Informational theory as a context for epigenetic reprogramming and aging | David Sinclair
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The processes that mediate aging can be likened to those that drive the sharing of digital information – the idea that, as a signal is transmitted, information is lost and must be continually resent to maintain signal integrity. This concept forms the basis of the Informational Theory of Aging, an idea put forth by Dr. Sinclair and elaborated upon in his book Lifespan, in which he analogizes aspects of the epigenetic signature of aging and its ability to be reset to the signal correction capabilities of TCP/IP protocol. In this clip, Dr. David Sinclair elaborates on his Informational Theory of Aging.
Rhonda: But just kind of to go back what you were saying about the epigenetic clock, and the aging, and I had always wondered about with the Yamanaka, you know, these transcription factors that are able to sort of take a already differentiated cell, like a skin cell, or a neuron, or a liver cell and turn it back into a stem cell, a pluripotent stem cell. You know, I always wondered, "What about the epigenome?" Right? Is it like, do you have an older epigenome but you're like somehow, you know, like...
David: You actually reset the epigenome, and that's how it works. Yeah. So, think of the genome as the digital information. So this is zeros and ones, or in this case, A, T, G, C. But the epigenome is the reader of that, and it's analog, and it's very hard to maintain over 80 years.
Rhonda: That has to be the key.
David: It's a loss of information.
Rhonda: It has to be.
David: Yeah. But how do you get back that information? So I'm going to geek out a little bit because your audience is a smart one. So back in 1938, there was a man, a brilliant person called Claude Shannon who was at MIT and he wrote a theory, mathematical theory on communication. And his goal was to correct the loss of noise during a transmission of a radio signal during World War II and beyond. And he came up with a mathematical theorem of how do you make sure that the signal that starts here is pristine when it gets to the actual receiver? And what he decided was you can either make it digital or you can have somebody who's observing the signal and then if it gets messed up, you then send a replacement signal. We now call that TCP/IP. It runs the internet. That's how it all works. That's why it works. And we wouldn't have an internet if it wasn't for Claude Shannon's work back in the '30s and '40s. I think that's a good recipe for understanding why we age, loss of noise over time, analog systems, very prone to noise. But that system of resetting aging, how do you get the original information back that it was when the signal was first sent, that's what we're working on. That's what we think the Yamanaka factors are able to do. They're the group that sits above and says, "Oh, that signal is degraded, use that signal."
Rhonda: Yeah. That's cool.
David: Well, so that's all part of...
Rhonda: High-five.
David: Thanks, Rhonda.
Rhonda: I'm excited.
David: That, I've been writing up in a book, which is coming out later this year in September. And so I've been so busy writing a book, I haven't even put this out in scientific publications. So maybe one of the first times that a scientist puts his whole ideas and theories in a book before it comes out in peer review. So, we'll see. But, you know, I think it's there for people to judge. Maybe by September, I'll have some scientific papers written up as well.
Rhonda: What an exciting field. Do you think other scientists in the aging field will start working on this? I feel like this needs to be...there needs to be a big push, like there need...
David: Yeah. It's going fast. So right now, I mentioned Juan Carlos Belmonte in the Salk, he's the pioneer. Steve Horvath is part of our dream team. There's another guy...unfortunately, they're all guys currently, but hopefully not forever, is Manuel Serrano. He's been working on... He's in Spain, in Barcelona. He's been putting these factors into mice, but there aren't just men working on the epigenome of aging. So a couple of really top leaders. So Anne Brunet is at Stanford. She's been working on the epigenomic causes of aging. And we have Shelley Berger at UPenn who's been studying, among other things, what makes the difference between a short-lived ant and a long-lived ant, they have the same genome, just different epigenomes. And Jessica Tyler works on the epigenetics of yeast cells and trying to work out exactly what I was describing earlier about the distribution of proteins between DNA breaks and controlling a cell's age. But that's it. That's basically the world's elite teams of epigenetics of aging, but it's exploding. Two, three years from now, we'll have hundreds of labs.
Rhonda: Yeah. It sounds... I mean, this is cool. It's something I've definitely... This whole idea, like, is definitely, in some way, come to my mind with the Yamanaka factor and using that to, like, reset, you know, for aging, not just about making... I mean, there's always the, okay, well, you can keep, you know, replenishing your cell types in different organs and kind of keep it going, but like, to like turn it back, to like think it's a young cell. Like, there's got to be a way, there's got to be a way.
David: Right. Yamanaka did us a big, a big favor. Actually, John Gurdon who won the Nobel Prize with Yamanaka, he really told us years ago, back in the 1980s, that reversal of aging is possible. And we didn't really get it. What he did was he took an adult cell nucleus from a tadpole, put it into a frog's egg, and made a new tadpole. What that actually tells you is that your genome can be reset to go way back, and aging is not a one-way street.
Rhonda: Yeah. The fact that you can take your adult cell and reset it to a stem cell is proof, right? I mean...
David: Right. But now we know the machinery, at least the beginnings of it, and it's a very exciting time.
Rhonda: Yeah. And I'm so excited right now. I'm like, there's all this other stuff we were going to talk about, you know?
A gene encoding a transcription factor (CLOCK) that affects both the persistence and period of circadian rhythms. CLOCK functions as an essential activator of downstream elements in the pathway critical to the generation of circadian rhythms. In humans, polymorphisms in the CLOCK gene have been associated with increased insomnia, weight loss difficulty, and recurrence of major depressive episodes in patients with bipolar disorder.
The biological process in which a cell matures and specializes. Differentiation is essential for the development, growth, reproduction, and lifespan of multicellular organisms. Differentiated cells can only express genes that characterize a certain type of cell, such as a liver cell, for example.
A biomarker of aging based on alterations in an organism’s DNA methylation (DNAm) profile. Methylations occur naturally and regulate gene expression. With age, the methylation state of a gene may change. These changes are quantifiable, serving as a means to gauge biological age, which is often different from chronological age. Several variations of epigenetic clocks have been identified. They are generally categorized according to the type and number of tissues used to formulate the calculation, as well as the type of age measured (e.g., epigenetic versus phenotypic). The most widely used clocks include: - HorvathAge, which predicts intrinsic epigenetic age acceleration, a phenomenon in which an organism's aging is influenced by internal physiological factors such as normal metabolism and genetics.[1] - DNAm PhenoAge, which predicts time-to-death among people of the same chronological age, based on biomarkers of age-related disease.[2] - DNAm GrimAge, which predicts lifespan and healthspan, based on DNAm surrogates in blood, including biomarkers of aging and alterations in blood composition.[3]
- ^ Horvath S (2013). DNA methylation age of human tissues and cell types. Genome Biol 14, 10.
- ^ Levine, Morgan E.; Lu, Ake T.; Quach, Austin; Chen, Brian H.; Assimes, Themistocles L.; Bandinelli, Stefania, et al. (2018). An Epigenetic Biomarker Of Aging For Lifespan And Healthspan Aging 10, 4.
- ^ Lu, Ake T.; Quach, Austin; Wilson, James G.; Reiner, Alex P.; Aviv, Abraham; Raj, Kenneth, et al. (2019). DNA Methylation GrimAge Strongly Predicts Lifespan And Healthspan Aging 11, 2.
Genetic control elicited by factors other than modification of the genetic code found in the sequence of DNA. Epigenetic changes determine which genes are being expressed, which in turn may influence disease risk. Some epigenetic changes are heritable.
The collective set of genetic instructions for a single organism. The genome is stored in an organism's DNA and provides all the information required for its function and survival.
An essential mineral present in many foods. Iron participates in many physiological functions and is a critical component of hemoglobin. Iron deficiency can cause anemia, fatigue, shortness of breath, and heart arrhythmias.
A chemical that causes Parkinson's disease-like symptoms. MPTP undergoes enzymatic modification in the brain to form MPP+, a neurotoxic compound that interrupts the electron transport system of dopaminergic neurons. MPTP is chemically related to rotenone and paraquat, pesticides that can produce parkinsonian features in animals.
Capable of developing into any type of cell or tissue except those that form a placenta or embryo.
A cell that has the potential to develop into different types of cells in the body. Stem cells are undifferentiated, so they cannot do specific functions in the body. Instead, they have the potential to become specialized cells, such as muscle cells, blood cells, and brain cells. As such, they serve as a repair system for the body. Stem cells can divide and renew themselves over a long time. In 2006, scientists reverted somatic cells into stem cells by introducing Oct4, Sox2, Klf4, and cMyc (OSKM), known as Yamanaka factors.[1]
- ^ Takahashi, Kazutoshi; Yamanaka, Shinya (2006). Induction Of Pluripotent Stem Cells From Mouse Embryonic And Adult Fibroblast Cultures By Defined Factors Cell 126, 4.
A type of white blood cell that plays critical roles in the body's adaptive immune response. T cells form in the bone marrow but mature in the thymus (hence the "T" designation). They destroy malignant cells by triggering apoptosis – a type of cellular self-destruct mechanism that rids the body of damaged or aged cells.
The highest level of intake of a given nutrient likely to pose no adverse health effects for nearly all healthy people. As intake increases above the upper intake level, the risk of adverse effects increases.
A protein that binds to specific DNA sequences, thereby controlling the rate of transcription of genetic information from DNA to messenger RNA. A defining feature of transcription factors is that they contain one or more DNA-binding domains, which attach to specific sequences of DNA adjacent to the genes that they regulate.
A set of networking protocols that allows two or more computers to communicate. TCP/IP specifies how data should be packaged, addressed, transmitted, routed, and received. It has been widely adopted as a networking standard.
Proteins that can reprogram differentiated (mature) cells into pluripotent stem cells. Yamanaka factors are highly expressed in embryonic stem cells in mice and humans. Five Yamanaka factors have been identified: Oct4, Sox2, cMyc, Klf4, and NKX3-1. In a mouse model of premature aging, short-term expression of Oct4, Sox2, Klf4, and c-Myc ameliorated cellular and physiological hallmarks of aging and prolonged lifespan.[1]
- ^ Ocampo, Alejandro; Martinez-Redondo, Paloma; Platero-Luengo, Aida; Hatanaka, Fumiyuki; Hishida, Tomoaki; Lam, David, et al. (2016). In Vivo Amelioration Of Age-Associated Hallmarks By Partial Reprogramming Cell 167, 7.
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