcome of the study. The scientists tried FOXO4-DRI on naturally aged mice AND GOT THE EXACT SAME OUTCOME. Elderly mice that were given FOXO4-DRI got healthier, more mobile, and generally displayed behavior usually attributed to young mice.
This is a huge discovery — FOXO4-DRI is one of the most promising developments in anti-aging in a long time and is particularly exciting because it doesn’t just seem to slow down aging, it actually reverses it. FOXO4-DRI is definitely an exciting piece of research to watch in the areas of anti-aging and anti-cancer.