The vast majority of people define aging as the passing of time, irrespective of anything else. For most, aging is an inevitable part of life. Few realize that there are examples of life on the planet that don’t age, and one that’s considered immortal.
Part of the problem is that people conflate aging with death. Death is absolutely an inevitable part of life, but we mustn’t believe that just because aging often leads to death that it too is inevitable. Part of this lies with people’s ignorance to the biological definition of aging.
In biological terms, aging is defined as the time-related deterioration of the physiological functions necessary for survival and reproduction(1). In other words, an organism “ages” when it’s risk of death increases year over year and it’s ability to produce offspring declines. This happens to us humans; although men maintain the ability to procreate for most, if not all, of their time.
This is why athletes slow down as they get older. Speed and reaction time decrease, strength decreases, and for some of us, we lose our marbles. For athletes this means their sport performance decreases. If we were out living in the wild, we’d either lose the ability to attain food or get taken by a predator. Well, maybe not this guy…
Taken from: http://media.vanityfair.com/photos/55512a451aaec7043ea47040/master/pass/tom-brady-nfl-suspension.jpg
Aging varies between species
It may come as no surprise to you that all species on the planet age at different rates. We all “know” that a year to us humans is 7 years to a dog. I put “know” in parentheses because a year is a finite amount of time and not relative to whatever experiences it. A year is a year, but a dog develops and deteriorates more rapidly than a human.
But what about a tree? As a tree grows older, its risk of dying actually decreases. The top of an older tree is higher than younger trees and blocks out much needed Sun. A larger tree also has a larger root system than a younger tree and can access more soil nutrients than the younger little guys trying to outgrow it. It also gets bigger around so it’s less likely to break or get toppled by the wind.
Being larger also gives an older tree a reproduction advantage. Larger trees produce more seeds than smaller trees, and trees continue to grow larger as they age. So if you think about it, given the biological definition of aging, trees barely age, if at all. They become more fit with age. Trees still die, they just don’t really age from a biological perspective.
There are plenty of examples of animals with a very slow rate of aging, also called negligible senescence. Rougheye Rockfish, Giant Tortoises, Bowhead Whales ,and Freshwater Pearl Mussels can live over twice as long as a human. The Greenland shark and Ocean Quahog Clam can live roughly 5 times longer than a human, and Hydra are biologically immortal(2).
But what dictates this large range of lifespans seen on the tree of life? In a word…epigenetics.
What is epigenetics?
Most people by now have heard of epigenetics. Epigenetics refers to the way gene expression is regulated by the epigenome. The epigenome turns genes on or off depending on signals from the environment. If you think about the way the lighting in your house works, your lights are the genes and they’re not always on. They’re on or off depending on whether you’ve turned them on or off. This is typically due to an environmental factor, you coming or going. That’s basically epigenetics.
The way the environment and epigenetics influences your genes can have a powerful effect on your health and lifespan. An easy way to conceptualize this is in identical twins. Identical twins have the exact same DNA but often diverge from one another as they get older. This is because despite having the exact same genes, the environment changes the way the epigenome regulates which genes are on or off.
Over time, it becomes easier to distinguish between a set of identical twins. Since their genes haven’t changed, it has to be the environmental factors changing the regulation of the genes causing them to look different. Sometimes it’s a mild change, but other times there can be major differences between twins. A great example of this is discordant twins.
Discordant twins have some distinguishable trait that differentiates them from one another. For example, if one twin is obese and the other is lean, they are said to be discordant for obesity. This can be seen in the picture below.
Taken from: https://www.nih.gov/sites/default/files/styles/floated_media_breakpoint-medium/public/news-events/resea
Since these twins have the same genes, some environmental factor is driving their discordance. It’s not difficult to imagine that some lifestyle factors such as diet, physical activity level, sleep quality, and stress are likely at play. This change in the way genes are being expressed over time is referred to as epigenetic drift.
Taken from: https://www.researchgate.net/profile/Waseem_Bihaqi/publication/226846253/figure/fig2/AS:39364066
Epigenetic drift isn’t just The Fast and the Furious 9
Epigenetic drift refers to the way an organism’s epigenome changes over time. This can occur both through environmental exposures as well as stochastic(random) ways in which the epigenome is altered. Not only does this change the way an organism looks, it also changes the way an organism ages.
One of the ways we measure epigenetic drift is by looking at DNA methylation of certain sites in the genome. DNA methylation is a way of regulating gene expression that usually decreases it. With aging comes a system-wide level of DNA hypomethylation, although specific sites are hypermethylated as well. As you can probably guess, different animals have different degrees of epigenetic drift, and this correlates with their lifespan.
For example, based on DNA methylation patterns, mice experience annual epigenetic drift of 4.1% per year while humans only experience 0.1%. Monkeys sit closer to humans at 3.4%(3). Epigenetic drift is believed to be one of the driving factors in the large range of lifespans seen in different species on the tree of life.
Of course, epigenetic drift doesn’t just differ between species. Each individual member of a species experiences differing levels of epigenetic drift that grows with time. Even in identical twins, there’s pretty significant epigenetic drift seen in the first 18 months of life, despite identical genomes and very similar rearing environments(4).
Even within the same individual, different tissues have different levels of epigenetic drift. We believe this is one of the drivers of organ failure with age. In other words, tissues with greater levels of epigenetic drift are more likely to fail as we grow older.
But how can we possibly know this? There’s an epigenetic clock, and it can predict your chronological age quite accurately.
The epigenetic clock
In 2013, Dr. Steven Horvath published an article in Genome Biology that few people outside of academia probably read. After 4 years of hard work, he came up with an age estimation biomarker based on DNA methylation of 353 sites on DNA. These markers correlate heavily with age, with a correlation coefficient of .96, 1.0 being perfect.
But why is Dr. Horvath’s clock so accurate? Because it correlates tightly to the number of times a cell has divided. Embryonic or pluripotent stem cells are mere infants at 0 years of age, but beyond that, every cell division yields a tick of the clock. Unfortunately, cells can only divide a certain number of times before they cease dividing. This number, called the Hayflick limit, is approximately 40-60 times in human cells.
Over time, DNA methylation patterns correlate very well with the number of times a cell has divided, at least at the points Dr. Horvath identified. Dr. Horvath’s research helped us understand that some people age faster than others. Some of this is due to lifestyle, some of it’s due to genetic factors outside of our control.
But it also gives us clues as to how we as individuals age, and why certain organs tend to fail faster than others. The epigenetic clock not only allows you to compare the difference in epigenetic age between individuals, it allows you to compare the difference in epigenetic age in different tissues of the same person.
For example, Dr. Horvath’s work found that breast tissue is typically older than an individual based on the epigenetic clock, while heart tissue is typically younger. Cancerous tissue tends to be decades older than neighboring healthy tissue, showing just how well Horvath’s clock correlates to the number of times a cell has divided, even in rapidly dividing tissue like cancer.
But the real value of the epigenetic clock, in my opinion, is that it can be used to validate what you’re doing with your lifestyle. While there’s great variability between the epigenetic age of different tissues, certain tissues correlate strongly to a human’s chronological age, or age in years. For example, as anyone who has read this blog recently can probably figure out, the epigenetic age of your blood can predict your age. This is probably why young blood rejuvenates old organisms, as I’ve gone over here and here.
The epigenetic clock: coming to a store near you
Since Dr. Horvath’s initial paper in 2013, research in to the epigenetic clock has exploded, and for good reason. We are just now coming up with drugs that may be capable of significantly reversing the aging process in humans. But in order to see if these approaches are effective, most 80 year olds don’t want to wait 15 years to see if these drugs will work for them because chances are they won’t be around to find out.
Mouse studies provide a good starting ground for things like heterochronic parabiosis, stem cell therapy, and senolytic drugs, but we need to be able to show validity in humans to get drugs or therapies approved by the FDA. Again, time is of the essence here, and since annual epigenetic drift is greater in mice, results from mouse studies may not be applicable to humans.
But for the regular old schmo like myself, just looking to be healthy and bide my time until valid age rejuvenation therapies become available, having access to something like this is pretty cool. Will all my work exercising, limiting certain foods, and playing with circadian rhythms bear any fruit? Will I become a Highlander? Probably not, but I’ll take not falling apart for the last decade and a half as a consolation prize.
Fortunately, a company called Epimorphy has released a consumer product that predicts age using Dr. Horvath’s clock called myDNAge. And even more fortunate, they hooked me up with a test to take for a test run. I’ve fired a bunch of questions their way, they’ve responded, and I’m ready to cover this stuff in a couple of future blogs. I’ll cover myDNAge, factors that may improve your epigenetic age, which genes are regulated differently with age, and how it all works.
Stay tuned and share!