Can deliberate cold exposure reverse ageing?
Summary
Genetics controls only 10% of ageing - the rest is lifestyle.
Experiences and exposures that damage mitochondria accelerate ageing.
A long lifespan requires protecting mitochondrial DNA from damage.
Cold therapy is one of the best things you can do for your mitochondria.
Add post-cold exercise & red light for an extra mitochondrial boost.
Chronological vs biological age
If you follow me on substack, then you may have seen my new article The Genetic Self: Biological Age. There, I explained the difference between chronological age, which is measured by your birthday, and biological age, which is supposed to provide an improved estimate of your expected lifespan. Here's an excerpt:
There are two criteria that any effective measure of biological age must demonstrate: For large statistical ensembles, it must correlate with chronological age. For individuals, the departures from chronological age correlation must be predictive of expected lifespan. Put another way, wherever biological age departs from chronological age, the biological must be a better predictor of mortality than chronological. According to the Elysium Health ‘Index’ test, my biological age is 51 — five years younger than my chronological age. That feels good in the sense that it’s better than finding out that my DNA methylation is typical of someone older than me, but it doesn’t help me understand what I might do to take care better of myself. - Thomas P Seager, PhD 2022
A reliable measure of biological age would be an enormous boon to anyone seeking to slow the rate at which they age, extend their life- and healthspan, and manage their overall wellness.
I'm one of those people. At 56 years old, I've started thinking about how I might live a longer, healthier (and happier) life than my Father and Mother.
Dad was morbidly obese and riddled with cancer when he passed away peacefully in his sleep at the age of 91. Mom died younger and more recently, but she suffered from acute dementia that meant the quality of her last decade of life was poor.
My parents always told me that I could expect to live a long life, because I (like them) had "good genes." After all, didn't my Grandmother Harriett live until the age of 99?
It was only recently that I discovered how wrong that thinking was.
An extensive review of the data available in ancestry.com revealed that less than 10% of lifespan could be explained by genetics (Ruby et al. 2018). The remainder, say the researchers, is due to lifestyle choices and associated with socio-economic status -- which is also transferred within families from the older to younger generations.
For example, diet, exercise, smoking, and alcohol consumption modify expected lifespan. It's obvious that my Father had access to better healthcare than my Nana Harriett, so why did Dad die seven years younger than she did (and a year younger than Papa)?
We don't know for sure, but maybe my Nana's longevity was because she preferred steak. Like George H.W. Bush (1924 - 2018), who famously hated broccoli, nobody could make Nana eat her vegetables.
My Father, on the other hand, had a sweet tooth.
The problem with biomarkers of biological age
There are several chemical biomarker tests that you can order online that purport to assess your biological age. Like the DNA methylation test that I took, you can also measure your telomere length. Both of these tests examine chemical markers of genetic health and function. For example, telomeres are nucleotides that protect chromosomes during replication. The longer you live, the shorter your telomeres get, leaving your chromosomes more vulnerable to copying errors. In theory, shorter telomeres are indicative of older age.
The problem is that telomere length doesn't correlate with chronological age, and measuring it doesn't improve prediction of lifespan. In fact, none of the material biomarkers that might be hypothetically associated with ageing do a good job of estimating expected lifespan better than chronological age (Jansen et al. 2021).
So my Elysium Health estimate of 51 years old doesn't mean a dang thing.
That's because all of these markers are examining the DNA in the cell nucleus, when the escapement that controls our biological clock is more likely found in the mitochondria.
As I explained in 4 Sources of DNA, the mitochondria contain their own DNA, independent of the DNA in your cell nucleus that you inherited from your parents. The mitochondria are called organelles, because they exist inside the cells of your body. Every cell in your body except red blood cells contains hundreds of mitochondria.
Brown fat cells contain thousands.
The mitochondria perform energy conversion for the body. They convert food substrates, glucose and fats, into electrical energy (stored in ATP) that can be used to move muscles, repair tissues, or fuel growth and tissue repair. So every function in the body depends on mitochondria for life.
But mitochondria are difficult to measure. They don't lend themselves to the same bioanalytic techniques that nucleic DNA do -- partly because there are so many of them and each mitochondria contains multiple copies of mtDNA.
Why mitochondria?
Although mitochondria were first discovered in 1857, and their essential function in energy conversion was understood even then, their origins remained a mystery until the 1970's. That's when Lynn Margulis hypothesized that mitochondria were once independent, single-celled prokaryotic bacteria that got subsumed by more complex eukaryotes and, instead of being digested, were put to work to convert energy inside their more complex, eukaryotic host organisms.
The idea seems far-fetched, and Margulis' hypothesis was initially rejected and ridiculed, only later to become accepted as fact.
As prokaryotes, mitochondria are distinct from eukaryotes in two critical ways:
prokaryotes do not have a nucleus to protect their DNA, and that makes mtDNA more vulnerable to damage than the nucleic DNA inside eukaryotic cells, and
prokaryotes reproduce by cell division, such that two mitochondria with identical mtDNA can be formed from a single mitochondria. In eukaryotes, this process is called mitosis, and it supports growth within a single organism, but not reproduction, per se. Eukaryotes depend on sexual reproduction, whereas prokaryotes are asexual.
Human beings are eukaryotes, and that means that reproduction requires a genetic copy from both a Mother and a Father to create a new organism with unique DNA. When that creature dies, its DNA dies with it.
However, as prokaryotes, mitochondrial DNA is immortal. It can keep reproducing itself into identical copies a theoretically infinite number of times.
To avoid genetic confusion inside the mitochondria, only the Mother's mitochondrial DNA is preserved. Although sperm also carry their own mitochondrial DNA, these are normally destroyed after fertilization of the egg, so that the baby's mitochondria are identical to its Mother's, and Grandmother's, and great-great-great-Grandmother's -- going all the way back to Eve.
In practice, mutations and oddball paternal contributions do occur within a mitochondrial lineage, so that mtDNA does evolve. However, when we say that mitochondria are immortal because of their prokaryotic origins, this is what we mean: your mtDNA will outlive you.
My energetic biological age
Because mitochondria are the locus of energy conversion within the body, they control the human electro-magnetic field. Although mitochondria are difficult to isolate and assess materially, it is possible to measure the electrical energy of the human body to get an estimate of health and well-being.
Dr. Patrick Porter, founder of Brain Tap, does exactly this. Using a test called Neurocheck, he measures the electrical activity of the body in several frequencies. He can then compare those measurements to patterns that are characteristic of people of different chronological ages, and estimate your biological age by matching your activity to a reference database of 10,000 samples, to see what age corresponds to your pattern.
According to Porter's Neurocheck, my energetic biological age is 30 years old.
When I first met Porter two years ago, he measured my biological age as 32. That means, according to Porter, I have been biologically ageing in reverse.
The idea that a 56 year-old man might have a biological age of 30 years seems preposterous at first. After all, no one who looks at my gray hair, the wrinkles and emerging age spots on my face, and the flab around my belly would confuse me for a man 26 years younger.
But when you remember that biological age is a predictor of lifespan, not gray hair, it begins to make more sense.
The life expectancy of the average American 30 year old man is about 48 more years. In other words, if a man has lived to his 30th birthday, he can expect to live, on average, until he's 78 years old -- a little longer than the American male life expectancy at birth.
Add a life expectancy of 48 more years onto my current age of 56, and Porter's estimate of my biological age suggests I can expect to live to 104.
Does that still sound preposterous?
Nana Harriett lived to 99, and she didn't have the benefit of advanced medical care. According to family legend, she was an state-champion caliber athlete (badminton) when she was young, but I never actually witnessed Nana so much as swing a golf club in her old age.
Why couldn't I outlive my Grandmother by a mere 5 years?
How to age in reverse
Carbohydrates reduce lifespan
The only reliable strategy for extending lifespan under laboratory-controlled conditions is caloric restriction. That is, animals who are underfed reliably live longer.
Ironically, it is the immortal mitochondria that hold the key to ageing, because immortal does not mean invulnerable. As damage to mitochondrial DNA accumulates, their function decays. When the mitochondria can no longer produce the energy required by the body to stay fit, healthy, and repair damage in our cells, we die.
That's how caloric restriction extends life -- by reducing mtDNA damage.
As the locus of energy conversion, a diet rich in carbohydrates puts an extra strain on the mitochondria to process the excess glucose that results from carbohydrate-rich foods. For example, when you drink fruit juice, your blood glucose spikes and your body produces extra insulin to shuttle the glucose into your cells where mitochondria must process it for one of four functions:
exercise,
cell growth & tissue repair,
cold thermogenesis (i.e., heat production), or
storage (i.e., white fat expansion).
When exercise, growth, and thermogenesis are insufficient to consume the excess glucose, the body must produce fats for storage. The problem is that exercise and cold thermogenesis use up glucose fast, while white fat storage is slow.
When dietary sugars & starches exceed immediate energy demands, the mitochondria become overwhelmed, and they produce what are called reactive oxygen species (ROS). In small quantities, these ROS signal metabolic changes (including production of new mitochondria) that help the body adapt to the new energetic condition. However, in larger quantities, these ROS will damage mtDNA.
Fatigue is one of the body's many defense mechanisms that help protect mtDNA from ROS damage. That is, when you exercise too hard and your muscles begin to heat up, so does production of ROS. Fatigue is the body's way of forcing you to slow down, giving your mitochondria a chance to recover without too much damage. That's how pre-cooling your workout leads to big gains in peak muscle power and endurance, by postponing the body's fatigue response.
Nonetheless, chronic overloading of mitochondria will lead to insulin resistance, in which the cells attempt to protect the mitochondria from damage by preventing insulin from shuttling glucose from the bloodstream into the cell. Elevated blood sugars result, and if the chronic condition continues, the result will be Type 2 diabetes.
This is how deliberate cold exposure reverses Type 2 diabetes -- by increasing cold thermogenesis, relieving the mitochondria, and recruiting new brown fat and the thousands of new mitochondria that go with them. Taking the load off the mitochondria relieves the pressure so that cells will allow the glucose in from the bloodstream, reversing Type 2 diabetes.
As many as 8 out of the 10 leading causes of death in the United States are associated with insulin resistance, including: diabetes, Alzheimer's, cancer, obesity, and cardio-vascular disease. So it makes sense that any practice that improves insulin function would extend lifespan.
Ice bath as mitochondrial therapy
There are several things you can do to improve and maintain mitochondrial health. For example, mitochondria need magnesium and giving them enough magnesium to synthesize the enzymes necessary for metabolism will improve mitochondrial function and may reduce the rate at which they are damaged.
However, there's something even more powerful than nutrition that might prove therapeutic for your mitochondria: an ice bath.
When mitochondria are damaged, mechanisms exist to repair them. When they are damaged beyond repair, the body is capable of selecting the best, least damaged mitochondria for replication so that new mitochondria can replace the old (Power, Sex & Suicide: Mitochondria and the Meaning of Life, Lane 2005). As you might imagine, this process is stimulated by exercise, cold thermogenesis, and growth -- all the functions that demand energy.
Of the three, the most powerful may be the ice bath (i.e., deliberate cold exposure).
Cold exposure recruits brown fat for cold thermogenesis, and because mitochondria are more dense in brown fat than any other cell type in the body, nothing stimulates mitobiogenesis quite like an ice bath. Moreover, following your ice bath with some exercise (as the Wim Hof and Morozko Methods recommend) may give your mitochondria a double-boost.
Red light for additional mitochondrial stimulation
It has long been understood that red light, near-infrared (NIR) light, and infrared (IR) will penetrate the skin to stimulate mitochondria (e.g., Karu 2008). That's why many regular ice bath practitioners will follow their Morozko with red light exposure and report that it "feels warm," even though the lights aren't producing heat. The heat is coming from inside the body, via stimulation of mitochondria by the red light.
Whether that stimulation promotes mitobiogenesis is an open question. Current research demonstrates benefits of red phototherapy for "ameliorating mitochondrial dysfunction, reducing inflammation, and modulating oxidative stress" (Magalhães & Ferraresi 2022), suggesting that enhanced mitochondrial function and reduced insulin resistance result. However, I haven't read any studies directly measuring mitobiogenesis as a consequence of red light therapy.
Protocols for mitochondria
To my knowledge, there are zero systematic studies of cold exposure dose, followed by exercise & red light recovery, and mitochondrial function of mitobiogenesis. Therefore, it's not possible to claim there is an optimal protocol for mitochondrial health. In fact, I've never had a mitochondrial assay of any type performed. Although I'm working with a research group at ASU on a new comprehensive metabolic analysis technique, the only measure I have that indicates I've improved my mitochondrial function is the BrainTap Neurocheck.
So all I can do is describe the routine I use, and speculate that maybe that's the reason I'm getting such good results from BrainTap.
First, I do 2-4 minutes in my Morozko Forge, set at 34F, with my little Mito Red Light at my feet, shining on my face. The red light has a timer, so if I want to make sure I get 3 minutes, or 4 minutes, I'll set the timer for that duration.
When I've had enough cold water immersion, I come out of the ice bath and reset the timer on the red light. As I'm drying off, I'll let the red light shine on my body. Like Ben Greenfield, I'll shine red light on my balls, my butt, my stomach -- any part of my skin that is convenient to get about 15" close to the light.
It takes me about 3-6 min to dry off and get ready to exercise, and the little red light is on all the time.
At last, I'm ready for my steel mace. I use a 25lb, which was way too big for me when I started, but I've gotten used to it now. I do 10-12 rotations on either side: first right hand on top, then left hand (going around the other way).
It doesn't take a lot of post-ice bath exercise to get the benefits of a testosterone boost. Twenty minutes is enough. Although Greenfield swears that red light on his testicles boosted his testosterone, my T-levels (1000 ng/dL) were measured before I started using the red light, so it's not like the light is the cause of my super total testosterone levels. Nonetheless, I usually want more exercise after my steel mace, because despite the red light, I'm still so dang cold.
I have several choices:
I'll often do 10-12 lunges with a 25lb barbell on my shoulders, and then 10-12 squats + shoulder press.
Pull-ups are one of my favorite post-ice bath recovery exercises. My personal best is six in a row, so that's what I'm shooting for, even if I have to take a short break after failing at fewer than six.
Finally, one of my favorite exercises after an ice bath is a brisk walk (or stairs, or both). That might sound trivial as a "workout," but that's what's worked for me.
Recently, I've been substituting a 45 minute circuit or a one hour yoga class for my post-ice bath exercise routine.
My guess is that you could do almost any exercise for recovery after your ice bath, and enjoy anabolic and metabolic gains.
Post-script
If you have the opportunity to use the BrainTap Neurocheck to assess your biological age, I'd like to hear from you in the comments below -- whether you're doing regular cold exposure or not. Porter says that the results he's measured in me are extraordinary, and he might be right. This summer I met a post-doctoral researcher at ASU who can measure almost 400 metabolites using a dried blood spot sample.
He collected my sample last week and run it through his lab. He's still processing the results, but because I'm impatient, I asked if he'd found anything interesting already.
"Yeah," he told me. "You've got great mitochondrial function."
I'll let you know how that goes.
UPDATE 23 Jan 2023
A reader sent me this recent paper on cold exposure and mitochondrial health. The researchers were investigating what happens to mitochondria in brown fat as a result of cold exposure.
When mice were exposed to 72hr of cold air, the activation of their brown fat induced two processes relevant to mitochondrial quality:
mitophagy, which is the process by which your cells identify and destroy defective mitochondria, and
mitobiogenesis, which is the process by which your cells make new mitochondria
In combination, these two processes improve the overall health and function of mitochondria by eliminating the damaged and replacing them with new. On the whole, these researchers found that the extended cold exposure resulted "both degradation of mature mitochondria by mitophagy and synthesis of new mitochondria that led to a net increase in the total amount of mitochondria" (Yau et al. 2021).
While 72 hours is a long time to be exposed to cold air, the mitochondrial benefits could likely be realized in any cold exposure practice that activates and recruits new brown fat. For example, short-term (i.e., acute) cold water immersion is more efficient for extracting heat from the body than cold air. A bath temperature that is cold enough to make you gasp will signal the sympathetic nervous system to activate brown fat. A duration that is long enough to induce shivering is sure to be signaling your body to recruit new brown fat.
To increase brown fat, go cold enough to gasp and long enough too shiver.
In Don't cold overdose: Hypothermia, frost bite, & brain health, I described some of the precautionary practices that will protect your from getting too cold, too fast, including:
keep your cold exposure temperatures above freezing,
dry off instead of allowing wet skin to be exposed to cold winter air,
rewarm using exercise,
red light will help you recover faster if you've overdone it.
Unlike the mice in the 72hr study, most people use their ice bath to practice acute cold exposure more often, rather than chronic cold exposure all at once. A short (2-4 min) burst of cold water immersion on a regular basis will give your body time to recruit the new brown fat and build mitchondrial health over several weeks, rather than a few days.
That allows your body to select the best, least damaged mitochondria for replication in mitobiogenesis, while it is cleaning out the old mitochondria with mitophagy. In this way, a regular practice of deliberate cold exposure may improve the quantity AND the quantity of your mitochondria.
That could extend your healthspan, because mitochondria are the timekeeper in your biological clock. Maintaining healthy mitochondria could be the key to slowing, or even reversing, some of the effects of ageing.
References
Jansen R, Han LK, Verhoeven JE, Aberg KA, van den Oord EC, Milaneschi Y, Penninx BW. An integrative study of five biological clocks in somatic and mental health. Elife. 2021 Feb 9;10:e59479.
Karu TI. Mitochondrial signaling in mammalian cells activated by red and near‐IR radiation. Photochemistry and photobiology. 2008 Sep;84(5):1091-9.
Magalhães FD, Ferraresi C. Photobiomodulation therapy on the treatment of insulin resistance: A narrative review. Photobiomodulation, Photomedicine, and Laser Surgery. 2022 Sep 1;40(9):597-603.
Ruby JG, Wright KM, Rand KA, Kermany A, Noto K, Curtis D, Varner N, Garrigan D, Slinkov D, Dorfman I, Granka JM. Estimates of the heritability of human longevity are substantially inflated due to assortative mating. Genetics. 2018 Nov 1;210(3):1109-24.
Yau WW, Wong KA, Zhou J, Thimmukonda NK, Wu Y, Bay BH, Singh BK, Yen PM. Chronic cold exposure induces autophagy to promote fatty acid oxidation, mitochondrial turnover, and thermogenesis in brown adipose tissue. IScience. 2021 May 21;24(5).
About the Author
Thomas P Seager, PhD is an Associate Professor in the School of Sustainable Engineering at Arizona State University. Seager co-founded the Morozko Forge ice bath company and is an expert in the use of ice baths for building metabolic and psychological resilience.
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