Live Longer World Podcast Episode #21 has been released!

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My guest in today’s episode is Dr. Vadim Gladyshev. He is a professor at Harvard Medical school and a director of redox medicine at Brigham and Women’s hospital, where he runs his own lab.

We had a brilliant discussion which started off by talking about his work on selenium. Selenium is found is Brazil nuts and we discussed its connection to aging and cancer prevention, and also some of the harmful effects it can have. Dr. Gladyshev calls it the good, the bad, the ugly nature of selenium.

Then, we discussed a fair bit on his theory of aging before and after development. Most people believe that the germline which is the reproductive cells do not age, but his lab’s work has shown how the germline does in fact age. On this point, his lab also has interesting results on how rapamycin during development extended lifespan in mice.

It’s important to understand the basic science and understand more on the aging process in order to crack it. Dr. Gladyshev shares his views on this too and his research is certainly a step towards cracking the aging code. I hope you enjoy the conversation!

[If you are a premium subscriber, you can also read the transcript of the episode below]

Best, Aastha

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Time Stamps:

0:00 Vadim Gladyshev Intro

1:28 Live Longer World

2:17 Selenium’s dual role in aging (the good, the bad, the ugly)

11:27 Antagonistic Pleiotropy

13:53 Selenium & Cancer

15:58 Selenium Dosage (don’t get too much!)

18:30 Reactive Oxygen Species, Antioxidants & Aging

22:30 Fundamental basis of Aging

24:09 Aging is damage

29:20 Single cell Epigenetic Clocks

34:22 Aging in the Womb

42:16 Parent’s lifestyle for aging in embryo

44:14 Rapamycin during development

49:06 Other compounds

51:53 Slowing Aging vs. Rejuvenation

56:08 New projects being worked on

57:17 Confidence level in extending lifespan within 30 years

59:17 Support Live Longer World

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Premium Subscriber Transcript:

Aastha Jain: I want to begin by talking a bit about your work on selenium, which is the micronutrient most commonly found in Brazil nuts and some types of fish as well. You've done a lot of extensive work on it, and you've documented that in some of your papers where you talk about the history of selenium and you talk about the good and the bad and the ugly, I loved that title of that paper, by the way.

You also show how selenium plays a dual role in aging where it is protective against cancer and also has other benefits, like immune function benefits but at the same time, it can also promote cancer. Maybe if you can talk to us a bit about what is the role of selenium and aging and why is it such an important micronutrient?

Vadim Gladyshev: It's a big topic. [chuckles] Actually, I've been interested in selenium since the time I was a postdoc working at NIH, and when I started my own lab, the first question that they asked is, how many selenium proteins are present or encoded in the genome, in the human genome, because at that point, only a few proteins were known? There was an attempt to explain the role of selenium through these proteins. Selenium, of course, is an essential trace element. We absolutely need selenium. If we would not have it, we would all die.

We developed this program to identify these genes computationally, and because selenium is present in proteins in the form of selenocysteine, which is the amino acid, and it's inserted cotranslationary meaning that it's inserted urine protein synthesis, so it has its own codon. It's actually the, we call it the 21st amino acid. In many textbooks, we would say that there are 20 amino acids and proteins, but in fact, selenocysteine is the 21st, it has its own codon, it has tRNA, and it has the machinery for biosynthesis and insertion.

What is needed is the particular RNA structure when the structure is present, then a code on UGA, which is normally a stop signal is recorded and instead inserts selenocysteine. What we did, we developed a computational algorithm to identify such structures in the genome. We couldn't search them for sequences or particular motives because they are just not conserved. We had to look for particular stems and loops, calculate free energy for various structures, and find conserved elements across multiple species.

This way, we were able to identify the structures in the genome and we found that there are 25 genes. This was about 20 years ago that we found it, and to this day, actually, it's still 25. It seems like we haven't missed a single one, and we also had no false positives. These genes explain why selenium is needed because selenium only works through these 25 genes.

Aastha: Then, the converse is also true where these 25 genes are dependent on selenium?

Vadim: Yes. The functions are, for example, some work in antioxidant defense like glutathione peroxidases or thyroidus reductases so methanol suboxide reductases. Some work in functions like thyroid hormone activation and inactivation like this so called deiodinase. They get a less reductive deiodination of thyroid hormone. There are other functions that are known. Basically, the major thing is that typically, selenocysteine is just one amination. It's always in the entire active side and serves some kind of catalytic redox-active function. This explains why we need selenium.

Several such proteins are essential like a couple of the reduction reductases. There is a very important protein called Gpx4, which is also known as phospholipid hydroperoxide glutathione peroxidase. This protein is needed for protection against ferroptosis. It's a new type of program cell death. It's now a very active area of research. There's a huge explosion, and that's a key protein in that, that's actually dependent on selenium. All this makes selenium really exciting.

Then when we think about the role of selenium and aging, so I view it as like a prototypic kind of a feature to examine aging, because it has both positive and negative sides. It's needed for proteins to maintain several sexual functions or some less essential. At the same time, it's also toxic. Actually, first, the body sees selenium as a toxic element, and 90% of it is being methylated and converted to acid as sugar and excreted, and only maybe 10% is actually used for essential functions. This damage due to toxic side of selenium can accumulate over time.

From the aging perspective, antagonistic pleiotropy function is essentially important function but then, also negative functions being that contribution of cumulative damage over time. In fact, this idea of biology having an inherent antagonistic pleiotropy function is something that we proposed some time ago. This idea of antagonistic pleiotropy is a central kind of evolutionary theory of aging, right?

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