Welcome to Running: A FEVER, a podcast about fitness, diet, and medicine. My name is Michael Davis. My goal is to live a long, healthy, happy, active life by loving my life enough to make it last as long as possible.
And long life is what this series, called Aging Reversed, is all about. What if aging were just a disease? A disease that could be treated? What if the Fountain of Youth consisted of behaviors and medication? What if you could live 150 years or even forever? You won’t find the answers to those questions in this series, but we will talk about how this could all come about, some of the research going into it, and what resources are available right now to lengthen your life scientifically.
Thus far, we’ve talked about classifying aging as a disease and the information theory of aging. In this episode, we will dig into the roles of sirtuins, NAD, and other longevity genes in extending lifespan.
Sirtuins are genes that act like worker bees to repair DNA. The name comes from SIR2, the first one that was discovered. There are seven known sirtuins. SIR2 stands for ‘silent mating-type information regulation 2′, the gene responsible for cellular regulation in yeast. 23% of yeast DNA is the same as in humans, so scientists like to use yeast to study human longevity.
What’s so essential about sirtuins? They sit at the top of cellular control systems. They tell our cells what to do, controlling reproduction and DNA repair. They are like orchestra conductors that make the horn section hush so the woodwinds can be heard, and vice-versa when the horn section should be heard. When DNA is broken, everything else stops, and all resources are devoted to repairs—especially reproduction, since that involves copying DNA, and you don’t want to copy broken DNA. When the repairs are done, sirtuins enable reproduction again and return to maintaining DNA. Sirtuins control all of this as part of the epigenome. You may recall that the epigenome is the dynamic information that reads the static digital data in DNA and tells it what to do by switching genes on or off. Sirtuins and the epigenome are the bosses of DNA for sure.
David Sinclair, author of the book Lifespan: Why We Age — and Why We Don’t Have To, calls this process of re-allocating resources in times of stress “buckling down”. When our bodies are buckling down, we’re in survival mode. By controlling this, sirtuins protect us against diseases commonly associated with age: diabetes, heart disease, Alzheimer’s disease, osteoporosis, and cancer. They reduce the inflammation that causes atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They reduce muscle wasting and macular degeneration.
So why do we age if we’ve got these sirtuins, and they’re so great? It’s a question of the amount of stress involved. I’m talking about a rough day at the office, but stress as in physical stress, for example, falling down a flight of stairs. Several things can cause stress to DNA, none of which, as far as I can tell, directly relate to aging. Some examples are environmental factors like ultraviolet radiation and chemotherapy. Whatever causes the stress that causes the DNA damage, if the damage is too great and overwhelms the sirtuins, chaos ensues, and the sirtuins can go nuts and start turning the wrong genes on and off. If the DNA is not repaired completely or timely, aging and all of the diseases I mentioned earlier occur.
Sirtuins also require a molecule called nicotinamide adenine dinucleotide, which is an excellent name for a girl, by the way. We call her NAD for short. As we age, we lose NAD, and our sirtuins become less effective and are more easily overwhelmed, leading to all the nasty diseases I mentioned earlier.
Since it came up, this is probably a good time to discuss NAD. NAD is a sirtuin-activating compound (STAC). The discovery of it is an interesting story. Two British biochemists, Arthur Harden and William John Young, noticed that adding boiled and filtered yeast extract accelerated alcoholic fermentation. It was later discovered that NAD cured black tongue disease in dogs, which is the equivalent of pellagra in humans. This disease causes skin inflammation, diarrhea, dementia, mouth sores, and death. It turns out that NAD is a product of niacin (vitamin B3), and pellagra is described as a disease of niacin (vitamin B3) deficiency.
NAD is used not only by sirtuins but also by over 500 enzymes. Without it, we would die. But moving on from booze and dogs, in the 1990s, two researchers discovered that NAD was fuel for sirtuins. Then, yeast experiments found that a gene called PNC1 could turn vitamin B3 into NAD. Copied four times in yeast cells, PNC1 caused them to live 50% longer. When the SIR2 gene was removed, this did not occur. So NAD activates sirtuins, and doing so increases lifespan, at least in yeast cells, which, as I mentioned before, share 23% of their DNA with humans.
Then, in an experiment in which mice were given an NAD-boosting molecule, mice the equivalent of age 65 in humans were running so much that they broke a lab treadmill. The higher NAD levels were causing new blood vessels to form in muscle tissue, enhancing oxygen delivery. If NAD were a drug, it would be a wonder drug. If it were a food, it would be a superfood. What scientists saw in the mice was a reversal of the aging process.
So that’s what NAD is. We’ll return to it when discussing future medicines and technologies in part 8 of this series.
The next type of longevity gene I want to talk about is target of rapamycin (TOR). Rapamycin is now a drug that is used to prevent organ transplant rejection, a rare lung disease with an 11-syllable name, and certain tumors. It is being studied as a treatment for age-related diseases like cancer, obesity, atherosclerosis, and neurodegenerative diseases (dementia, among other things).
Like sirtuins, mTOR (as it’s called in mammals) can signal cells in stress to buckle down in survival mode. It boosts DNA repair, reduces inflammation, and digests old proteins. It signals protein production in the exact amounts needed by the body.
The other longevity gene is a metabolic control enzyme called AMPK, which stands for AMP-activated protein kinase. It detects low cellular energy levels and activates when stressed by hypoxia, hypoglycemia, mitochondrial poisons, or muscle contraction. It also restores energy balance by increasing glucose and fatty acid uptake and oxidation, inhibiting fat synthesis, enhancing mitochondrial biogenesis, and switching off energy-consuming processes. Exercise can activate AMPK, which may be one of the reasons why exercise can lead to weight loss.
All of these defense systems are activated in response to biological stress. And you can see that they can benefit the body’s health by resisting disease. As you’ll see in the next three episodes, there are many ways to induce the right amount of stress. That which is enough to activate the longevity genes putting cells into survival mode, and not so much as to cause cell damage. These are ways to increase our longevity by putting our bodies’ natural defenses to work.
So don’t miss these upcoming episodes. I hope you enjoyed this one. I used quite a few references in preparing this show; as always, I have included those in the blog post at RunningAFEVER.com/391. Go there if you want to dig deeper than we have in the short time here. On that page, you can also watch the video or re-listen to the podcast while reading and researching. Sound like fun?
Well if you have the fever already, keep it burning. And if you don’t, catch the fever. And I’ll see you next time on Running: A FEVER.
References:
Sinclair, David A. and LaPlante, Matthew D. (2019). Lifespan: Why We Age — and Why We Don’t Have To. Atria Books.
https://en.wikipedia.org/wiki/Sirtuin
https://en.wikipedia.org/wiki/Microvoluta_superstes
https://tinyurl.com/yeast-human-dna
https://tinyurl.com/broken-dna-aging
https://en.wikipedia.org/wiki/Nicotinamide_adenine_dinucleotide
https://tinyurl.com/rapamycin-uses
https://my.clevelandclinic.org/health/diseases/24976-neurodegenerative-diseases