Information Theory of Aging

The Information Theory of Aging (ITA) is a mechanistic approach to health management that exploits epigenetic [ bodily ‘terrain’] factors for life extension and vitality purposes, presently being popularized by David A. Sinclair, PhD, and his colleagues at Harvard. Sinclair’s ‘healthspan’ views seem to dovetail smoothly into the biological-psychology field of sociogenomics which blends human behavior and performance with controllable environmental factors. Both ideas use concepts of epigenetic programming to alter and promote lasting and even hereditary changes in mental and physical aptitude, however Sinclair’s brand of ITA promotes direct genetic modification.

According to psychologist Brent W. Roberts, in this 2018 peer professional talk, “The sexiest research you could possibly do right now is intergenerational transmission of epigenetic phenomena… [describing how] you get a certain experience and not only does it change you, it’s going to change your offspring… If you read the [Mary Jane] West-Eberhard books, she has profoundly amazing stories about how phenotypes [gene expression] can be created entirely through environmental means, maintaining a variation until the genome catches up…and then select[s] for it… So, it does happen in animals and [in] humans we have suggestive studies, [such as] the deprivation studies…” [minute 29, thanks, Alison, for the link!] Measuring and Assessing Skills 2018: Brent Roberts - YouTube

David Sinclair’s 2019 book, LIFESPAN; Why We Age—and Why We Don’t Have To, explains the benefits of deprivation among his topics (such as calorie restriction, exposure to cold and similar ‘survival’ triggers) in a molecular biochemical context along with ‘stress’ products from plants and other living things as nutrients and drugs of the future. But it’s Sinclair’s gushing enthusiasm for biometric technology and medical intervention that really puts him on the radar:

“As I write this [‘Lifespan’], I am wearing a regular-sized ring that is monitoring my heart rate, body temperature, and movements. It tells me each morning if I slept well, how much I dreamed, and how alert I will be during the day” [p189]… “I am fortunate to have been one of the first people to get an early look at what this sort of technology can offer us…[as] a scientific adviser to a local [Boston] company, spun out of MIT, called Inside Tracker.” [p191] –in which Sinclair is an investor and former member of the Board of Directors. He adds, “Researchers at MIT are working on scanners straight out of Star Trek that can give readouts of thousands of biomarkers.”[p188] “…we are about to enter a world in which our genomes will be sequenced, stored, and already red-lighted…[or] green-lighted for treatments…” [p184] …”Now having seen the changes on my dashboard, I cannot imagine living without it. Just as I now wonder how I ever managed to drive without a GPS, I wonder how I ever made decisions about what I should be eating and how I should be exercising before I received regular updates from my biosensor ring and blood biomarker reports.” [p199, Lifespan]

Here’s an online source introduction to ITA:

“[S]everal practical approaches to extending both lifespan and healthspan (the period of one’s life when in generally good health) have become prominent among later 20th and 21st century longevity enthusiasts, including caloric restriction and anti-oxidant supplementation. [4]

One particular pharmacological cocktail of three drugs has recently gained attention when Dr. David Sinclair, one of the discoverers of the role of sirtuins in lifespan regulation, revealed in a LinkedIn post [5] (posted on June 25th, 2018) and later in his book [6] (published September 19th, 2019) that he was taking these “longevity molecules” every day. The combination consists of the anti-diabetes medication metformin, the mTOR inhibitor rapamycin/resveratrol, and nicotinamide mononucleotide (NMN), a precursor to nicotinamide adenine dinucleotide (NAD+), an essential co-factor of sirtuin function. Here, we examine the justification for

taking these three drugs in context with Dr. Sinclair’s mechanistic theory of aging, which he calls the “Information Theory of Aging” (ITA). –Epigenetic Control of Aging, The Sinclair Theory-- (continue reading)

–September 19, 2019 (9-19-19) highlighted here for putting some “spook in the book” which I’ll explain later.

Below is the post I’m transferring over from the original start-up forum:

According to…Sinclair, humans and other lifeforms have two modes of generating the necessary information that sustains life; one being the DNA/RNA ‘digital’ encoding of genomes (genetic) and the other being the heritable ‘analog’ activity of metabolism (epigenetic). He writes that “Unlike digital, analog information degrades over time—falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied… [But]…As cloning beautifully proves, our cells retain their youthful digital information even when we are old.” As Sinclair describes it, “The Information Theory of Aging starts with the primordial survival circuit we inherited from our distant ancestors. Over time, as you might expect, the circuit has evolved… Scientists have found more than two dozen [survival circuits] within our genome. Most of my colleagues call these ‘longevity genes’… But these genes don’t just make life longer, they make it healthier, which is why they can also be thought of as ‘vitality genes.’ Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is… And now that we know [about] these genes…, scientific discovery has given us an opportunity to explore and exploit them… [u]sing molecules both natural and novel, using technology both simple and complex… we can read them, turn them up and down, and even change them altogether.

“The longevity genes I work on are called ‘sirtuins,’ named after the yeast SIR2 gene, the first one to be discovered. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body… [S]irtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. After a few billion years of advancement since the days of yeast, they have evolved to control our health, our fitness, and our very survival. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD… [The] loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.

“Trading reproduction for repair, the sirtuins order our bodies to ‘buckle down’ in times of stress and protect us against the major diseases of aging: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis and asthma. They prevent cell death and boost mitochondria, the power packs of the cell. They go to battle with muscle wasting, osteoporosis, and macular degeneration. In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help the mice stay thin, regardless of what they eat. These are not wild guesses as to their power; scientists have established all this… And in no small measure, because [NAD+dependent] sirtuins do all of this based on a rather simple program—the wondrous gene B in the survival circuit—they’re turning out to be more amenable to manipulation than many other longevity genes. They are, it would appear…the key to understanding how our genetic material protects itself during times of adversity, allowing life to persist and thrive for billions of years.” —pp22-25, Lifespan, by David A. Sinclair, 2019

“Without any NAD we’d be dead in thirty seconds”

David Sinclair explains:
“In 2002, antioxidants were all the rage. They might not have been the anti-aging and health panaceas some believed them to be, but that wasn’t yet known. One of [those] antioxidants… was resveratrol, a natural molecule that is found in red wine and that many pants produce in times of stress… [Konrad] Howitz and I were fascinated by the fact that resveratrol is produced in greater quantities by grapes…experiencing stress. We aso knew that many other health-promoting molecules, and chemical derivatives of them, are produced in abundance by stressed plants; we get resveratrol from grapes, aspirin from willow bark, metformin form [‘French’] lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic. This, we believe, is evidence of xenohormesis –the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive… What this means, if it’s true, is that when we search for new drugs from the natural world we should be searching the stressed-out ones; in stressed plants, in stressed fungi, and even in the stressed microbiome populations in our guts. The theory is also relevant to the foods we eat; plants that are stressed have higher concentrations of xenohormetic molecules that may help us… Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue. One added benefit: they tend to taste better… –pp130-131

“As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut… [But] By studying resveratrol, we also learned that it is possible to activate sirtuins with a chemical. This prompted a flood of research into other sirtuin-activating compounds called STACs that are many times more potent than resveratrol… There are today hundreds of chemicals that have been demonstrated to have an effect on sirtuins… NAD, sometimes written as NAD+…has an advantage over other STACs because it boosts the activity of all seven [human] sirtuins… And because NAD is used by over five hundred different enzymes, without any NAD, we’d be dead in thirty seconds.” –pp133-134

“In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones. These beads on a string self-assemble to form loops, as when you tidy your garden hose…by looping it into a pile… If you could somehow plug one end of the DNA into a power socket and make the histones flash on and off, a few cells could do you for holiday lights… Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities. If the genome were a computer, the epigenome would be the software.” –p21

“A few recent studies have suggested that the so-called selfish genes we all carry in our genome, called LINE-1 elements, replicate and cause cellular havoc as we get older, accelerating our physical demise… Does it matter whether LINE-1 comes from your parents directly or via a virus? Would you want to eradicate LINE-1 from humanity or let it grow in your kids and inflict horrible diseases on them? Would you say that LINE-1 causes a disease or not?… Whether it’s a virus, a selfish DNA element, or simply the makeup of our cells that causes these health problems, what’s the difference? The end result is the same.” –p82, ibid.
Genes behaving badly seems to be Dr. Sinclair’s point in Lifespan. Despite the Human Genome Project announcement in 2003 that mapping was complete, he writes, “it really wasn’t. There were, in fact, huge gaps in the sequence… The parts of the genome that were missing, generally overlapping sections of repetitive nucleotides, were just not considered important. These were areas of the code…once derided as ‘junk DNA’ …[and]disregarded as ‘noncoding.’ From… the best minds in science at the time, those regions were little more than ghosts of genomes past, mostly remnants of dead hitchhiking viruses that had integrated into the genome hundreds of thousands of years ago… Yet by some estimates, that genetic dark matter accounts for as much as 69 percent of the total… [Since 2003, scientists have found thousands more genes, with some tiny ones] as short as 21 base pairs…[but] there’s something we still won’t be able to find. We won’t be able to find an aging gene…because our genes did not evolve to cause aging.” –pp27-28, Lifespan
–Read: “did not evolve to cause aging” or disease because in this mindset aging is disease leading to untimely death.
He states: “If the information theory is correct –that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning [after repairs] to other places along the genome where they are silencing genes that aren’t supposed to be silenced… It’s not hard to intentionally break DNA [to prove it]… You can do it with chemotherapy. You can do it with X-rays. (p48).
…”[In mice] we’d simply broken the mice’s DNA…and forced the cell to paste, or ‘ligate,’ them back together… Those breaks had induced a sirtuin response…[and] their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time… The digital code…was the same as it has always been. But the analog machine built to read that code was able to pick up only bits and pieces of the data. (p50).
…”Here’s the vital takeaway: we could age mice without affecting any of the most commonly assumed causes of aging. We hadn’t made their cells mutate. We hadn’t touched their telomeres. We hadn’t messed with their mitochondria…[or] exhausted their stem cells…[A]ll the symptoms of aging…were being caused…by the epigenetic changes that come as a result of DNA damage signals. We hadn’t given the mice all of those ailments. We had given them aging. And if you can give something, you can take it away.” –p52, Lifespan, by David A. Sinclair, 2019, Thorsons/HarperCollins publisher.

-Here’s a give-and-take example in a bacterium:
In this 2021 experiment to create ‘self-sufficient’ engineered cells, mutant E.coli use NAD to generate an ‘alternative’ redox circuit that substitutes the nucleobase cytosine (‘C’, and CTP) for adenine (‘A’, ATP), creating an NCD-dependent circuit, versus an NAD-dependent circuit, which the researchers anticipate as useful in synthetic biology. Their successful conclusion suggests,“This will be amenable to those on-going efforts using non-natural bases and non-natural amino acids to expand our capacity in terms of understanding and reprograming life.”
They write: ”To facilitate NCD-linked redox chemistry in vivo, it is essential to realize NCD biosynthesis. In bacteria, nicotinic acid mononucleotide (NaMN) adenylyltransferase (NaMNAT) catalyzes the condensation of ATP and NaMN to form nicotinic acid adenine dinucleotide (NaAD) (Fig. 1a), which is the key step for de novo NAD biosynthesis16. Conceptually, if the binding pockets of ATP and NaMN of NaMNAT [its analog enzyme] are redesigned to favor cytidine triphosphate (CTP) and NMN [the common vitamin product of NAD used by humans], respectively (Fig. 1b), the engineered enzyme is expected to make NCD following a similar condensation mechanism, and can be designated as NCD synthetase (NcdS). As both CTP and NMN are endogenous metabolites, no auxiliary nutrients are required to synthesize NCD by those NcdS-empowered cells… However, it is intimidating to engineer a two-substrate enzyme for active variants specific with two new substrates. On one hand, simultaneous mutating key residues within two-substrate-binding pockets will lead to large [metabolite] libraries beyond our screening capacity. On the other hand, engineered molecular interactions favoring one substrate may have unanticipated effects on those for the other, and vice versa.”
…and what happens to the organism?
“Again, NCD production led to reduced NAD levels…”
Read it here, April 2021—Nature Magazine
Sinclair and Lifespan

Hey @jenlake and @Stephers I found an article about Sinclair and ITA linking it to deep learning that brings up hormesis.

" The duality of rest and activity is pervasive in biological function. Sinclair recommends that it is important to activate this preservation and repair mechanism. This is known as hormesis. This is the biological phenomenon that low dose exposure to harmful toxins can have beneficial effects.

The phenomenon of hormesis applies also to the less ancient immune system. One can characterize the immune system as a kind of liquid cognitive system. That is an intelligence that has dynamic connectivity with its components. An ant colony is also an example of a liquid cognitive system. Some would call this a liquid brain. Allergies are an example of when the immune system overreacts to the presence of non-toxic substances."

When I read that, I’m thinking low-dose radiation for Evolution 2.0. Do you read it the same?

" Radiation hormesis is the hypothesis that low doses of ionizing radiation (within the region of and just above natural background levels) are beneficial, stimulating the activation of repair mechanisms that protect against disease, that are not activated in absence of ionizing radiation. The reserve repair mechanisms are hypothesized to be sufficiently effective when stimulated as to not only cancel the detrimental effects of ionizing radiation but also inhibit disease not related to radiation exposure (see hormesis).[1][2][3][4] This hypothesis has captured the attention of scientists and public alike in recent years.[5]"

This paper may offer some hints (confirmation?) - relative to radiation hormesis and “evolution” - perhaps even by design (?).

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