Is Reversing Age Really Possible?
The most recent breakthrough in age reversal in rats
Everyone (or at least everyone that isn’t a child) hates getting older.
I mean why wouldn’t we? Every single year we add on to our age is like taking one more step towards a cliff. Sooner or later, you’re gonna reach the cliff, and the next step you take will be your last.
Except, we’re blindfolded as we take these steps, and we don’t have a clue how far from the cliff we start. For all we know, the next step could be our last.
But some people might be able to grab the cliff and hold on after they step off. Someone else (i.e. doctors and the healthcare system) might even come along and hold on to us, trying to stop us from slipping. But they can’t actually pull us back up. We’re stuck there, hanging on, clinging for our life. Everything hurts from holding on for so long, and, in true cinematic fashion, our hand finally slips, and… we fall.
Now, I realize that was a depressing start to the article. But, that’s the point. I wanted you to realize how sad and depressing all of this is. What’s even worse is the fact that this isn’t the story of a couple or a group of people. No, it happens to EVERY. SINGLE. PERSON. And yet… we don’t do anything about it.
I mean, from the starting days of humanity on this planet, living longer and being immortal have been our dreams. We have tons and tons of stories of people that became immortal, or lived on for thousands of years, throughout every single culture.
We’ve had crazy hunts for the Philosopher’s Stone, or for the Moon Rabbit (look it up. It’s a real thing), which might hold the secrets to living forever.
Now, what if I told you that might not completely be impossible? What if I told you, that there’s a possibility, that you could live much longer, and even reverse aging?
Well… that’s exactly what I’m telling you.
What The Hell Am I Talking About?!?!
Let me explain.
Based on a recent experiment, scientists determined that it might actually be possible to significantly reverse aging (or at least in rats).
Essentially, the scientists carried out what is known as a heterochronic plasma exchange (HPE) experiment on rats. Translating to normal English, that means they transferred the blood plasma from young rats to old rats, to see if it could reverse aging.
Setting the Scene
So, the idea behind this experiment isn’t completely novel. In fact, there have been previous experiments testing similar ideas.
But, they used another, more scary (and gruesome), method known as heterochronic parabiosis. Basically, they connected the blood circulation of an old and a young mouse together, allowing them to “share” their blood.
Now, the results from this experiment were surprising. It demonstrated numerous beneficial impacts on the muscle, heart, and brain, among other organs, and confirmed the beneficial effect of blood-borne factors. Following this experiment, there have been many investigations that try to extract these “rejuvenation” factors to mitigate or treat various age-related conditions.
At the same time, this approach has some problems. The most obvious one is the fact that… well… we’re literally sewing two mice together 🤢. There’s a whole bunch of ethical problems surrounding that. But from a more research-oriented lens, this approach also puts extra stress on both mice, and, since the blood from both mice mixes, it will still contain the aging factors from the old mouse.
And so, the researchers in this new study decided to instead just transfer the blood plasma without connecting the circulations. This way, we can not only reduce the stress on the rats, but also eliminate 100% of the old rat’s blood, leading to a more significant effect (BONUS points: it’s not gross either).
Designing Epigenetic Clocks
Now, before we even start testing the treatment, we have to determine a way to calculate their age biologically (since their chronological age will remain the same).
In this case, the researchers used both clinical and molecular biomarkers of aging. But, while the clinical biomarkers have many obvious advantages (they can clearly show organ dysfunction or disease), they are neither sufficiently mechanistic, nor proximal to fundamental mechanisms of aging, to serve as indicators. Meanwhile, on the molecular level, changes in the epigenome (the system that controls how our genes are expressed) have been determined to be one the determining hallmarks of aging (check out my last article on the hallmarks of aging). And so, methylation array platforms can be used to provide accurate profiles of specific CpG methylations (basically methyl groups at sites that have cytosine followed by guanine). Combining this with the methylation levels of multiple DNA loci across the genome can be used to accurately measure DNA methylation (DNAm) age. The best part is that DNAm age estimates apply to all sources of DNA (any cell in the body), and to the entire age spectrum (from a premature blastocyst to an old person).
And so, the researchers developed 6 different epigenetic clocks that estimate DNAm age. Some of these clocks applied to all tissues in rats, while others applied to specific tissues:
- The rat-pan tissue clock was trained on all available tissues
- The brain clock was trained on samples from the whole brain, hippocampus, hypothalamus, neocortex, substantia nigra, cerebellum, and the pituitary gland.
- The liver and blood clocks were trained on the liver and blood, respectively
- 2 human-rat clocks applied to both humans and rats
- One measured absolute age (in terms of years)
- The other measured relative age, as a ratio of chronological age to the max lifespan, with values between 0 and 1. This ratio allowed alignment and comparison between species with very different lifespans (like humans and rats), which is just not possible with the absolute age clock.
After training all the clocks on their respective tissues/species, the researchers obtained correlation R values, calculated as Pearson correlations between DNAm and chronological age (that’s some stats jargon for the math nerds out there 😉), all higher than 0.90 (so basically… they worked really well).
Hypothesis and Experimental Plan
The researchers hypothesized that plasma fraction treatment would reduce epigenetic age in the 2 year old rats they were using for the experiment.
The experiment lasted over 155 days in total, and used 18 Spraque Dawley rats. These 18 rats were divided into three equal groups:
- group of 6 young rats (30 weeks, or roughly 7 months, old)
- group of 6 old, untreated rats (109 weeks, or around 2 years, old)
- group of 6 plasma-fraction treated old rats (also 109 weeks old)
The plasma fraction treatment itself involved 2 series of intravenous injections of plasma fraction, with each series involving the rats being injected 4 times on alternative days (for 8 days). The second series of injections was administered 95 days after the first.
Hematological and Biochemical Analysis
During the course of the experiment, blood was regularly drawn from the mice for hematological and biochemical analysis to monitor the impact of the treatment on the blood and vital organs.
For the hematological analysis, the researchers measured hemoglobin levels, mean corpuscular volume (MCV; average volume of a red blood cell), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), hematocrit (HCT; volume percentage of red blood cells in the blood) levels, and red blood cell, white blood cell, platelet, and lymphocyte counts, at 0, 60, and 155 days.
In terms of the biochemical analysis, the researchers measured levels of different biomarkers in the blood to determine the effects on function of many vital organs (on 30, 60, 90, 120, and 155 days). The biomarkers they measured allowed them to determine liver, kidney, and pancreas function, and determine the risk of developing atherosclerosis, heart disease, and diabetes.
Testing Cognitive Function
The researchers used a Barnes maze to measure the period required by rats to escape through the right hole, also known as the latency period. This depends on the ability of the rats to remember which holes they have already checked, and the result they got from that.
Measuring Cellular Stress
To determine the effect the treatment had on cellular stress, the researchers considered two of the main types/results of cellular stress: oxidative stress and chronic inflammation.
Oxidative stress occurs due to the presence of excess reactive oxygen species (ROS), which can degrade proteins and genetic information. The high ROS can be caused by excessive production and/or by insufficient clearance of the ROS by molecules known as antioxidants (yeah, the molecules that the food industry puts a huge hype around).
To measure levels of ROS, the researchers measured the levels of a molecule known as malondialdehyde (MDA), which is one of the end-products of a process responsible for the majority of ROS production.
Also, to determine the efficacy of the cells to remove these ROS species, they also measured the level of three specific anti-oxidants: glutathionine; catalase; and superoxidase dismutase.
Chronic inflammation, which usually increases with aging, was measured by determining levels of interleukin-6 (IL-6) and tumor necrosis factor a (TNF-α), which are two of the most reliable and common biomarkers of chronic inflammation.
And… that’s enough biology for now. Let’s move on to the results (we all know that’s what you really care about).
And What Did They Find?
Let’s talk about the results from the epigenetic clocks first.
Based on all of the epigenetic clocks, the ages of the untreated old rats and young rats were highly distinguishable from one another. However, plasma treatment of the 6 old rats resulted in reduced epigenetic ages of the blood, liver, and heart tissues significantly, and even to levels comparable to young rats.
The treatment rejuvenated the liver by around 73.4%, both the blood tissue and the heart tissue by 52%, and the hypothalamus by 11%. Averaging across all four tissues gives an average rejuvenation of 54.2%, meaning that the plasma fraction treatment more than halved epigenetic age.
Furthermore, when checking methylation at individual locations across the genome, the researchers also found that the plasma treatment reversed methylation that normally accumulates with age.
So how exactly did these epigenetic changes have effects on the physiological capabilities in the treated rats?
Well first off, only 15-days after treatment, the researchers saw an increase in strength, to the point that the strength of plasma-treated old rats was indistinguishable from young rats. Similarly, there was also increase in the grip strength of these rats.
Meanwhile, there was no significant change in weight, nor was there any abnormalities observed in organs through histological examination. Furthermore, they also observed a reduction in the accumulated fat in old tissues.
The levels of all the biomarkers measured also shifted to match those in young rats, showing that the function of all the tested organs were also rejuvenated.
Similarly, the markers of oxidative stress and chronic inflammation also shifted to match the levels observed in young rats, once again showing benefits of the plasma treatment in reducing stress on cells.
What Does This Mean?
Well, first off, this definitely does not mean you should run into the nearest hospital and ask them to inject you with the blood of some youngster. In fact, if you live in the United States, you don’t even have this option, since the FDA banned all plasma fraction treatment experiments.
That’s why the entire experiment was carried out in India, where such experiments are legal. But still… don’t run to India and demand this treatment.
But on a larger scale, this experiment is great news for the longevity world. It proves that, not only can aging be prevented/slowed down, like many other researchers have found, but it is also reversible. This is going to unlock a wider range of research into not only slowing down aging, but reversing it altogether. Perhaps we can someday find a drug, or a group of drugs, that can replicate, and even amplify, these results. Imaging being able to run into your physician’s office every few years (given that you’re above a certain age in the first place), and just getting a dose of youth.
And so, I think it’s safe for me to end by saying that the field of longevity has a very bright future ahead of it, and it might not be too long before we no longer even have to worry about getting older at all.
On A More Personal Note:
I am a 17-year old currently obsessed with the science behind aging, and if we could live forever (because, let’s be honest, no one wants to die).
If you want to read more of my articles, follow me here on Medium and check out some of the other articles I have written, on various topics from AI, to gene editing, to life and philosophy. To find out more about me, check out my website, and my Twitter.
If you want to read the original (unpublished) paper that I summarized above, check it out right on bioRxiv.
That’s all for me now. See you next time!