Genetic strategies for reversing epigenetic age (Horvath Clock) | David Sinclair
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The Horvath clock, a means of assessing a person's “epigenetic age," measures DNA methylation levels, which increase as a person ages, and can even predict how long a person will live. Recent discoveries in the field of aging research may have identified the signal that can manipulate the epigenome to restore proteins – including sirtuins – to their earlier, younger functional capacity. In this clip, Dr. David Sinclair describes how epigenomic modifications can influence how an organism ages, potentially reversing years of age-related damage.
Rhonda: Well, if you think about, as you know, Steve Horvath's work on this epigenetic clock and how he's shown now, I mean, in several different cell types, you know, including from humans, that there's this very distinct epigenetic aging clock that...
David: So, what... You know, I got to jump in because I get a little excited about this. What I've been telling you about the sirtuins and their movement, we've shown, is intimately linked to Horvath's methylation clock.
Rhonda: Really?
David: Yeah. It's all part of the same process. So this distracted protein DNA repair system, what's happening as that happens is that you get the methyls on the DNA that we use as a clock, but what we're finding is that clock is a way of resetting the proteins to go back to where they came from. That there are modifications on the genome that say, "Hey, sirtuins and these other proteins, go back to that gene because that's where you belong 20 years ago and ignore these other changes which have come on since you were 20." And we think we've literally found what the signal is to get them to go back. Now NAD is part of that. You need the fuel, but what's the genetic trigger to say, "Get off there and go back there"? And we think we've found that and it's got to do with the Horvath clock being reversed.
Rhonda: Is this in your publication?
David: It's something we were writing up right now for a journal.
Rhonda: That's super exciting. That's really exciting. Has there been any...and I know we're going on a tangent here, but has there been any evidence looking at, like, for example, like supercentenarians, what their epigenome is, like do we know?
David: Very... I mean, they've done the Horvath clock on it.
Rhonda: They have?
David: Yeah.
Rhonda: And is it different than, like, elderly?
David: For the same age, yes. Right. And actually, the Horvath clock has now been done on people who are smokers or obese and it's quite clear.
Rhonda: Cancer [crosstalk 00:22:18] or... [crosstalk 00:22:20] tumor tissue, yeah.
David: Is that right?
Rhonda: Yeah. Yeah. Tumor tissues, like, looks like 10 years older in the same person, like age match, normal tissue.
David: That's interesting because we're reversing the Horvath clock with our new found genetic trick and we're finding that we're having benefits on those cells as well. So I think this could be...
Rhonda: On cancer cells.
David: Yeah.
Rhonda: Wow.
David: And damaged neurons.
Rhonda: That's so cool. I'm so excited.
David: It seems to be something radically new, but... So I know Steve well and his research is really interesting in that it is showing that it doesn't just predict your chronological age, it's predicting also how long you have to live, which is a really interesting thing that if you've abused your body and had a lot of smoking and been sedentary, Steve can take your blood and he can say, "Hey, you're 10 years older than you should be."
Rhonda: Even if you... Let's say you were a previous smoker, you know, and you hadn't smoked for 20 years and you've become active and eat healthy, do you think that epigenetic mark is there or do you think that....
David: I think it is.
Rhonda: It's there.
David: Yeah. Well, we know the rates of cancer go down, but all the other damage, the changes to the epigenome, what I'd been drawing with my hands, this movement of proteins, that's one-way street. It's not that if you suddenly start running in your 60s that it's all going to be reset.
Rhonda: Unless you can identify the signal.
David: Well, the signal, yeah. We've been putting that into animals and restoring eyesight in old mice and regrowing optic nerves in old mice and it seems to be safe. They're not getting any...no downsides there.
Rhonda: And this is by manipulating the epigenome?
David: Right.
Rhonda: Wow.
A person who is 100 or more years old.
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.
A major contributing factor to aging, cellular senescence, and the development of cancer. Byproducts of both mitochondrial energy production and immune activity are major sources of DNA damage. Additionally, environmental stressors can increase this base level of damage. DNA damage can be mitigated by cellular repair processes; however, the effectiveness of these processes may be influenced by the availability of dietary minerals, such as magnesium, and other dietary components, which are needed for proper function of repair enzymes.
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]
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 biochemical process involving the addition or subtraction of a methyl group (CH3) to another chemical group. In epigenetics, a methyl group is added to an amino acid in a histone tail on DNA, altering the activity of the DNA segment without changing its sequence. Under- and over-methylation are referred to as hypomethylation and hypermethylation, respectively.
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.
A class of enzymes that influence that influence aging and longevity through multiple molecular pathways. Sirtuins regulate a variety of metabolic processes, including release of insulin, mobilization of lipids, response to stress, and modulation of lifespan. They also influence circadian clocks and mitochondrial biogenesis. Sirtuins are activated when NAD+ levels rise. The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or nicotinamide or a combination of these variables. There are seven known sirtuins, designated as Sirt1 to Sirt7.
A person who is 110 years old or more.
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.
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