The “Scientific World-view” Needs an Update

At the end of each year, I take the liberty of speculating on a scientific subject beyond the usual scope of this blog. This one is the broadest yet.

We live on an island surrounded by a sea of ignorance. As our island of knowledge grows, so does the shore of our ignorance.
— John Archibald Wheeler

The more you know, the more you know you don’t know.
— Mrs Haine, my 6th Grade teacher (1961)

It ain’t what you don’t know that gets you into trouble. It’s what you know for sure that just ain’t so.
erroneously attributed to Mark Twain

The community of scientists has bequeathed to us a picture of the world that is fundamentally wrong. The picture so many of us carry in our minds is derived from 19th Century science. It is utterly inconsistent with quantum physics, and has been contradicted directly by a body of research on powers of the mind that has been marginalized by the mainstream. Somehow, the picture has survived and become ossified in some of the smartest minds on the planet.

The big-picture stories that our culture carries have consequences for the way we live our lives and the way we organize our communities. The ”scientific world-view“ is not only deeply at odds with science, it is also related to the ways our world is falling apart—the sense of powerlessness and hopelessness that we carry, and especially the sense of isolation and existential loneliness.

What is the scientific world-view?

How do we know it is wrong? Six stories

  1. The Anthropic Principle
  2. Memory is not only in synapses. Thought is not confined to brains.
  3. PSI research, especially the REG experiments of Jahn and Dunne
  4. Bell’s Theorem is a proof that the observer participates in the creation of reality.
  5. QM of many-particle systems
  6. Quantum Zeno Effect

What will our world look like after the coming paradigm shift?

What is the scientific world-view?

Physical reality is the only reality. Particles and fields are real. Thoughts, emotions, desires are abstract concepts useful to us, but not fundamental constituents of reality. Elementary particles can be visualized well enough as miniature billiard balls. They interact with their near neighbors, following fixed laws. The laws of physics explain properties of the chemical elements, and the known laws of chemistry and physics are sufficient to understand biology, ecology, sociology, and on up.

Life is subject to the same physical laws as non-living matter. Life has no fundamental relationship to the physical universe. It’s just something that happened, going along for the ride.

There is no room for free will. Our feeling of making choices must be an illusion. The future is determined by the past plus pure chance. “Quantum random” is the gold standard for random events absolutely unpredictable and unrelated to anything else in the world.

This view is sometimes called “physicalism”—the physical world is the only thing that is real; and it is sometimes called “reductionism”—everything on large scales can be explained in terms of emergent, aggregate properties of smaller systems, coming down ultimately to the level of particles.

The perspective of the mechanical universe was inherited by Nietzsche, who declared that “God is dead”. There followed the nihilistic movements of the 20th Century: Dadaism, Existentialism, atonal music and punk rock, Post-modernism. If, as Yeats says, “the best lack all conviction…”, perhaps part of the reason lies in the fact that our best and brightest have been drawn to the Scientific World-view, with its subtext that all is mechanical, random, and ultimately meaningless… Am I being unfair, linking all this to a belief that the only things that exist are particles and fields?

How do we know it is wrong?

1. The Anthropic Principle

All physical theories rely on fundamental constants, numbers that are arbitrary inputs that just happen to be what they are. Examples are the speed of light, the mass of the electron, the size of Planck’s constant (which scales quantum effects), and the strength of gravity. After accounting for the arbitrariness of scales in mass, length, and time, there are about 20 such arbitrary constants. Beginning in the 1970s, it has been noticed that the kind of universe we live in depends sensitively on these numbers. In fact, many of them seem to be very finely tuned in the sense that if they were a little bit different from what they are, our universe would be vastly simpler and less interesting than it is. For example, if the gravitational constant were smaller, then there would be no galaxies or stars, just hydrogen and helium forever spread through space. If the strong force were a little less strong, there would be no chemical elements except hydrogen; and an extremely precise coincidence accounts for the abundance of carbon, which otherwise would be a trace element, far too rare to support life. Here are three books on the Anthropic Principle (Barrow & Tipler 1988, Davies, 2007, Rees, 1999).

How do scientists interpret this fact? The majority eschew any implication of design by positing that our universe, infinite though it may be in space and time, is but one among a truly stupendous number of universes that exist. The vast majority of such universes are incapable of supporting life. The very fact that we’re here to ask the question explains the special combination of constants that characterizes our particular universe.

But to me, all those extra universes are a gross violation of Occam’s Razor. The “Anthropic Coincidences” say to me that life is a fundamental reason why our universe is the way it is. I connect this idea to experiments of Robert Jahn cited below.

2. Memory is not only in synapses. Thought is not confined to brains.

Every October, Monarch butterflies across ⅔ of North America turn around and fly home, up to 2,000 miles, to find the exact tree (in California or Mexico) where their great, great, great, great grandparents overwintered the previous year. How is the road map transmitted from generation to generation? Plants don’t have anything that corresponds to nerves or brains, but Monica Gagliano has demonstrated that plants can learn, can store memories, can sense their environment and make decisions that have all the appearance of signal processing. Even single-celled ciliates can learn and remember. Caterpillars’ nervous systems are dismantled completely in the chrysalis, yet memories of the caterpillar survive in the butterfly. Humans who receive a heart transplant can take on some of the tastes, interests, and personality traits of the heart donor. There are too many stories of young children remembering verifiable details of a past life to dismiss the possibility of reincarnation.

Memory plays such a key role in defining our identities and personalities. These examples indicate that memory is not just in our brains, but at least sometimes can be in tissues other than nerves, or even outside the body altogether.

3. PSI research, especially the REG experiments of Jahn and Dunne

Almost everyone will acknowledge precognitive dreams or uncanny premonitions. We have learned to dismiss these as chance occurrences, coincidences without significance. We may be unaware there are surveys and statistical studies of such stories, arguing that explanations from selective memory or embellished storytelling are absurdly inadequate to account for their frequency and specificity. Studies of telepathy and precognition under laboratory conditions complement this anecdotal evidence and lend it credence. A robust, incontrovertible body of research on the paranormal demonstrates the reality of telepathic communication with an aggregate p value that is astronomically small. (If this assertion is new to you, I recommend Etzel Cardeña for a scientific review, or Dean Radin for an entertaining overview backed by rigorous science. A protocol called Ganzfeld produces consistent effects of size 14%, averaged over thousands of experimental trials in the last 30 years.)

I find special significance in a series of experiments done by Brenda Dunne and Robert Jahn, Dean of the Princeton University School of Engineering, over a 35-year period, using Random Event Generators (REG). They showed that the conscious intent of a human can bias the results of a quantum random process. This is of special significance because it cries out to us to consider that consciousness may play a role in fundamental physics. Standard quantum physics tells us that exactly half the information necessary to predict the result of any experiment is coded in the wave function. The other half does not exist. An element of pure randomness enters into every observation of reality. Jahn and Dunne’s results have been corroborated with completely different equipment, using optical interference fringes instead of REGs. They offer us a radical idea: that “quantum random” may not be random at all, but the gateway by which conscious intent creates physical effect. I’ll have more to say below.

James Carpenter cites evidence that psychic abilities inform our subconscious minds just as commonly as other, well-acknowledged subliminal input, but most of this information is never delivered up to the conscious mind that sits atop a far more extensive cognitive process. We who have been raised to trust our senses and our reason suppress these ubiquitous psychic messages far more thoroughly than indigenous peoples, who routinely regard extra sensory perception as part of their everyday reality.

4. Bell’s Theorem is a proof that the observer participates in the creation of reality.

Irish/Swiss physicist John Bell proved (1964 original) that the known and accepted principles of quantum mechanics imply that every observer affects what is being observed, and furthermore that that effect transcends space and time. The observer affects anything that has ever interacted with what he observes, and the effect can act on the past as easily as the future. (Subsequently, it has been verified in lab experiments that real physical systems do behave in this way, so you don’t even have to accept quantum mechanics to know that observers affect what they observe.

The implications of this force us to rethink the idea (fundamental to the scientific method) that there is an objective physical world, independent of the scientists who study it. Do we find a clue to the physical basis of the intention effect that Jahn and Dunne observed? Might we imagine that the Big Bang event (when, for a tiny fraction of a second, all matter was packed so tight that every particle interacted with every other) was caused in some sense by our looking out at the universe 14 billion years later?

John Wheeler describes the observer’s participation in creating reality by analogy with a game of 20 Questions, in which the observer asks the question and Nature makes up her answers ad libitem.

We think of observers as independent humans with free will, but the model of participatory co-creation raises the question, how does it come about that there is so much we can agree on in the one universe co-created by you and me and at least 7 billion other observers? Considering this question has led me to the conclusion that our consciousnesses are not really so independent as we experience them to be. This idea seems puzzling and wildly counter-intuitive, but it aligns well with the wisdom of mystics throughout the ages.)

5. QM of many-particle systems

Quantum mechanics is essentially about situations, not particles. We associate quantum physics with experiments and high-energy particles and with physics of the atom. The reality (rarely acknowledged) is that we do quantum experiments with single particles because that’s all we know how to calculate. Quantum mechanics provides a prescription for calculating future probabilities based on present measurements, but that calculation is utterly intractable except in the very simplest cases. Yes, the simple Schrödinger equation (not even relativistic QM or second-quantization quantum field theory) becomes completely intractable for any system more complicated than two particles. This is different from classical mechanics. You can solve the equations of motion for 2 particles in classical mechanics with twice as much computational effort as 1 particle, and 3 particles require 3 times as much computation. But in QM, a 2 particle system is represented by a wave function in a 6-dimensional configuration space, and a 3-particle system requires 9 dimensions, etc. This is sooo different from tracking one more particle in the same 3-dimensional space. In practice, a 2-electron computation requires a billion times more computing power than a single electron, and a 3-electron computation is beyond the conceivable ability of any transistor-based computer that will ever be built. A garden variety biomolecule typically contains a few thousand electrons.

(In practice, physical chemists do computations of large atoms and complex molecules all the time, but to do so they start with the fiction that electrons don’t interact with one another (except through the Pauli exclusion principle) and then correct their calculation based on experimental measurements of chemical properties.)

We do experiments to test quantum mechanics on systems with a single particle, isolated through careful laboratory conditions, because that’s all we know how to calculate. But quantum mechanics is fundamentally a theory of systems. It applies naturally to many-particle systems, and to single particles in idealized circumstances that only obtain in specialized laboratories. The observations that we make in everyday life measure macroscopic properties of Avogadro’s numbers of particles. We cannot in practice perform quantum calculations for such systems, so we do non-quantum calculations that work well in most circumstances.

But we know there are exceptions. There are bulk quantum properties that occasionally surface, and we understand them only dimly. Superconductivity was observed for 50 years before there was a theory of it. Lasers are another bulk quantum phenomenon. Low energy nuclear reactions have been reported in dozens of laboratories around the world, but there is no accepted theory for them. They are a complete surprise to physicists who work with the standard approximations [New Scientist article]. Evidence from a handful of experiments suggests that plants and even bacteria are able to harness nuclear physics to transmute one element into another [reviewed by C. L. Kervran]. Biological nuclear transmutation is an observed phenomenon that defies explanation in terms of the usual approximations made by physicists when they apply quantum mechanics to macroscopic objects.

There is a small, pregnant field called quantum biology which has carefully documented a few examples of biological effects. I hold with those who speculate that life is an essentially quantum phenomenon, and that the observer effect is being harnessed continually to maintain the living state. A suggested approach to this topic derives from the

6. Quantum Zeno Effect

If you don’t watch an atom of Carbon 11, it will emit an electron and transform itself into Boron in about 20 minutes. But if you observe it after 1 minute, chances are 95% that it hasn’t decayed yet, and the 20 minutes starts all over again. You can observe it much more often, say every second, and then the probability that it has decayed in that time can be infinitesimally small. Curiously—this is a purely quantum effect—frequent observation helps to keep the atom in its metastable C11 state, and can greatly delay the average half-life. This is called the Quantum Zeno Effect (named for the Zeno paradox from the ancient Greek philosopher).

It is only slightly more complicated to use the same principle to guide one quantum state into another. You can demonstrate this easily in asimple home laboratory setup. If you polarize light with a horizontal polarizing filter, then none of it will get through a second filter that is rotated to be vertical. But if you insert a third filter halfway between the two, and you rotate that filter 45 degrees, then half the originally polarized light gets through the 45 degree filter, and half of that gets through the final vertical filter. The result looks like magic. You have complete dark at the back end, then you insert another dark filter into the system, and the light coming out the back becomes visibly brighter. You can extend the idea by using a dozen or a hundred different filters between the front (horizontal) and back (vertical) polarizers, with each one rotated just a smidgen compared to the previous one. The result is that you gradually rotate the polarization in many steps, and almost all the light that was horizontally polarized emerges as vertically polarized.

This is called the Inverse Quantum Zeno effect, and it could be used (in principle) to guide complex quantum systems along any desired path. In a brilliant book published 20 years ago, Johnjoe McFadden outlines a way in which the Quantum Zeno effect might be a breakthrough concept in explaining the origin of life and the efficiency of the evolutionary process in general.

Combining the Jahn experiment with the Quantum Zeno Effect, we can imagine how consciousness (or subconscious intent) might guide chemical processes inside a living cell, such that living cells really are subject to different laws than non-living matter. This is a return to vitalism, that was discredited by 19th Century science.

What will our world look like after the coming paradigm shift?

Life is not an opportunistic happenstance that took advantage of a set of arbitrary rules of physics to construct a self-reproducing hypercycle of chemical catalysts, primed to transform itself by the laws of chance and competition for resources into a diverse community of “forms most beautiful and wonderful”.

Conscious awareness is not an illusion, nor an epiphenomenon that arises whenever a sufficiently sophisticated computational algorithm achieves a threshold of self-reference.

While quantum mechanical equations are well-established, there are conflicting interpretations of what they mean . What is a measurement? And what happens when the wave function collapses. When we take Jahn and Dunne into account, there is a strong preference for the view that consciousness has an independent existence, outside the equations of QM, and that it is conscious observation that collapses the wave function. (This perspective was championed by von Neumann, Wigner, and others, but is currently out of fashion.)

Beyond this, anything I say about the coming paradigm will be hubris and foolish speculation. I’m not going to let that stop me.

There is a new science waiting to be formulated that will fundamentally redefine the way we think of our relationship to the universe and to the biosphere. It can only be called “biophysics”, though it will have nothing in common with what today is called “biophysics” (=application of known principles of physical chemistry and of fluids to cell structures.) My guess is that the new theory will embrace Cartesian dualism, and bring consciousness into the fold of physics, as a third realm of existence distinct from particles and fields.

Quantum biology is going to grow and morph from a quirky intersection of two largely-independent fields of science, and become our fundamental understanding of what life is. The non-living world is steered and guided loosely by a global Conscious observer or by many competing or reinforcing consciousnesses (small “c”). But a living being has an observer inside who is constantly asking the question of Schrödinger’s cat, “Am I alive or dead?”. The Quantum Zeno effect sustains life.

Medical research is going to realize that what we have swept aside as the “placebo effect” is a window into a much richer realm in which the mind influences the body via attention, expectation, and intention. Western medicine based on chemistry will be seen as tapping only half the potential ways in which we can create health and wellness.

The tension will be resolved between Christians who insist that all life is the handiwork of an old man who lives in the sky, and the Darwinian fundamentalists who insist that all evolution from a dilute pool of simple molecules to the diverse biosphere has been the result of chance mutations and a race for the fastest reproducer. Evolution is directed by consciousness through the Quantum Zeno Effect, as Johnjoe McFadden described 20 years ago .

The Life Extension movement and the transhumanist movement will embrace the solid evidence for reincarnation , and for the reality that consciousness is flavored by but not dependent upon a physical brain . Freed from the desperate urgency that derives from belief that death is the end of all, we will continue to pursue life extension, but moved by love of life, rather than fear of death; and we will supplement the tools of biochemistry and regenerative medicine with technologies of the traditional shamans and spiritual masters.

There is a biological destiny in which we all participate, a guiding hand pulling us toward an ever richer and more diverse biology. Planet Earth is probably just one among trillions of ecosystems that are destined to merge and co-evolve as humans learn the technology of space travel from alien visitors who are, in fact, far less alien than we imagine.

New Aging Clock based on Proteins in the Blood

Methylation clocks are far and away the most accurate markers of a person’s age, and so are a promising tool for evaluating anti-aging interventions, but they are a bit of a black box. We know from statistics that certain places on chromosomes become steadily methylated (or demethylated) with age, but we often don’t know what effect that has on expression of particular genes. 

For the first time, a clock has been devised based on proteins in the blood that is comparable in accuracy to the best methylation clocks. This has the advantage of being downstream of epigenetics, so it is less of a black box. What can we learn from the proteins that are increased (and decreased) with age?

I’ve written often and enthusiastically about the utility of methylation clocks for evaluation of anti-aging interventions [blog, blog, blog, journal article]. This technology offers a way to promptly identify small age-reversal successes (perhaps not in individuals, but averaged over a cohort of ~50 to 100 subjects). Before these tests were available, we had no choice but to wait — usually 10 years or more — for enough experimental subjects to die that we could be sure the intervention we were evaluating affected life expectancy. (This is the plan of the worthy but ridiculously expensive TAME trial promoted by Nir Barzilai.)

Can we rely on methylation clocks to evaluate anti-aging interventions? If we succeed in setting back the methylation clocks, are we actually making the body younger? The answer depends critically on the relationship of methylation to aging. 

The majority view derives from the belief that aging is a passive process, while methylation (epigenetics) is a process under tight evolutionary control. The majority holds that methylation changes with age are a response to the damage that accrues unavoidably, and the changes in gene expression that result are actually the body’s best effort to fight back against this damage.

My view is with the minority. Aging is a programmed process (evolved, I believe, for the purpose of demographic stability). Changes in methylation and epigenetic changes generally are the primary cause of aging. Far from being a response to damage, epigenetic changes with age invoke the very signals that cause damage (e.g. inflammation) and simultaneously cut back our repair processes (e.g., detoxification and autophagy). 

If you hold with the majority, then setting back the methylation clock (with drugs or gene therapies or …) could actually shorten our lifespans. Setting back the methylation clock means thwarting the body’s efforts to rescue itself. We should not use methylation clocks as a measure of whether a particular technology has achieved rejuvenation. 

If you hold with the minority, then setting back the methylation clock is an indication that whatever we have done has struck at the root cause of aging, reversing the epigenetic changes that are the primary driver of senescence.

(In the scientific community of aging, there are a few of us speaking directly about the primary importance of epigenetics [Horvath, Barja, Johnson, Rando, Mitteldorf ], and many more who are tacitly accepting the idea that setting back the methylation clock is a good thing. Most scientists remain skeptical and are not embracing the methylation clocks as a reliable gauge for anti-aging technologies [Han, West].)

The battle lines are not clearly drawn, and the basic conflict in beliefs is not yet out in the open. But resolution of this issue is a major next step for geriatric research. I say this because it is likely there is some truth on each side. Most of the epigenetic changes with age are drivers of senescence (Type 1), but some are the body’s attempts to rescue itself from damage (Type 2). Each of the methylation clocks that are now available averages hundreds of methylation sites, and it is likely that they are a mixture of sites that play these two opposing roles. [background in my October blog]

So the urgent need is for a clock that is constructed exclusively of drivers of aging (Type 1), so that we can use it with confidence as a measure of whether an intervention that we are testing will extend lifespan.

Can we design experiments with the methylation clock that would tell us which of the age-related methylation sites are Type 1 and which are Type 2? It’s hard to know how to begin, because we don’t yet have a way to do controlled experiments. What we want is a molecular tool that will methylate a selected target CpG site while leaving everything else untouched, and we don’t have that yet. (It may become feasible as CRISPR technology improves.) Based on present technology, the only way to tell for sure is to compare how different interventions affect the methylation clocks in thousands of experimental subjects, and then wait and wait and wait and see how long these subjects live. LEF is undertaking this ambitious plan, but it will be decades before it bears fruit.

Clocks based on the proteome

This month, a new clock came out of the Stanford lab of Tony Wyss-Coray that is based on measuring levels of proteins in blood plasma, rather than patterns of methylation on chromosomes. It is not the first proteomic clock, but it is the most accurate. For some of the proteins that feature prominently in the clock, we have a good understanding of their metabolic function, and for the most part they vindicate my belief that epigenetic changes are predominantly drivers of senescence rather than protective responses to damage

Wyss-Coray was one of the people at Stanford responsible for the modern wave of research in hetrochronic parabiosis. In a series of experiments, they surgically joined a young mouse to an old mouse, such that they shared a blood supply. The old mouse got younger and the young mouse got older, though both suffered early death from their cruel and macabre condition (excuse my editorial license). Later, it was found that chemical constituents of the blood plasma (proteins and RNAs but not whole cells) were responsible for moderating the effective ages of the animals. As part of the current study, Wyss-Coray compared the proteins in the new (human) proteome clock with the proteins that were altered in the (mouse) parabiosis experiments, and found a large overlap. This may be the best evidence we have that the proteome changes are predominantly Type 1, causal factors of senescence. (Here is a very recent BioRxiv preprint of a UCSD study relating epigenetic clocks in people to mice and dogs.)


Different proteins change at different ages

The Stanford group notes that some of the proteins in their clock increase in the blood with age and some decrease. Typically, the changes do not occur uniformly over the lifespan. Though none of the curves is U-shaped (on-off-on, or off-on-off), some proteins do most of their changing early in life, and some later. 

The group identifies three life periods and three groups of proteins: mid-30s, ~60yo, and late 70s. 

At young age (34 years), we observed a downregulation of proteins involved in structural pathways, such as the extracellular matrix. These changes were reversed in middle and old age (60 and 78 years, respectively). At age 60 years, we found a prominent role of hormonal activity, binding functions and blood pathways. At age 78 years, key processes still included blood pathways but also bone morphogenetic protein signaling, which is involved in numerous cellular functions. Pathways changing with age by linear modeling overlapped most strongly with the crests at age 34 and 60 years (Fig below), indicating that dramatic changes occurring in the elderly might be masked in linear modeling by more subtle changes at earlier ages. Altogether, these results showed that aging is a dynamic, non-linear process characterized by waves of changes in plasma proteins that reflect complex shifts in biological processes.

This paragraph doesn’t tell all we need to know to decide which changes are Type 1 and which Type 2. There is more information in their Supplementary Tables 5 and 14. I don’t have the expertise in biochemistry or metabolics to extract the information, but if you do and you are reading this, I hope you will contact me.


“Intriguingly, the three age-related crests were largely composed of different proteins”

For example, the top four proteins changing at age 78 are

  • PTN.3045.72.2
  • CHRDL1.3362.61.2
  • SMOC1.13118.5.3
  • CCDC80.3234.23.2

With Google searches, what I could find about all of these was that they have been previously identified as CV risk factors, and they all are increasing rapidly at age 78. The third one (SMOC) is described as binding calcium, which presumably affects blood clotting. All are clearly Type 1 — an important bottom line — but it would be nice to know more about their metabolic roles. Caveat: the technology used to measure these proteins comes from SomaLogic, and their mission was to look for proteins that could signal CV risk.

I could find nothing about numbers 5 through 8

  • WFDC2.11388.75.3
  • PTGDS.10514.5.3
  • SCARF2.8956.96.3
  • SVEP1.11178.21.3

It is interesting to me that almost all the proteins identified as changing rapidly at age 78 are increasing. The few I have identified seem to be increasing in a way that makes us more vulnerable to CV disease. It is natural to interpret this phenomenon as programmed aging.

In contrast, a few of the fastest-changing proteins at age 60 are decreasing (though most are increasing). The one decreasing most significantly is identified as SERP a2-Antiplasmin, which seems to me to be involved in autophagy, but I’m out of my depth here. At age 60, the proteins increasing most rapidly is PTN.3045.72.2, another CV risk factor, and GDF15.

GDF15 deserves a story of its own. The authors identify it as the single most useful protein for their clock, increasing monotonically across the age span. It is described sketchily in Wikipedia as having a role in both inflammation and apoptosis, and it has been identified as a powerful indicator of heart disease. My guess is that it is mostly Type 1, but that it also plays a role in repair. GDF15 is too central a player to be purely an agent of self-destruction. 


Why not make use of different proteins at different ages in constructing the clock?

The implication is that a more accurate clock can be constructed if it incorporates different information at different life stages. Age calculation should be based on different sets of proteins, depending on how old the subject is. (You might object that you have to know how old the subject is in order to know which proteins to emphasize, but this problem is easy to overcome in practice, by calculating age in two stages, a rough cut using all proteins, and then a fine tuning based on proteins that change most rapidly around that age.) In my reading of the paper, the Stanford team prominently notes that patterns of change roll along in waves through the lifetime, but then they fail to incorporate this information into their clock algorithm, which is independent of age. This seems to be a lost opportunity. The methylation clocks, too, might gain accuracy by this approach. (All the Horvath clocks use the same collection of CpG sites for young and old alike.)

Maybe I am misreading the text about how the clock was constructed, and maybe the authors have already optimized their algorithm with different proteins at different ages. The text in question is

To determine whether the plasma proteome could predict biological age, we used glmnet and fitted a LASSO model (alpha= 1; 100 lambda tested; ‘lamda.min’ as the shrinkage variable was estimated after tenfold cross-validation). Input variables consisted of z-scaled log–transformed RFUs and sex information. [ref]

In any case, I know that none of the Horvath clocks have been derived based on different CpG sites at different ages, and this suggests an opportunity for a potential improvement in accuracy.

Comparison to Predecessor

Last year, this paper was published by a group at NIH, describing their own study of how the human proteome changes with age. Their sample was smaller, but they also found that aging is characterized more by increasing plasma proteins than by proteins lost with age. They also singled out GDF15 as their most prominent finding. They didn’t look for different proteins at different ages, as the Stanford group did. “The functional pathways enriched in the 217 age‐associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis.” The clock they constructed showed correlation with age r=0.94, compared to r=0.97 for the new Stanford clock. (The difference between 0.94 and 0.97 implies that the Stanford clock is twice as accurate (half the uncertainty)).


The bottom line

If proteome clocks eventually replace methylome clocks, the process will take several years. Proteome lab procedures are more complicated and more expensive than technology for measuring methylation. More to the point, the Stanford results must be replicated by independent labs, and must be stress-tested and cross-checked against other markers of aging. For the next few years, we have more confidence in the methylation clocks, which have been through this process and found to be solid.

But starting immediately, we can use the specifics of the proteome clock to engineer anti-aging remedies. The plasma proteome is directly related to the metabolism, and it can be altered with intravenous transfusions. (We cannot yet directly directly modify the methylome.) So let’s apply the results of the proteome clock. Most of the significant changes with age involve increases in certain proteins, so we will have to either remove these from the blood or infuse antibodies designed to bind to them and neutralize them. The infusions will probably have to be carefully titrated so as not to overdo it.

The large and crucial question hanging over the clock technologies (methylome and proteome) is which of these changes are drivers of senescence and which are protective responses to damage.  The new proteome data provides reassurance that the predominance are of Type 1 (drivers of aging), and we can safely use them to gauge the effectiveness of our anti-aging interventions. But this issue is central, and deserves explicit attention. Every methylation site and every plasma protein that we use to evaluate new technologies should be individually validated as Type 1.