Where did COVID-19 come from? Part 2

Last week, I outlined genetic evidence that the present pandemic had its origin in a laboratory. In the segment below, I tell two stories of how this might have occurred, one as leak from an American lab and one from a Chinese lab. I was surprised to find that there is a history of collaborative work between American and Chinese bioweapons labs on exactly the kind of Coronavirus responsible for the current epidemic, in which a protein that binds with ACE2 was artificially spliced onto the genome of the bat virus ancestor.


After I posted this, Yuri Deigin, who is a frequent commenter on this page, posted this article on Medium. It is great background reading for anyone who wants to understand more deeply how viruses get inside cells, how they manipulate the cell chemistry, and how SARS-CoV2 is related to its ancestors. Spoiler: The virus seems to combine the backbone from a known bat virus genome with a spike protein (the part that binds to a target cell) from a pangolin virus. These two animals share no common habitat, so it is possible but unlikely that they could have combined in nature. Newly added to the SARS-CoV2 binding protein is a precisely placed insert that acts as an instruction to the cell, “cut here” making the virus a great deal more infective.


Here’s a puzzle worthy of Sherlock Holmes’s story of the dog who didn’t bark. The Chinese are eagerly promoting narratives about the SARS-CoV2 virus originating in America, while the Americans assume that, of course, the virus evolved where the first cases were identified, in Wuhan, China. But both sides agree, SARS-CoV2 had a natural origin, and had nothing to do with genetic engineering or breeding in a laboratory.  As we shall see below there are credible links to both the Wuhan Institute of Virology and to the US bioweapons HQ at Fort Detrick, MD and a university lab at Chapel Hill.

Why wouldn’t these two propaganda machines be eager to demonize one another by promoting stories about leaks from the other’s weapons lab? If one but not the other of these spin-control states were too eagerly dismissing the bioweapons meme, I know what I would suspect. But what does it mean that both these rivals are suppressing all discussion of the issue?

Two stories—they can’t both be true

There is a plausible story about a Chinese origin for COVID. There is another story, in my view equally plausible, about an American origin. The two stories are not easily reconciled, and that suggests to me that I have been suckered by disinformation, one way or the other. Some part of what I am about to report is not true. More confusion: there are hints that fall short of being a “story” about coordinated bioweapons development between China and the US. I like to think of it as a real-life mystery novel. I ask you, dear readers, to help figure out who is telling the truth, who is lying, and whodunnit. America? China? A cooperation between the two?

Or maybe it was Professor Pangolin*.

Outline of the Chinese story:

  • China’s main bioweapons research facility is right there in Wuhan, where the first patients were identified.
  • The laboratory has published papers in which they were doing closely-related research. [2009, 2013, 2015]
  • In fact, we know that they were harvesting bats from SW China, extracting SARS virus from them, genetically modifying the virus to enable “gain-of-fuinction” to infect human cells in vitro. (see 2015 link above)
  • Even the human ACE2 receptor used by SARS-CoV2 is mentioned in published articles from the Wuhan research facility.  (see 2015 link above)
  • Security at Chinese facilities is reported to be more lax than at comparable American facilities.
  • The Chinese government has reportedly silenced discussion of bioweapons research at the Wuhan facility, and of a possible leak. (Here’s an early complaint about lack of transparency. I offer this video as a source because it documents well the Chinese suppression of discussion of the bioweapon question. In other respects, the video is misleading, blaming the Chinese government as if the American government were not equally culpable.)

Outline of the American story:

  • The world’s most extensive bioweapons facility is at Fort Detrick, MD.
  • The Fort Detrick lab was closed by CDC for undisclosed security leaks last August.
  • I personally had a persistent cough for more than 2 months beginning in November. Other (American) friends have told me of similar unusual respiratory infections last fall and early in the winter. CDC reported in early December that “The U.S. winter flu season is off to its earliest start in more than 15 years.” [NBC news] Could this have been early cases of COVID-19, undetected as such?
  • The SF Chronicle reports today that an American who had not traveled recently died of COVID Feb 6, so he must have contracted the disease early January, a month earlier than the previous “first” American case which arrived in Seattle from Wuhan in February. It may be that we have not found even earlier examples because we have not been looking.
  • Late last October, there were military games, a kind of Olympic competition for the world’s armies, held in Wuhan. This was 6 weeks before the first COVID-19 cases were recognized by the Chinese, but only 3 weeks before the first Chinese case identified with hindsight.
  • Some of the American military personnel attending the Games in Wuhan were stationed in Maryland and had recently frequented Fort Detrick.
  • The entire American team, 300 strong, stayed at the Oriental Hotel, just a half mile from the infamous open-air market which has been blamed for the outbreak.
  • According to one report, the entire first cluster of 42 COVID patients were employees and their families of the Oriental Hotel.
  • Genetic diversity analysis can be used to estimate how long a virus has been mutating away from Patient Zero. One such analysis is consistent with an origin last fall.
  • Maximum Likelihood Analysis for the evolutionary tree of the SARS-CoV2 virus worldwide indicates that the “A” strain from which all other strains were derived is present only in America and Australia. The predominant strain in China is “B”. [ScienceDaily]
  • According to ABC News, “As far back as late November, U.S. intelligence officials were warning that a contagion was sweeping through China’s Wuhan region, changing the patterns of life and business and posing a threat to the population, according to four sources briefed on the secret reporting.” The Defense Intelligence Agency had already identified it as a coronavirus in November. But the “first 41 patients” in the Lancet article were admitted to Wuhan hospitals in December. Please stop and consider the implications of the fact that the US Dept of Defense knew that there was a dangerous coronavirus and knew it was in Wuhan before the first reported COVID patients. Pepe Escobar conjectures.
  • The only countries in the world where all known strains of COVID have been identified are China and USA.

Reports of bioweapon collaboration between USA and China

Exhibit A for this hypothesis is this Nature Medicine article from 2015. It describes a collaboration between University of North Carolina scientists and the Wuhan Virology Laboratory, funded jointly by American agencies, including Fauci’s NIAID, and the Chinese National Science Foundation. They describe modifying the bat coronavirus, the very one that is most closely related to the SARS-CoV2 pandemic. They use genetic engineering to add an ability to bind to the human (and mouse) ACE2 receptor, the very same modification that makes SARS-CoV2 so contagious.

The nominal justification for such research is to understand how such recombinations might occur in nature, so that we might be better prepared to defend against them if such a recombination should happen to take place. The number of such recombinations that could conceivably take place is enormous. But this group was lucky to anticipate the exact virus and the exact modifications that would make it a problem five years later. They had a jump on the competition. “Our work suggests a potential risk of SARS-CoV re-emergence from viruses currently circulating in bat populations.” Prophetic. And the research took place in the Chinese city where the current pandemic was first recognized. Coincidental.

It is morally outrageous that such research should be proceeding. It has been against International Law since 1975 (based on a 1969 treaty), and explicitly outlawed in the US since 1989. “Whoever knowingly develops, produces, stockpiles, transfers, acquires, retains, or possesses any biological agent, toxin, or delivery  system for use as a weapon, or knowingly assists a foreign state or any organization to do so, shall be fined under this title or imprisoned for  life or any term of years, or both.” The law singles out research in gain-of-function engineering, as described in the Nature Medicine article.

Layered on my moral outrage is a head scratch: Why would a government agency steeped in secrecy publish such research? Even if we grant that their intent was not to produce a bioweapon but to learn about what might, at some future date, happen in nature, the fact remains that the paper contains explicit instructions that anyone with hostile intent might use to create a bioweapon.

Earlier in my career, I had security clearance as part of my research at Physical Sciences, Inc in the 1970s. I saw just enough of the Defense Department’s security system to extrapolate that the CLASSIFIED stamp was used liberally on any finding that might conceivably be used as part of a weapon system, even if the work described basic physics that had been well known for a century or more. Contrast this institutional paranoia with treatment of the Nature Medicine article, which is published freely, though it includes explicit instructions with which a competent but malevolent biochemist might produce an artificial pandemic.

What were the authors thinking when put such research out for the world to read? I have written to two of the authors to ask them.

  • Luc Montagner, French national hero and Nobel laureate in medicine, worked in China for several years. He claims there is a cooperative bioweapons program between China and the West.
  • Francis Boyle, professor of international law and world expert on bioweapons law, claims to have first-hand knowledge of cooperation in developing weapons between China and USA. He also says that the original SARS virus from 2003 was an American bioweapon, and that the high-security facility within Wuhan Virology Lab was set up to study it [interview transcript]
  • Three Published papers on SARS-derived viruses that were authored by scientists at the Wuhan Institute of Virology list sponsorship by American funding agencies, including NIAID, which has been directed by Anthony Fauci for 35 years. [20092013, 2015]
  • Last summer, the National Microbiology Laboratory in Winnipeg abruptly cut off a Chinese-Canadian researcher’s access to her own laboratory. Details of the reasons were not disclosed. “A number of observers have speculated that case involves concerns about the improper transfer of intellectual property to China,” according to Science Magazine. What the Science article omits to say is that NML Winnipeg is Canada’s primary bioweapons laboratory.
  • The chair of Harvard’s Chemistry Department is a specialist in the technology of microparticles. He has had long-standing contracts with the Wuhan University of Technology (not to be confused with the Virology Institute), and was recently dismissed by Harvard, where the Administration claimed to be ignorant until recently of his work with the Chinese university. [February news article from Nature] [EuroWeekly article] [Wall St Journal]

American work on bioweapons can be traced to Nazi scientists who had been experimenting with non-consenting human subjects, exempted from being charged as war criminals and imported to the US to continue their work under Operation Paperclip. The current wave of research sponsored not by the Defense Department but by civilian NIAID was begun in 2003, and protested widely in 2005.

More than 700 scientists sent a petition on Monday to the director of the National Institutes of Health protesting what they said was the shift of tens of millions of dollars in federal research money since 2001 away from pathogens that cause major public health problems to obscure germs the government fears might be used in a bioterrorist attack. [NYTimes]

Regardless of whether COVID-19 derived from a laboratory, let’s put an end to state-sponsored bioweapons research. It’s already illegal.


The case for the Wet Market origin has gained popular acceptance despite evidence that is thin to nonexistent. Pictures like this one are used to appeal to our lizard brains. Of course something so disgusting must be a breeding ground for germs.

Here’s how we do it in America. Is it any less distasteful?

Yes, the way in which animals are killed for food is disgusting, and we don’t like to look at it. But does it have anything to do with the way viruses mutate and acquire new functions?

Standard evolutionary theory tells us that mutations are random. (I’ve been a critic of standard evolutionary theory, but for reasons that I think are not relevant to the present discussion.) Occasionally, a random mutation makes it possible for a virus to jump from one species to another. But these mutations are rare enough that we don’t expect them to occur simultaneously with three other gain-of-function mutations that make a virus both more lethal and more contagious. Computer models based on the full SARS-CoV2 genome have trouble accounting for all the differences from the bat genome in a sufficiently short time frame. The wet market hypothesis is a politically convenient fallback, without a proposed mechanism. The bats that harbor SARS viruses live 1,000 miles from Wuhan and are not sold in the local meat market at Wuhan.


* The pangolin that has been proposed as an intermediate host is an endangered species. It cannot be sold legally in China, and the idea that there were underground pangolin vendors in the Wuhan wet market has not even been alleged, let alone researched. This Guardian article is appropriately skeptical. The Nature article which is the original source of the pangolin theory does not claim there were pangolins at the Wuhan market. A follow-up Nature article points to further weaknesses in the pangolin hypothesis, and clarifies that the pangolin virus genome is not closer than the bat virus to SARS-CoV2.

Where did COVID-19 come from?

There is genetic evidence suggestive of human tinkering in the genome, and there are news stories suggesting the virus might have been developed either at the Wuhan Institute of Virology or at the American virology lab at Fort Detrick. There are even some suggestions that the American and Chinese bioweapons labs may be working together, sharing samples and exchanging funding.


Part 1: The Genetic Evidence

Preface

We rely on the scientific community as a context for almost every public policy decision. People who want to influence policy know this, and they don’t just lobby Congress, they also buy scientists, scientific reporting, and placement in prominent journals. Most scientists are honest, but they have to survive in a world where funding is tighter than it should be. It’s not surprising that some of them succumb and publish what powerful and corrupt institutions want them to.

The question of a laboratory origin for COVID is politically explosive, so we expect a heavy hand restraining the science establishment. Those of us seeking an honest answer, who have a little expertise, a little horse sense, and a lot of patience, are left to sift through information, misinformation, and disinformation in a politicized environment.

My personal opinion is that I don’t like having to wonder if global pandemics have been created, accidentally or otherwise, by my own government. Bioweapon research is extensive in several countries, but dominated by the US. The disclosed US budget is over $10 billion per year, and who knows what the black budget is. There is no legitimate purpose for this “research,” and it is illegal. No bioweapon can ever attack “enemies” without unacceptable risk of infecting “friends”. Over time, it is virtually certain that there will be leaks with horrific consequence. Lyme disease is a case in point.

Regardless of whether COVID19 came from a lab, we the people must demand disclosure of this secret “research”, and demand an end to the American bioweapons program in its entirety.

I know of no coalition organized to this end. We’ll have to start one.

Three useful books to get into this subject:

Bitten: The secret history of Lyme disease and biological weapons
Poisoner in Chief: Sidney Gottlieb and the CIA Search for Mind Control
Lab 257: The disturbing story of the government’s secret germ laboratory

Expert opinion

Here’s an interview by Dr Francis Boyle describing the big picture. Boyle is a professor of international law at University of Illinois with a history in both government and academia working on the limitation of biological weapons. In this interview he alleges:

  • The US program in biological weapons was jump started after WWII by giving a new home to Japanese and German scientists who had been doing horrific human experimentation.
  • These programs continue to this day, at Merck, U of NC, U of Texas, Harvard, NIH and elsewhere.
  • Anthony Fauci and NIAID have also been tied to sponsors of bioweapons research, specifically relating to making coronaviruses more lethal. Boyle sites this NYTimes article about the shift of NIAID money in 2001 to bioweapons applications.

    Wikipedia states: “Since the 2001 anthrax attacks, and the consequent expansion of federal bio-defense expenditures, USAMRIID has been joined at Fort Detrick by sister bio-defense agencies of the U.S. Department of Health and Human Services (NIAID‘s Integrated Research Facility) and the U.S. Department of Homeland Security…”
  • American bioweapons labs are sharing knowledge and specimens with foreign labs, including the high-security (BSL-4) Chinese installation at Wuhan.
  • Boyle believes that the origin of COVID was a Chinese-American research project, and that the proximate cause was an accidental release from the Wuhan facility.

Whoever knowingly develops, produces, stockpiles, transfers, acquires, retains, or possesses any biological agent, toxin, or delivery system for use as a weapon, or knowingly assists a foreign state or any organization to do so, shall be fined under this title or imprisoned for life or any term of years, or both. 
The Bioweapons Anti-Terrorism Act of 1989, authored and promoted by Prof Francis Boyle 

Since passage of this Act in 1989, offensive bioweapons research has been illegal in America. But Boyle claims that the research has continued under the guise of bioweapons defense or pandemic control. It is explicitly forbidden to genetically engineer pathogens for gain-of-function. That would mean deliberately making them more lethal or more contagious, or modifying an animal pathogen so that it is able to infect humans. Boyle charges that the most explicit violations have been outsourced to avoid technical violation of the Act, and some contracts have been with China.

This british news article claims NIAID gave a $3.7 million grant to the Wuhan Institute of Virology. The Virology Institute is in the same city where COVID-19 was first reported and is reputed to be the largest center for bioweapons research in China.  Here is a 2017 article from PLOS that comes from the Wuhan Institute, describing genetic experiments with SARS virus extracted from bats. In acknowledgments of support, the authors list NIAID as a funder.

And here is an  article that appeared on the Web yesterday, titled Evidence SARS-CoV-2 Emerged From a Biological Laboratory in Wuhan, China. The article is unsigned, but contains only verifiable information in the public domain. It cites this article from 2007, in which Chinese researchers in collaboration with Australian researchers modify a bat coronavirus to enable it to infect humans. “A second paper, from 2015, not only reiterates the first paper’s findings, but outright claims they ‘synthetically re-derived an infectious full-length SHC014 recombinant virus and demonstrate robust viral replication both in vitro [human cell cultures] and in vivo [mouse models].”” Also in the anonymous article are recent job postings from the Wuhan lab, seeking researchers expert in bat virus and cross-species transmissions.

Not in this article, but also of interest, were a FEMA report from last summer that was eerily prescient. A job listing at CDC last November seemed to anticipate a coming need for emergency management. And a conference sponsored by Johns Hopkins University and the Gates foundation last October simulated a coronavirus outbreak that started in China and spread worldwide.

Where did COVID come from?

I don’t pretend to know the answer, and based on publicly-available information, I don’t think it is knowable. But there is genetic evidence suggestive of human tinkering in the genome, and there are news stories suggesting the virus might have been developed either at the Wuhan Institute of Virology or at the American virology lab at Fort Detrick. There are even some suggestions that the American and Chinese bioweapons labs may be working together, sharing samples and exchanging funding. I will defer these stories for Part 2 of this report.

The official story is that the origin of the epidemic was the “wet market” where meat and some wild livestock is sold to consumers in Wuhan. This hypothesis was challenged by an article in Lancet, summarized here in Science Magazine. The authors interviewed the first 41 known patients in Wuhan, who were assumed to have contracted COVID concurrently from “patient zero”. For 28 of them, there were links to the Market, either personal or through a family member, but for 13 of them, no links to the Market could be identified. In this neighborhood of Wuhan, most people did shop at the Market, so the authors were more impressed with the 13 who had no link, and suggested that 28 out of 41 could have been consistent with a random sample of people from that neighborhood.

Other sources claim that all 41 had links to the nearby Oriental Hotel, a short walk from the Market, and that Patient Zero was an American soldier/cyclist. I will have more to say in Part 2.

Is it plausible that the SARS-CoV2 mutated directly from a virus that infected local bats? For this question, I am dependent on evolutionary geneticists for an opinion, and there is a divergence of opinion on the scientific literature. Geneticists who say evidence points to a laboratory origin are typically cautious, but they make these points:

  • Wuhan is in central-eastern China. The bats that carry SARS come from Yunnan province in the southwest, about 1,000 miles away. It is known that the bats were collected for research on the SARS virus conducted at the Wuhan laboratory.
  • The genome has at least 4 gain-of-function mutations (if they are mutations) compared to the ancestor bat virus. Gain-of-function mutations are rare compared to loss-of-function, and usually the virus makes its leap when there is one gain-of-function. 
  • About a fourth of the genome looks nothing like a coronavirus, and must have arrived via genetic recombination. The recombined part bears a resemblance to HIV. Viral genome recombinations do occur in nature, but this one is particularly hard to explain, since HIV is a fragile virus that can’t survive outside human blood. How would it get into a bat virus? 

  • COVID has some pathological effects never before seen in a coronavirus, including attack on the GI tract and on artery walls. There are some reports that the virus’s lethality comes from its attack on hemoglobin, the red blood molecule that carries oxygen around the body. 

The claim that the four insertions look suspiciously like HIV was considered shaky, but it is supported just today by a testimonial from a French Nobel laureate. In 2008, Dr Luc Montagnier was awarded the Nobel Prize in medicine for having discovered (much earlier) the HIV virus that causes AIDS. In this radio interview (in French) with Dr Jean-François Lemoine, Montagnier expresses his conviction that the SARS-CoV2 genome points to a laboratory origin. 

“Indian researchers have already tried to publish the results of the analyses that showed that this coronavirus genome contained sequences of another virus, … the HIV virus, but they were forced to withdraw their findings as the pressure from the mainstream was too great.”

Against these analyses, there is one prominent article in Nature Medicine that claims to “irrefutably” rule out a laboratory origin. Their basis for saying this is

  1. That computations suggest that the virus’s surface proteins are not ideal for binding to a human enzyme called ACE2, and that if the virus were designed in a lab, the designers would certainly have found the ideal solution, and used that instead.
  2. That the backbone of the virus contains a piece that looks like a pangolin virus, and the pangolin virus genome wasn’t published until very recently, so lab scientists could not have used it. 

(The pangolin is a rare, endangered species of armored anteater. It looks a bit like an armadillo.)

I’m always suspicious when scientists use words like “irrefutably” and “definitive”. But, more objectively, I would point out that none of the four bullet points above were refuted or even considered in the Nature Medicine paper.

There is also a statement in Lancet signed by 27 researchers which was prominently echoed in Science Magazine that “strongly condemns rumors and conspiracy theories”, without refuting any of the geneticists’ claims. They cite dozens of papers that they say support a natural origin, but, reviewing these papers, I find that they rather assume a natural origin. In fact several of the papers note difficulties with this hypothesis. One of the papers concludes on the basis of evolutionary models that, if SARS-CoV2 evolved naturally from a bat ancestor, it must have diverged at least 40 years ago. This is difficult to reconcile with the story that SARS-CoV2 jumped from bats to humans just last year.

My personal perspective inclines me to think the Lancet statement is politically motivated. I find it suspicious that prominent scientific publications have seen fit to deny claims that COVID had a laboratory origin, but none have refuted the considered details of those claims.

The US Military has been studying Coronaviruses as bioweapons 

It is undisputed that the US has an extensive bioweapons “research” program, and that modifying Coronaviruses to make them more dangerous is part of their program of work.

Here is the first person account of Judy Mikovits, who claims she worked in the 1990s at Fort Detrick, an Army biology lab in Maryland. Part of her job was to weaponize coronaviruses. This work was ongoing and controversial as late as 2015. President Obama approved and extended the programs. Three years ago, Nature reported that “the SARS virus has escaped from high level containment facilities in Beijing multiple times”. Only in China? Also in 2017, the House Committee on Energy and Commerce requested from CDC information about leaks from similar research facilities in the US, and they got back a 503-page document with all specifics redacted.

Conclusions

I find it suspicious that the debate over whether COVID came from a laboratory is being avoided with ad hominem attacks, blanket denials, and straw man arguments. I’m impressed that the people who are supporting a laboratory origin have promptly corrected their misstatements, while I see no such willingness on the other side.

The totality of evidence for the hypothesis is not conclusive. The most compelling evidence I see is 

    • Bats that are reputed to be source of the virus are found naturally more than 1,000 miles from Wuhan, but we know that the Wuhan Laboratory was studying just these bats and just this virus, and further that they were experimenting with modifying the spike protein that the virus uses for entry, to make it compatible with human ACE2. 
    • The virus gained several new abilities on emerging from bats. Usually, we would expect just one.
    • Closely related to this, the genome shows four RNA segments that differ substantially from the bat ancestor where, again, we would expect just one.
    • Genetic analysis indicates that the divergence from bats happened decades ago, and yet the disease only appeared in humans recently.

I take Francis Boyle’s testimony quite seriously. He’s a career expert in biological warfare. Luc Montagnier is as credible a source as they come, but I don’t know what to make of how certain he seems about genetic evidence that others have said is inconclusive.

In Part 2, I hope to tie in American bioweapons research. Linking the American and Chinese bioweapons programs seems stranger than science. Teaser: Evidence suggests that SARS-CoV2 has been in America longer than it has been in China.

Overreaction

I have become concerned that dangers of the COVID pandemic have been overstated, perhaps deliberately. The containment measures adopted in most Western countries have had little effect on the spread of the virus, but they have been maximally disruptive of our economic and cultural lives, and have produced loneliness and isolation, while throwing millions of people living on the edge of their means into desperate poverty.

(graphic is my own, based on data from http://OurWorldInData.org/coronavirus )

Here is Dr John Ioannidis, professor of epidemiology at Stanford Medical School, speaking to this point.

The good news is that daily deaths from the virus have peaked worldwide, and begun their decline. Since death rates trail the rate of new infections by 2-3 weeks, we expect that spread of the virus peaked worldwide in mid-March and in the US 10-12 days ago.

Does it make sense to continue with policies of economic shutdown and social isolation now that COVID is declining? The answer depends on whether these policies have been responsible for the decline, or whether COVID is declining for other reasons. I tend to think “other reasons”, but I’ll try to present both sides. I recognize that there is no definitive proof, but only judgment in the face of diverse evidence. My bias is that in such situations I lean toward a contrarian view. 

There are three factors which I consider to be plausible reasons for the decline of COVID:

  1. Warmer weather is arriving
  2. Doctors are learning how to treat COVID from others’ experience
  3. Saturation / herd immunitymost people have already been exposed and have built up immunity

1. Respiratory illnesses tend to be seasonal. Reasons for this are not fully understood, and there may be several factors [ref, ref, ref]. Every year, there is a flu season, and deaths from flu are down almost 100-fold from winter to summer.

Is COVID19 likely to be an exception to this rule? We already see that cold countries have much higher incidence and much higher death rates from COVID than warm countries.

India may be the most striking example, a very hot country with weak central controls and a large population that is unreached by medical services. There has been no effective lockdown in India, yet COVID deaths per million population are comparable to the US.

The above leaves me very hopeful that, like SARS and MERS and countless strains of cold and flu that went before it, COVID is dying out as spring weather sets in.

In this week’s Science magazine, an article (summarized on ScienceBlog) argues that unlike these predecessors, COVID may not slow down with warm weather. As I read it, their basis for this claim is that these other seasonal illnesses spread sufficiently to engender herd immunity in the spring, but because of lockdown COVID has not crossed that threshold. Both these assumptions, in my view, are suspect. There is no scientific agreement why respiratory infections are so deeply seasonal, but it’s an empirical fact. If it were just about herd immunity, then we would see some waves of cold and flu that start in the spring or summer and die out by fall; but we rarely see this. And below I argue that if COVID is as contagious and as persistent as is claimed, then we (America and the world) may be acquiring herd immunity already.

2.  In just a few months, doctors have shared their successes, and there are now several promising treatments (though there has not been time for blinded, controlled clinical trials).

3.  It’s more difficult to know whether herd immunity is already being established around the world. We depend here on experts and on computer models. Here’s an expert (Professor Knut Wittkowski, head of Rockefeller University’s Department of Biostatics):

COVID is reputed to be extraordinarily contagious, and if that is so, I would argue that the kinds of half-measures used in the US and other Western countries are slowing but not preventing spread of the virus. People are still shopping in supermarkets and drug stores. Labs are claiming the virus remains active on surfaces we touch for 24 hours, but we are still freely sending and receiving mail and packages. 

If claims that non-symptomatic carriers can be contagious are credible, then surely a majority of people have been exposed by now, enough that our immune systems have generated the first few antibody-producing B cells, which can multiply rapidly (exponentially) when we are exposed to more virus.

If claims that non-symptomatic carriers can be contagious are not credible, then why are we locking ourselves away from people who look and feel perfectly healthy?

Herd immunity is the population’s usual way to stop an epidemic, and social distancing may have slowed the acquisition of herd immunity, but by now we have all touched someone who has touched someone who has touched someone who has been exposed.

Possibility number 4: Can we credit the lockdown for present decline of COVID?

There are many politicians and policymakers who will line up to take the credit for COVID’s decline. We would all like to think that the individual sacrifices we are making these months have achieved a collective purpose.

Empirically, we can never resolve the counter-factual, “what if we had not locked down?” The best we can do is to compare regions that have locked down to regions that have remained open. If we do this, then, subject to the caveat that all these numbers have been gamed in the reporting, we have to conclude that the evidence for effectiveness of lockdown is not strong.

The scale on the left is in deaths per million population. For comparison, the ten most recent flu seasons in the US have caused death rates ranging from 34 to 175 (according to CDC).

Rates of COVID deaths vary widely. But countries that have locked down do not appear to have an advantage over countries that have not.

As of this writing, there are 8 US states that have not locked down by executive order: Arkansas, Iowa, North and South Dakota, Oklahoma, Nebraska, Utah and Wyoming. Their death rates per million are, respectively, 11, 15, 7, 12, 27, 9, 6, and 3, all well below the national average of 77.

Looking at the state and country data, it appears to me that lockdown has been a response to high COVID mortality, rather than a preventer in advance of mortality. Perhaps this is the nature of political humans, to respond only after a threat becomes serious. But as policy, it is (to use the technical term) bass ackwards. Quarantine measures are very effective in early stages of an epidemic, but of limited usefulness once the epidemic has gotten its toehold in the population. 

China locked up quickly, cutting off all travel out of Wuhan in late January. Rules were liberalized and commerce resumed 2 months later. This makes sense. The US waited too long to lock down, and now, at a time when isolation measures are least useful, they are being intensified. I fear that the economic, psychological, and cultural consequences of this new wave of restrictions will be severe, while the epidemiological benefit will be marginal.

Greece locked down promptly and probably saved the whole country an ordeal. (I’m grateful to Zisos in the comment below.)

Theoretically, is there reason to believe that limited social contact and economic activity slows the spread of the disease. Yes, without a doubt. But is there reason to believe that it can affect the number of people who will eventually be exposed? Much less clear. I would say, only if the disease is truly wiped out in its early stage, before it becomes widespread and engenders herd immunity.

Costs

Heaven knows we all could use a few weeks of vacation. But we wouldn’t choose to spend it indoors, apart from our friends, deprived of cultural events and social supports, church, Kiwanis and AA meetings and yoga classes and folk dancing and community theater. 

Congress has appropriated $2.3 trillion for the Covid Relief Act (CARES), but some claim the true cost is $6 trillion. On Wall St, the S&P lost $10 trillion in March. If we were willing to spend any tiny fraction of this money on a rationally-designed program of public health, the number of lives saved would be far greater than the highest estimate of COVID’s potential toll. Diabetes is an eminently preventable disease that causes more deaths every year than COVID will cause over its entire lifetime, and NIH spends $0.0002 trillion to prevent it. 

Millions of small businesses are bankrupt. Tens of millions of people are unemployed. Depression and isolation have major impacts on health, much more so if they are prolonged as some are proposing.

Politics

I am all too aware of the potential for scientific opinion to be swayed by money and political influence. In the shadow of these unimaginable economic costs, there are a few who are profiting handsomely. Why did so much of the CARES money go to banks? Why is so much of the reporting promoting a vaccine to rescue us from COVID, when many past attempts to develop a coronavirus vaccine have been halted because test animals died. Vaccines are the most profitable segment of the pharmaceutical market, and drug companies are spared by law the costs of safety tests and are indemnified from legal liability.

The thing that keeps me up at night is not fear that I might catch the disease, but fear that Constitutional liberties in America are being systematically erased. “Hate speech” laws are being used to censor inconvenient political truths. The US government is barred by the First Amendment from direct censorship, but Google and Facebook and Twitter are immune because they are private companies, and they collectively have enormous influence on what we can find out and what we can discuss. They are doing the government’s bidding, suppressing dissent.

Dear readers, this is how fascists take power. They don’t say “Ha ha ha HA…now I’ve got you where I want you.” Rather, they get everyone scared, declare an emergency, and they offer to save us all from danger.

Read Naomi and Naomi. Remember the Reichstag fire. Discover, if you have not already, the shocking history of Operation Northwoods. Read Sinclair Lewis, It Can’t Happen Here (1936). 

Eternal vigilance is the price of liberty has been attributed to Thomas Jefferson so often that he might as well have said it.

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.

Pulsed Yamanaka Factors Set Back Epigenic Age

(without going all the way back to the womb, or causing cancer)

In a column last month, I posed the question whether the methylation clocks of Horvath are drivers of aging or responses to aging. If we intervene so as to set back the clock, are we signaling the body to be younger, or are we shutting down the repair mechanisms that the body has engaged in response to the damage of aging? 

There’s a preprint from David Sinclair’s Harvard laboratory, posted on BioRxiv but not yet published, with very encouraging news for those of us who think that resetting the epigenetic (methylation) clock is a path to anti-aging. They suggest that 3 of the 4 Yamanaka factors, administered in short pulses, can set back the Horvath methylation clock without turning functioning tissues back into stem cells. The same study offers evidence to support the hypothesis that the epigenetic clock is a lethal driver of aging, rather than an adaptive response to damage.

Cellular reprogramming slows aging in mice

Sinclair opens the paper with an un-footnoted statement that aging consists in accumulated damage, as if this is uncontested and incontrovertible. He refers to the straight-line methylation changes that happen predictably and consistently with age as “epigenetic drift”, as if these changes were random. He believes that they are ‘loss of information” when these changes show every sign of being predictable and directed.

In the standard evolutionary paradigm, the mouse is evolved to live as long as possible, all other things being equal. (To be explicit: I don’t believe this; I think the mouse is evolved for a lifespan optimized to its ecology, not longer or shorter.) If you believe this standard paradigm, then why doesn’t the old mouse reset its epigenetic clock without our having to do it for him? In Sinclair’s account, the mouse has lost information, and can’t do it. But the Yamanaka factors are all in the mouse genome, and if that is all the information the mouse needs, we have to ask why the mouse needs us to send the signals.

We wondered whether mammalian cells might retain a faithful copy of epigenetic information from earlier in life, analogous to Shannon’s “observer” system in Information Theory, essentially a back-up copy of the original signal to allow for its reconstitution at the receiving end if information is lost or noise is introduced during transmission17.

It’s cute that Sinclair invokes Claude Shannon’s foundational theory from the 1930s on transmission errors and signal correction. But is it relevant? The reason that Sinclair and many others assume the information (how to be a young mouse) is lost is that they believe that evolution has motivated the mouse to stay young and keep making babies if only it could. If the information isn’t lost, doesn’t that defeat the very premise of Sinclair’s “lost information” theory of aging?

The point is that Sinclair is a superb experimentalist. He is also realistic enough to accept the overwhelming evidence that aging is an epigenetic program, and that the best way to influence it is to reset our epigenetics. But he is still mired in the old theory that denies it is possible for an aging program to evolve, so his efforts to frame his work in the context of “lost information” and “random drift” are strained to say the least.

Now that I’ve got that off my chest, let’s get on to the substance of this new finding, and the carefully-designed experiments that support these findings. He and co-authors demonstrate that mice treated with OSK (the first 3 out of the 4 Yamanaka factors OSKM) have restored capacity to regenerate damaged nerve cells, a capacity which is normally lost early in life. They go on to show that OSK isn’t directly responsible for regenerative capacity. And they demonstrate that resetting the methylation pattern on the mouse DNA is necessary for the restoration.

Specifically, they engineer mice with a cellular switch that can turn on OSK in response to a applied antibiotics. They flip the switch in the eyes only, then crush the optic nerve to see if it grows back. Normally, a mouse is able to regenerate nerves only while it is in early stages of development.

Yes, the nerves grow back if the eyes are pre-treated with pulsed OSK. And the benefit is lost in the absence of methyl transferase enzymes. This last result was part of the experiment in order to demonstrate that the mechanism for restoration involves re-programming methylation patterns on the chromosomes.

rDNA methylation age of 12-month-old RGCs FACS isolated from retinas infected for 4 weeks with -OSK or +OSK AAV together with short-hairpin DNAs with a scrambled sequence (sh-Scr) or targeted to Tet1 or Tet2 (sh-Tet1/sh-Tet2).

Questions not addressed yet

I’m inclined to interpret this article as much for what it doesn’t report as for what it does.

In the main experiment, OSK was induced just in the eyes, so it was just the eyes that were rejuvenated. But they also report a “safety” test done, in which OSK was induced in the whole body at a low level for an entire year without toxic effects. Of course, it’s nice to know that the low-dose OSK was not toxic and that cancer risk did not increase. But did the mice benefit from the whole-body treatment? Did they show any signs of rejuvenation, or of enhanced stem cell function?

There is a Horvath methylation clock for mice. Did the mice get younger according to the Horvath clock? The authors report that damaging the retinal nerve made the nerve cells older according to the methylation clock, and that the application of OSK brought the cells back. But I don’t see anywhere in the paper a measurement of the eye’s methylation age before and after the OSK treatment, independent of injury. For that matter, there is no discussion of the methylation age of the mice treated with whole-body OSK for a year. These omissions are curious. Are they suspicious? Have they tried and failed to set back the methylation clock, and they don’t want to report it? Certainly it’s a question I would ask if I were reviewing this ms. Maybe we’ll know the answer when the paper is published.

Did mice live longer after treatment with OSK? Answering this one takes time, and perhaps the Sinclair lab has mice even now that are living longer, but it will be a few years before we know. Or perhaps the treatment has failed so far to extend lifespan, and Sinclair is reluctant to report a failure.

Telomeres: The Longer the Better

Mice have much longer telomeres than we do, long enough that telomeres never get critically short in a mouse lifetime. Yet, when designer mice were engineered to have even longer telomeres (hyper-long by any standard, longer than we can account for the use of them), these mice lived longer and were healthier in every way than mice with normal-long telomeres. Lab mice usually die of cancer, and these with the longer telomeres were protected from cancer, along with every other ailment that was looked at.


First, I ask your indulgence if I harp on the obvious: this result is not consistent with the prevailing theory of telomeres. In most vertebrates, telomerase is rationed so that telomeres are allowed gradually to shorten over a lifetime, and this is explained by most evolutionary biologists and geroscientists as an anti-cancer program. According to theory, in each species, telomere length has been optimized by natural selection as a compromise between longer telomeres (allowing stem cells to last longer without senescing) and shorter telomeres (which provide a firewall against cancer, a drop-dead signal when unchecked cell growth might be life-threatening). In contrast, experiments have frequently shown that longer telomeres lead to a lower cancer rate. Blasco’s new result is a clear case. We can’t explain telomere dynamics as a cancer prevention program.

(For background on what telomeres are and how they function, I refer you to my early blogs on the subject.)

But beyond this, there remain many mysteries. This study highlights the truth that we don’t understand the mechanisms. How exactly are hyper-long telomeres working on a biochemical level? What can a hyper-long telomere do that an extra-long (regular mouse) telomere can’t do?

Known mechanisms include:

  • Senescent cells. Much of the literature has focused on the importance not of average TL but on the shortest because a few cells run out of telomere and become senescent, and they poison the rest of the body. This is called SASP, for Senescent-Associated Secretory Phenotype.
  • Telomerase as an enzyme. Telomerase is best known for its ability to elongate telomeres, but there is evidence that it has other effects as well.
  • TPE – the telomoere position effect.  This is the only one that fits. Long telomeres wrap back around the end of the DNA, actually masking expression of the genes closet to the end of the chromosome.  The Blasco study raises the possibility that we’re better off when the genes near the ends of the telomeres are silenced.

In my story, genes that have legitimate uses are turned against the body in old age. But there are no pure “aging genes” because it’s hard for such genes to evolve uphill (against individual selection). Has Blasco discovered an exception? Are these genes near the end of the chromosometrue “aging genes”? Or is it an example of evolved pleiotropy [my blog; BioRxiv preprint].

From Munos-Lorente, 2019, https://www.nature.com/articles/s41467-019-12664-x/

Context

Maria Blasco’s Madrid telomere lab has been at the forefront of this field for more than a decade. The new experiment is right on the bleeding edge of biotech and genetic manipulation, where the Blasco lab has staked out territory.

I learned that you can’t make mouse egg cells with long telomeres because the body’s process of making the egg standardizes the telomere length as it wipes clean the epigenetic markers and rewrites a starting imprint. How to get around this? Blasco grew eggs just until the third cell division (8 cells), then injected embryonic stem cells that had been grown saturated with telomerase to give them the hyper-long telomeres. Yes, this tiny embryo, just 8 cells in size, was micro-injected by hand with many stem cells, cloned to be genetically identical, so they would not fight immunologically with the cells already in the embryo. The injected cells were marked with a gene for green fluorescent protein (GFP) so descendants of the long-telomere stem cells could be identified later. The article doesn’t indicate exactly how, but the original 8 cells were induced to bow out, so that 100% of the cells in the mice that grew from these embryos had the GFP marker, and presumably, they all had the hyper-long telomeres as well. Thus, the lab made “designer” mice out of cells, every one of which had telomeres that (AFAWK) were longer than nature has any use for.

The stated inspiration for the experiment was to determine whether the hyper-long telomeres led to any detrimental effects. What they found was that hyper-long telomeres were beneficial in every way. The effect seems to be related to caloric restriction, since the mice are noticeably leaner and their insulin sensitivity remains high at advanced ages when mice usually become insulin resistant. Perhaps independent of these changes, the hyper-long mice had less DNA damage with age and more efficient mitochondrial metabolism.

Telomeres are full of surprises, and this may signal a new telomere mechanism, probably epigenetic, that is undescribed previously. But if it is to be described with known biochemistry, the only candidate is TPE, the telomere position effect. Long telomeres fold back on the end of the chromosome, masking some genes that are located near the end. It is already known that unmasking those genes when telomeres become short has pro-aging effects. But the new result involves telomeres that are (presumably) longer than anything that is found in nature or in the mouse evolutionary history. It follows that the hyper-long telomeres are folding back so as to mask genes that just happen to be near (but not to near) the chromosome end. In this picture, these genes just happen to be pro-obesity, or insulin-blocking. The effect is not evolved, but just a chance occurrence. I don’t like such explanations from chance, so I’d bet on a new telomere mechanism that is yet to be characterized.

 

Related study from the Blasco Lab

Another study (last summer) from the Blasco lab looked across species for relationships between telomere dynamics and species life span. This follows on the work of Seluanov and Gorbunova a few years ago. The previous work concluded that telomere length is most closely related to the body mass but not lifespan across rodent species. The authors tried to relate this to Peto’s Paradox, which is the observation that large, long-lived animals ought to have much higher cancer rates than observed, assuming that cancer results from a random transformation event in a single cell. In the new work, Blasco finds the closest correlation between lifespan and the rate of telomere loss.

We observed that mean telomere length at birth does not correlate with species life span since many short-lived species had very long telomeres, and longlived species had very short telomeres.

In short-lived species, telomere erosion happens much more rapidly: 7,000 base pairs per year are lost in mice, compared with less than 100 in humans.

In the old story [as I have reported it], telomeres shorten over a lifetime because stem cells lose a little telomere length with each cell replication. But this huge difference in telomere attrition rates can’t be accounted for in this way. Stem cells in mice don’t replicate 100 times faster than in humans. So something else is going on. Probably, there is partial expression of telomerase in a way that is programmed under control of natural selection. Telomere shortening with age has evolved in a way that contributes to aging via TPE. But (probably, by my account) telomere shortening is not the principal means of programmed aging, because the correlation between telomere length and age is too weak. Mike Fossel continues to promote the idea that relative but not absolute telomere length is a good indicator, and indeed a driver of aging. That sounds like it accords in the abstract with the new results, but details remain elusive.

The Bottom Line

It’s clear that telomere shortening plays a role in aging, though not a dominant role. It’s clear that telomere shortening is completely under the body’s control, therefore an evolved adaptation. Beyond this, the subject seems complicated, and there is good evidence that there are mechanisms involved beyond what we know about.

At a given age, telomere length in humans does not correlate with health risks. On this basis, I have argued that various methylation clocks are far better measures of biological age, and perhaps the GrimAge clock is best.

Interview with Josh Mitteldorf

Transcript of interview 10/14/19.
IP = Ira Pastor, Health and Longevity Ambassador for IdeaXme, founder of BioQuark JJM = Josh Mitteldorf, author of Cracking the Aging Code, and the AgingMatters ScienceBlog


IP: We’ve been spending time on hierarchical levels of the aging process: the genome, the microbiome, systems biology. There is an extensive catalog of hallmarks of aging. This lengthy list includes inflammation, oxidation, microbial burden, somatic mutations, epigenetic modifications, stem cell exhaustion, senescent cell accumulation, damaged mitochondria, telomere erosion, and on and on. All very interesting topics, and good topics for intervention. But we have not found a unified picture of why we age. We have not touched the paradoxes that challenge the prevailing theories. Why do some damaged organisms live a long time? Why do pristine animals drop dead after reproduction in some species? Why do some of these hallmarks of aging appear, sometimes, in the earliest stages of life, when we’re first developing? So we have an incomplete picture of aging. Joining us today is Dr Josh Mitteldorf. Dr Mitteldorf earned a PhD in astrophysics here in Philadelphia at UPenn, and spent a decade or so in that field, “wandering in the plasma physics of extragalactic radio sources.” (This is after earlier careers working in optical design and energy conservation.) Then Dr Mitteldorf made a move into evolutionary biology, where he currently studies evolutionary biology of aging using computer simulations. He spent a lot of times correcting what he feels are errors in the foundations of evolutionary theory. Maybe the theory has focused too much on selfish genes, as opposed to the ecological context that determines a relative notion of “fitness”. In his paradigms, this has a lot to do with why we age in the first place, and, by extension, what we can do about it with medical interventions. Dr Mitteldorf has lectured extensively at Harvard, Berkeley, MIT, her in Philly at LaSalle and Temple Universities. He is the author of two books:

Cracking the Aging Code: The new science of growing old and what it means for staying young.
Aging is a Group-Selected Adaptation: Theory, evidence and medical implications

He is also responsible for the Aging Matters ScienceBlog, and he is organizing a new study called DataBETA, in cooperation with the UCLA lab of Steve Horvath, evaluating combinations of anti-aging supplements and interventions, looking for possible synergies which so many studies focusing on single interventions may have missed.

JJM: Wow! You’ve said it all. I think we’re done.

IP: We can do a lot more. Can you introduce yourself, your background, how you got in astrophysics, then evolutionary biology, and where you find yourself today in terms of these innovative theories of aging.

JJM: In 25 words or less?
I grew up in New York and New Jersey. I was a wunderkind and went to Harvard early, and then I just dropped back, became a hippy for awhile, went to Taiwan, learned to speak Chinese, started a skills coop, became a yoga teacher, wandered back into science a few years later with a commitment, not just to solving equations but trying to figure out how the world works. My generation grew up with a disdain for the Military-Industrial Complex and all things capitalist. I have just enough money in the family that I don’t have to depend on a salary from industry or academia, and I have the privilege to investigate what I want to investigate. If I have anything to offer this field, it’s that I have a broad perspective and sometimes I can tie things together.

IP: I find your background in astrophysics fascinating. I come from the pharmaceutical industry, a very siloed place. One of my critiques of anti-aging biotech is the belief that if you’re not a specialist in cell biology you can’t contribute to the discussion. On this show, we’ve talked to people about the very small (quantum biology) to the very large (chronobiology). Before we get into your theories, talk about what it’s like for you as an astrophysicist coming into the field of aging biology as an outsider.

JJM: Not so much the outsider. Actually, the field was already dominated by mathematicians when I came aboard. Evolutionary biology during the first half of the 20th Century was two different fields. There were the mathematicians who knew precious little biology. These were brilliant people, including R.A. Fisher who invented the whole idea of correlation coefficients, analysis of variance–the foundations of how we evaluate significance in all fields of science today. But Fisher was also a passionate eugenicist. He felt the world was going to hell in a handbasket because the poor were having too many children. The rich people, who are intellectually superior to the poor, were not reproducing themselves, and he developed the whole theory now called “the selfish gene” based on fitness as a property of individual genes. [These ideas are uber-politically incorrect at present, but in the early 20th Century, before the Third Reich, they were mainstream among British intellectuals.] He recast Darwinian evolution as a 20th Century theory, making it quantitative, he modeled exclusively the competition which was part of Darwin’s thinking, and de-emphasized cooperation, which Darwin was very aware of. Darwin was a naturalist, who traveled the world describing different life forms and their relations.

So, back to the 20th Century, we have the naturalists, continuing in Darwin’s tradition: “This is what we see, and this is the explanation in terms of natural selection.” These people were observers of nature, using qualitative reasoning. On the other side, we had the mathematicians, who were developing selfish gene theory as a mathematical abstraction. This came to a head in 1964, with a book by George Williams, who had training in biology, but also deep respect for the mathematicians. He said, “You observational biologists, you naturalists will have to get your act together. You have not been rigorous in your idea of what fitness is and how evolution works. You have to embrace this mathematical theory and use it in every evolutionary explanation. Along with John Maynard Smith, he engineered a hostile takeover of the naturalists by the mathematicians, and the naturalists didn’t have the mathematical chops to challenge them. The idea of the selfish gene became dominant; cooperation was swept aside. “We know by theory that the only kind of cooperation that can possibly evolve is in lineages that share genes. For example, I share half my genes with my brother. I share one eight of my genes with first cousins. There’s a quip attributed to the mid-century theorist J.B.S. Haldane, asked whether he would ever sacrifice his own life for his brother’s sake. He replied, “No, but I would lay down my life for 2 brothers or 8 cousins.” This idea of “inclusive fitness” became the narrow lens through which all examples of cooperation in nature had to be explained.

Back to your question, What was it like for me to come into evolutionary biology as an outsider from mathematical physics? Well, the field was already dominated by mathematicians. I saw my role as taking the field back for the observational biologists. In science, observation is the highest authority whenever there is conflict with theory. I hoped that I might give the observational biologists the rigorous mathematics they needed to take back the field from theorists who had imposed a paradigm that didn’t fit the facts.

What facts in particular? If you think just about selfish genes, then what is aging? Aging has to be a mistake. Aging only detracts from individual fitness, and you’re not allowed to think about the fitness of the community because there’s no such thing as cooperation. Well, over the long haul, evolution doesn’t make mistakes, so there must be constraints, physical limitations or parts of fitness space that were unavailable. There were tradeoffs imposed, and therefore evolution is not able to make animals and plants that live and grow stronger for an indefinite period of time. This “wearing out” that we observe is an inevitable consequence of physical constraints that are imposed on evolution.

When I first learned this in the mid-1990s, I thought, “this has got to be wrong.” There is so much cooperation in nature that is not between close relatives. And not only this, aging has a deep heritage. There are genes that control aging in us that have been around for a billion years. They’re the same genes that control aging in worms and in yeast cells, separated from us by half a billion and a full billion years, respectively, since our last common ancestor. So maybe evolution has some constraints, but what constraints could conceivably apply equally to yeast cells and mammals? Any gene that’s been kept around for a billion years has to have a purpose. Of course, there are many genes that we share with these primitive eukaryotes, and these genes program the basics of cell chemistry, energy metabolism, and protein synthesis. These genes control functions that are so important that evolution does not want to mess with them. Well, genes for aging are in this same category. Evidently, the genes for aging must have a purpose that is just as central, just as important as genes for the metabolic machinery of the eukaryotic cell.

IP: When you talk about a billion years, I think of deep lineages with evolving purpose. For example, the amoeba dictyostelium, pond scum has genes that are used to swim around and hunt for food, but when food is scarce, these same genes are used to organize the cells into multicellular structures. We find that a billion years later, these same genes lead to tumor formation and metastasis. So there are these fascinating connections across time. Take us a little further now into your book. What are we missing when we look at aging from a cell perspective and not considering the organism or the ecological context?

JJM : Let me add one more hint that brought me into this field, the thing that lit the lightbulb in my head. It was 1996, and there was a cover story in Scientific American by Richard Weindruch about caloric restriction. We all know today that animals that eat less live longer, pretty much across the animal kingdom. But this was new to me at the time, and it got me thinking, what can an individual do when it’s starved that it couldn’t do when it was well-nourished? We’re not just talking about 10% less food. In a cohort where some of the animals are dropping dead from starvation, the ones that survive are living almost twice as long. What can an animal do in extremis of caloric deprivation that it couldn’t do when fully fed? This led me at the time to think that lifespan must be a choice the metabolism is making. The individual is programmed to live a shorter time when fully fed so that it can live a longer time when the community needs them most. The fully-fed animals are programmed by evolution for lower individual fitness. If this is true for so many species, there must be a deep and quite general explanation.

An aside here — I learned later that one well-accepted way to get around this conclusion is to posit that there’s an energy tradeoff, that food energy can be used either for longevity or for reproduction. When there’s plenty of energy, it all goes into reproduction and this somehow causes a shortage of the portion for repair. Then, when energy is in short supply–this makes no sense, but it’s part of the canon of what’s called Disposable theory–when food energy is severely restricted, there’s actually more of it available for keeping the body in repair long-term. I wrote a rebuttal at the time, pointing out some of the cheats that the author was using to reach this paradoxical result, which he needed for his theory. For one thing, his model only worked for pregnant females, not for females kept in lab conditions in cages with other females, and certainly not for males, which can maintain their fertility when calorically restricted.

This one example was enough to make me question the Fisher model. Fitness is not just about getting more of your genes into the next generation. It’s also about sustainability, about community, about ecological homeostasis. This has been my major contribution to the field. I callit the Demographic Theory of Aging. The reason there is aging is so we don’t all die at once. Imagine a world in which we did not suffer aging, in which we got bigger and stronger and less likely to die with each passing year. Well, we wouldn’t live forever, of course. Something would kill us eventually. The population would grow so high that our food sources would be pushed to extinction. We would die in a famine. Or maybe our population would grow so dense and so homogeneous that conditions are ripe for an epidemic to come in and decimate the population. Aging evolved so that we die continuously over time, rather than everyone dying at once. Without aging, populations would cycle severely, with exponential rise and sudden population crashes. Ecology can’t sustain this. It’s terribly unstable. Maybe the population can recover once or twice from such a crash, but we’re pushing our luck, and one such crash will lead to extinction. Well, natural selection is highly motivated to avoid extinction–isn’t this the core of Darwin’s theory? We die individually of old age, one at a time, so that we don’t all die at once.

This was the evolutionary explanation for aging that I came up with in the late 1990s. It took a long time to get it into print. It’s very gratifying for me to see, 20 years later, that much of the medical community, the research community has embraced the idea that aging is programmed. Even some people in the evolutionary community recognize this. Aging is on purpose. It’s not something that “happens to us”. It’s internally programmed. And fitness is not just about individuals, but also about communities.

 

IP : Moving from your book to your blog, where you discuss different interventions– pharmacological, nutritional, lifestyle–can you tell us what your targets are. At the same time, you’ve created the DataBETA project, a new kind of clinical trial. You’re working with Steve Horvath’s group which developed this epigenetic clock for aging. You’re measuring combinations, and not just individual treatments. Regulators have traditionally been down on this. If you want to develop a combination treatment A, B, and C, you first have to prove that A and B and C are individually safe and effective. Only then can you put them together. Perhaps this is beginning to change. Our FDA and the PMDA in Japan are starting to recognize the potential of combined treatments. Can you talk about going beyond the pharmacological model of one treatment at a time?

JJM : I’ve been an advocate for the idea that we need to test medicines and anti-aging interventions in combinations, not just one-at-a-time. That the interactions among these treatments are just as important as the individual effects. We’re not looking for the magic bullet but maybe the “magic shotgun”. I think in terms of the Yamanaka factors. What a genius it took to find this combination of four proteins that together are able to turn a fully-differentiated cell back into a pluripotent stem cell. No one of these has that effect. No three of them together will do the job. How did he discover this synergistic combination of four factors? My hope is that anti-aging research will also discover such combinations that have synergies.

Before we get into that, I want to go back and fill in the gaps: How did I get from an evolutionary theory to an attitude toward medical research? The big message from medicine in the 20th Century is that the body has robust healing power, and if we can harness that, to turn on the latent healing, remove obstacles so the body can do what it is designed to do–that is the essence of good medicine. Restoring the body’s natural healing. That’s taken us far, and it’s the right paradigm for infectious disease, for trauma, for everything that afflicts us when we’re young. But it’s not going to work for the diseases of old age. We’ve focused on seeing how the body has been derailed and helping it get back on track. But with aging, the body is already on track–it’s on track to destroy itself. This is why natural medicine, holistic medicine if you will, will not work for the diseases of old age. Once you realize that the body is programmed for a finite lifespan, for deliberate self-destruction, it changes the picture. Inflammation is a good example. Inflammation is a protective mechanism. That’s its original purpose. But late in life, inflammation turns on the body and destroys perfectly good cells. Autoimmunity is another example. The immune system is essential for our lives, but as we get older, autoimmunity becomes a problem. Arthritis is an autoimmune disease. We’ve learned that dementia and Parkinson’s are also deeply connected to autoimmunity. Apoptosis is a third example, programmed cell death. Again, we need it. When a cell is in the wrong place at the wrong time or when it is diseased, the cell is programmed to eliminate itself. But as we get older, perfectly good cells, nerve and muscle cells are committing suicide. These are the mechanisms of programmed death that collectively constitute aging. Getting the body back on track is the medicine we’re used to. It’s natural medicine, the medicine of the 20th Century, and it works great when we’re young. But for the diseases of old age, we will need to interfere with the program. We will want to thwart the body’s self-destruction. I’m knocking on doors, shaking people and telling them that this is what we need to realize. In the anti-aging community today, there is a deep divide between those who look at aging as damage that accumulates over time despite the body’s best efforts to protect itself. Our job, then, is to assess the damage at the cellular level and come up with ways to repair these damaged cells. The other half of the community–my half–says that aging is controlled at a systemic level by signal molecules in the blood. It’s true that cells suffer damage, but they’re damaged because they’re getting signals that tell the cells to shut off their repair mechanisms. Of course, we could figure out how to repair the damage. But this may take many decades of research to figure out all the different things that need repair and how to fix them. Once we realize that all this damage is happening under the regulation of signal molecules, a shortcut suggests itself. If we can understand the signaling system well enough to intervene there, we can tell the body in its own biochemical language to repair itself. Our job is to rebalance the signal molecules at their youthful state so the body thinks it’s young and takes up these repairs is it did so well in its prime. This is the royal road to anti-aging medicine, a great shortcut.

IP : I’m a big fan of the history of regenerative biology. There’s a fascinating body of work from the 1940s-60s, when they were transplanting cells from old bodies to young, taking off a right hand and sewing it on the left. We learned that putting young cells into an older environment doesn’t usually show any benefit. But when the old cells are exposed to a young environment, they move toward being youjng again. This concept of the higher-level signals controlling things at level of whole tissues is going to be extremely important. I completely agree with you on that. Talk a little about DataBETA. What stage is it at, and how can people get involved.

JJM : DataBETA is the Database for Epigenetic Evaluation of Treatments for Aging. We have a natural experiment out there. Millions of people trying to extend their life expectancy using a variety of strategies–medications, diets, exercise, in different combinations. If this were ten years ago, we’d ask, How can we know what is working? We’ll have to wait decades for enough people to die that we can count them and know which groups are succeeding in lowering their mortality risk. All that is changed with the Horvath clock. The Horvath clock looks at gene expression, one particular mechanism of gene expression called methylation. It may not be the most important epigenetic mechanism, but is the one we have the best handle on. We know how to assess methylation, to map it quickly and cheaply. So Horvath developed a clock based on methylation patterns on DNA that change consistently with age. If you look at certain methylation markers, you can tell within a couple of years how old a person is. In some cases, the methylation clock turns out to be a better indication of how long a person is going to live than the chronological age–which was the original calibration for the methylation clock. You can make a strong case that these methylation clocks are a true measure of your body’s metabolic age, and if you succeed in setting back the methylation clock, it is a sign that you’ve actually made the body younger. If you slow the progression of the methylation markers, you’ve probably slowed down the aging process itself. This is an opportunity for a revolution in anti-aging research. At last we can know what works without having to wait decades, but maybe just a year or two to see changes in people’s epigenetic markers. The idea for DataBETA is to recruit 5,000 people with 5,000 different strategies, recruiting for great diversity. Measure methylation ages at the beginning, middle, and end of a two-year period. See which are aging faster, which are aging slower. Is there a sub-population that is aging backward, getting younger over the course of the study? Look for the people who are doing best, and then look for commonalities. What combination of strategies characterize the people who are most successful at slowing or turning back the clock? The easy part is going to be collecting data, and the hard part will be making sense of it. Maybe there will be a signal buried in the noise, and my hope is that we will be able to use statistical methods to disentangle all these interacting effects. If we can find a common theme among the people who are most successful in slowing or reversing aging, then we’ll have an idea what combination of strategies is likely to work.

IP : I don’t know how many biohackers and how many amateurs are out there trying to find what works, but it seems like an untapped population to gather data from.

JJM : News from just the last week: For several months, I’ve been looking for university partners to actually run the study. I need people with experience running a trial. I need an Institutional Review Board to make this kosher. Just last week I was up at McGill (in Montreal) and met Moshe Szyf, who was a pioneer in studying methylation markers on DNA, starting 30 years ago. He is a world-class expert in the statistics of methylation patterns. He loved my project, and he wants to take it under his wing at McGill. So I now have the partner I need to move forward. We will need another couple of months to get necessary permissions and to set up a secure online database, but I’m hoping that by the end of the year we will begin accepting people into the program.

IP : Excellent! You’ve got to have good partners and the right connections to get the job done in this increasingly connected world, and it sounds like you’re doing it.

I read your bio, and you’re involved in so many other things in the Philadelphia area where we both live. I mentioned that you teach yoga, you’re actively involved in meditation, you are an amateur musician on piano and French horn with Olney Symphony, you’re an environmentalist, you were president of the Coalition for a Tobacco-free Pennsylvania. Many other things that are extremely important in aging include our mental health, the environment around us. Talk a little about the importance of all these things in your personal anti-aging protocol.

JJM : There are so many people who know one aspect of me. They think of me as the neighborhood yoga teacher, where I’ve been teaching one class a week for 40 years. They don’t know that I’m an astrophysicist. There are people who know me from the amateur music community who have no idea of my work in evolution. I’m known in the election integrity community for using statistics to root out election theft. I’m grateful that you’ve looked up all these other parts of me. It’s a privilege to live the way I live. I don’t have a lot of money, but the thing it’s most important for me to buy with what I have is freedom to pursue the activities and ideas and the ways of giving back that mean the most to me. I live a life of service to the community where I live, service to the scientific community, service to a political community as well.

One activity you didn’t mention is that I am an editor at OpEdNews, which is a people’s forum on current affairs, debunking the lies that are routinely fed to us by the news media we trust most–the lies of the New York Times and CNN and National Public Radio. I try to call them out, and I rely on a broad knowledge of science to counter the political propaganda, not just of the Republicans but the Democrats, too. It’s a great privilege to live the way that I live, to be independent of a boss or of an institution. Sometimes people pay me for what I do, but often I’m doing it because it’s what I’m interested in, what I believe in. I would hope that we might all live this way. But I recognize that the economy is being controlled so that very few people have that option today. People have to think about paying the rent and keeping food on the table, and they have little energy for anything else. It doesn’t have to be that way.

IP : I agree with you in a major way.

JJM : The other half of what you asked, what does this have to do with aging? When you think about anti-aging interventions, you imagine a pill or a medical treatment. Or maybe you think, if I really starve myself–if I’m willing to be hungry all the time, I can live a long time. Twenty years ago, the book came out The 120-Year Diet, which was about caloric restriction in humans. We now know that this works much better in short-lived species than in long-lived humans. We can double the worm’s lifespan with CR, and the mouse might live 40% longer. But in humans, we’ll be happy with an extra 5 years–maybe 10 years if you compare the strictest caloric restriction to the obesity brought on by the Standard American Diet. We’re not gong to live 120 years just by starving ourselves? What is the most powerful thing we can do to extend our life expectancies? It’s to live in a way that’s socially connected. To have loving relationships with our families. To be engaged in our communities. To have service relationships, and to be needed. To be a leader. People who have these things in their lives can expect to live 10 to 15 extra years, compared to the depressed and the lonely who are probably the predominant majority in this country. This is the largest increment in life expectancy that we know how to control, far larger than anything you can get from pills. And it’s good news because it says that the most fulfilling way to live is also the healthiest in the long haul.

IP : That’s an extremely wonderful message, especially in 2019 when, as connected as we may all be electronically, we experience a lot of distance from one another in a human sense. Josh, one final question that I like to ask my guests: Who is the person in history you most would have liked to have met. If you could ride my hypothetical time machine and visit for awhile, who would you sit down with? An astrophysicist? An evolutionary biologist? Who would be most rewarding for you to meet?

JJM : I had a bunch of people over just last Friday night reading the Tao Te Ching of Lao Tzu. This is the bible of Daoism, and I’ve been absorbing the message of the master Lao Tzu, about whom very little is known, where he lived and even if he was one person or a composite of several. The book dates from 2500 years ago, around the time of Confucius and Socrates and Zoroaster and the Buddha. This was an amazing age when all over the world, there was a simultaneous flourishing of wisdom among communities that had no contact with each other. The one that speaks to me the best is Lao Tzu. Tao Te Ching means literally, Moral Text, and you think, What are the rules for good living? What are the 10 Commandments of Daoism? But that’s not what the book is about. It say, Yes, there’s good and there’s evil in the world, but it’s not your place to take sides. Don’t try to fight for the good to defeat the evil. There’s no need for that. The Dao of the world is taking care of that. The Tao Te Ching counsels you to become a natural person, in touch with your instincts, with the part of you that is the Dao. Then you don’t worry about what to do, don’t struggle with decisions. You don’t look back and lament, “If I had only done such and so.”  But if you’re motivated in each moment by connection with the Dao that leads you into harmony with the way the world is unfolding. How different this is from a life of trying to figure out the difference between right and wrong.

When I was growing up, I was the smartest kid to come out of my high school in a generation. I thought, “I am my brain.” I had no idea there was anything valuable in me besides the extraordinary brain I’ve been given. It’s been a lifelong lesson for me that the brain is a great servant but a poor master. If I got to meet one person from the past, it would be Lao Tzu.

IP : Josh, it’s been a great pleasure to hear your story and the way your mind works. It’s completely fascinating. You truly bring together a convergent expertise in an area that requires synergy and combinatorial thinking.

Methylation Clocks and True Biological Age

The good news is that the DataBETA project has found a home.  After several months of seeking a university partner, I am thrilled to be working with Moshe Szyf’s lab at McGill School of Medicine.  DataBETA is a broad survey of things people do to try to extend life expectancy, combined with evaluation of these strategies (and their interactions!) using the latest epigenetic clocks.  Szyf was a true pioneer of epigenetic science, back in an era when epigenetics was not yet on any of our radar screens. No one has more experience extracting information from methylation data.


DataBETA is just the kind of study that is newly possible, now that methylation clocks have come of age. Studies of anti-aging interventions had been impractical in the past, because as long as the study depends on people dying of old age, it is going to take decades and cost $ tens of millions. Using methylation clocks to evaluate biological age shortcuts that process, potentially slashing the time by a factor of 10 and the cost by a factor of 100.  But it depends critically on the assumption that the methylation clocks remain true predictors of disease and death when unnatural interventions are imposed. Is methylation an indicator, a passive marker of age? Or do changing methylation patterns cause aging?

Two types of methylation changes with age

Everyone agrees that methylation changes with age are the most accurate measure we have, by far, of a person’s chronological age—and beyond this, the GrimAge clock and PhenoAge clock are actually better indications of a person’s life expectancy and future morbidity than his chronological age.

Everyone agrees that methylation is a program under the body’s control. Epigenetic signals control gene expression, and gene expression is central to every aspect of the body’s metabolism, every stage of life history. Sure, there is a loss of focus in methylation patterns with age, sometimes called “epigenetic drift”.  But there is also clearly directed change, and it is on the directed changes that methylation clocks are based.

But there are two interpretations of what this means. (1) There is the theory that aging is fundamentally an epigenetic program. Senescence and death proceed on an evolutionarily-determined time schedule, just as growth and development unfold via epigenetic programming at an earlier stage in life. Several prominent articles were written even before the first Horvath clock proposing this ideas [ref, ref], and I have been a proponent of this view from early on [ref]. If you think this way, then methylation changes are a root cause of aging, and restoring the body to a younger epigenetic state is likely to make the body younger.

(2) The other view, based on an evolutionary paradigm of purely individual selection, denies that programmed self-destruciton is a biological possibility. Since there is a program in late-life epigenetic changes, it must be a response and not a cause of aging. Aging is damage to the body at the molecular and cellular level. In response to this threat, the body is ramping up its repair and defense mechanisms, and this accounts for consistency of the methylation clock. In this view, setting back the methylation pattern to a younger state would be counter-productive. To do so is to shut off the body’s repair mechanisms and to shorten life expectancy.

So, if you believe (1) then setting back the bodys methylation clock leads to longer life, but if you believe (2) then setting back the bodys methylation clock leads to shorter life.

I think there is good reason to support the first interpretation (1). Epigenetics is fundamentally about gene expression. If you drill down to specific changes in gene expression with age, you find that glutathione, CoQ10=ubiquinone, SOD and other antioxidant defenses are actually dialed down in late life when we need them more. You find that inflammatory cytokines like NFκB are ramped up, worsening the chronic inflammation that is our prominent enemy with age.  You find that protective hormones like pregnenolone are shut off, while damaging hormones like LH and FSH are sky high in women when, past menopause, they have no use for them. There is a method in this madness, and the method appears to be self-destruction.

Until this year, I have been very comfortable with this argument, and comfortable promoting the DataBETA study, which is founded in the premise that setting back the methylation clock is our best indicator of enhanced life expectancy. The thing that made me start to question was the story of Lu and Horvath’s GrimAge clock, which I blogged about back in March. 

The GrimAge clock is the best predictor of mortality and morbidity currently available, and it was built not directly on a purely statistical analysis of direct associations with m&m, but based on indirect associations with such things as inflammatory markers and smoking history. (This is a really interesting story, and I suggest you go back and read the March entry if you have not already. The story has been told in this way nowhere else.)

(Please be patient, I’m getting to the point.) Years of smoking leave an imprint on the body’s methylation patterns, and this imprint (but not the smoking history itself) is part of the GrimAge clock. I asked myself, How does smoking shorten life expectancy? I have always assumed that smoking damages the lungs, damages the arteries, damages the body’s chemistry. Smoking shortens lifespan not through instructions imprinted in the epigenetic program, but quite directly through damaging the body’s tissues. Therefore, the epigenetic shadow of smoker-years that contributes to the GrimAge clock is not likely to be programmed aging of type (1), but rather programmed protection, type (2).

For me, this realization marked a crisis. I have begun to worry that setting back the methylation clock does not always contribute positively to life expectancy. The canonical example is that if we erased the body’s protective response to the damage incurred by smoking, we would not expect the smoker to live longer.

The bottom line

I now believe there are two types of methylation changes with age. I remain convinced that type (1) predominates, and that setting these markers to a younger state is a healthy thing to do, and that it offers genuine rejuvenation. But there are also some type (2) changes with age—how common they are, I do not know—and we want to be careful not to set these back to a younger, less protected state. 

The methylation clocks promise a new era in medical research on aging, an era in which we can know what works without waiting decades to detect mortality differences between test and control groups. But it is only type (1) methylation changes that can be used in this way. So it is an urgent research priority to distinguish between these two types of directed changes.

This is a difficult problem, because the obvious research method would be to follow many people with many different methylation patterns for many decades—exactly the slow and costly process that the methylation clocks were going to help us avoid. My first hunch is that we might find a shortcut experimenting with cell cultures. Using CRISPR, we can induce methylation changes one-at-a-time in cell lines and then assess changes in the transcriptome, and with known metabolic chemistry, make an educated guess whether these changes are likely to be beneficial or the opposite. As stated, this probably will not work because methylation on CpGs tends to work not via individual sites but on islands that are typically ~1,000 base pairs in length. Perhaps changes in the transcriptome can be detected when we intervene to methylate or demethylate an entire CpG island.

Perhaps there is a better way. I invite suggestions from people who know more biology than I know for experimental ways to distinguish type (1) from type (2) methylation changes with age.

Scaling the Alzheimer’s Cure

This edition of Aging Matters is stolen from Rhonda Patrick’s interview of Dale Bredesen. That hour is so packed with actionable information and theoretical background that I found myself going through it slowly to understand and digest it. The result was an appreciation for the breadth of vision embodied in Bredesen’s comprehensive program to combat Alzheimer’s Disease, and also discovery of some gaps in which the story appears incoherent.

For my own health and to learn more, I’ve personally signed up for the RECODE program as a patient. After the video analysis I talk about my experience.


The RECODE program in a nutshell
from Deborah Gordon video

  1. Diet
  2. Lifestyle
  3. Hormone re-balancing
  4. Supplements
  1. Diet: Low grains, low glycemic, high fats, quasi-ketogenic, anti-inflammatory. Intermittent fasting (e.g., 13 hours overnight fast every day). Eggs are good. Cilanthro is detoxifying. Ketones are good for the brain. Medium-chain triglycerides (MCTs) are a good shortcut to ketogenesis.
  2. Lifestyle: Exercise 30-60 min each day, the more the better. Weights and interval training are particularly good. Sleep 8 hours each night. Challenge the mind with active learning and problem-solving.
  3. Hormones: Estradiol, testosterone (DHEA), Pregnenolone, Thyroid hormones, Progesterone (but not progestins)
  4. Anti-diabetic supplements: Magnesium, Chromium, Berberine, Vinegar, Cinnamon
    Nootropic supplements: Ashwagandha, Gotu kola, Curcumin, Bacopa, NR, Mg Threonate
    Lion’s Mane, ALCAR=Carnitine, Citicoline, DHA=Omega 3, PQQ,

Blood targets:

  • Homocysteine <7 (!)
  • Vit B12 >500
  • CRP <1
  • HbA1C <5.5
  • Insulin < 5
  • Vit D >50, up to 100
  • Zn/Cu >1 and Zn >100

Also from the Deborah Gordon video: The APOε4 allele is the biggest genetic risk factor for AD. It was the ancestral form of the gene, from early hominid history. In European populations, only 15% of genes are ε4, but there are tribes in Nigeria where the APOε4 gene still predominates and, paradoxically, they have low rates of AD, even lower than Nigerians who don’t have the APOε4 allele. (Maybe it’s something they ate.)

A simple blood test or 23andMe can tell you if you have the APOε4 risk factor, but many people don’t want to know. Bredesen’s program offers differential treatment for APOε4 patients, and can greatly reduce the excess risk if started early.


Notes from Rhonda Patrick’s interview with Dale Bredesen

AD is the 3rd leading cause of death in America, after cardiovascular disease and cancer, and it is rising as the population ages and as better treatments become available for the other two. 5.2 million Americans have been diagnosed with AD, and a substantial fraction remains undiagnosed.

Diagnostic markers of AD are tau tangles and amyloid-β placques in the brain. Amyloid-β is a protein byproduct that aggregates into clumps about the size of a nerve cell. Tau is another protein that clogs microtubules, preventing chemical transmissions. Curiously, most AD patients have these markers, but some people have the markers without dementia symptoms, and others have dementia without the markers.

Plaques are pink, Tau tangles black

Spinal fluid taps can be assayed for presence of Amyloid-β, and this is the most sensitive test we have for AD, with an accuracy of 90%

A-β is both a neurotoxin and a neuro-protector, in different contexts. So the theory is that A-β is produced by the brain in response to insults. A-β can neutralize toxic metals and can kill invading microbes. Some people’s brains produce A-β and it successfully protects them, while others are producing A-β though their brains are overwhelmed. One difference seems to be inflammation. Inflammation in combination with A-β creates a strong dementia risk.

Sirtuins and NFκB are mutually inhibitory. The body flips between a pro-inflammatory state (NFκB) and anti-inflammatory (sirtuins), and age almost always tips the balance toward more inflammation (NFκB).

Microglia are environmental brain cells, not neurons, but important to brain function. They are activated in two forms, called M1 and M2

There’s an ideal ratio of M1:M2 = inflammation:resolution = 2.5 

The amount of A-β in the brain comes from a balance between A-β production during glial metabolism and A-β elimination through phagocytosis. That is to say, A-β is constantly being consumed and eliminated by a class of white blood cells. A blood test by George Bernard has shown that almost everyone diagnosed with AD is not eliminating enough A-β via phagocytosis.

Maresins and resolvins are members of a group of cell signaling molecules called SPMs or “specialized pro-resolving mediators.” Many SPMs are metabolites of omega-3 fatty acids and have been proposed to be responsible for the anti-inflammatory benefits of omega-3 in the diet. Patrick says that in her own research she has found that people who are APOε4 positive benefit from fish in the diet, but not from omega-3 supplements. Bredesen speculates that this might be true generally, and that there are anti-oxidants in fish flesh that we haven’t yet catalogued.

How RECODE Works

Bredesen has identified 36 risk factors for AD, and different patients suffer from different combinations of these. The factors break down into just six categories:

Type 1 AD is primarily caused by Inflammation.

The inflammation may come from a variety of causes, for example

  • leaky gut (which also contributes to arthritis)
  • P gingivalis (a periodontal infection that can spread to the brain)
  • Borrelia burgdorferi is the Lyme bacillus
  • Mold and other fungi in the environment

Type 2 AD is atrophic

Some of the nutrients or hormones necessary for nerve growth and synaptic connection are missing. Examples include

  • Estradiol
  • Vitamin D
  • Progesterone
  • Testosterone
  • Pregnenolone
  • Thyroid hormones

In a healthy brain, there is a balance between learning and forgetting, of growing new synapses and recycling old ones. We can think of Type 1 as too much destruction of synapses, and Type 2 as failure to grow new synapses.

Type 1.5 AD is glycotoxicity=too much sugar

Diabetes has two components: depressed response to insulin (insulin resistance) and excess sugar in the blood (because the insulin signal is not being heeded). The excess blood sugar causes Type 1 symptoms, while the insulin resistance causes Type 2 symptoms. There is both too little creation of new neural connections and also too much loss of existing neural connections. Type 1.5 really means a combination of Type 1 and Type 2, and it is associated with metabolic syndrome or diabetes.

Edward Goetzl of UCSF has shown that AD is characterized by insulin resistance in brain neurons even when the rest of the body is not insulin resistant.

Sugars can bind to proteins, gumming them up, creating Advanced Glycation Endproducts, or AGEs. When this happens because of sugar levels that are too high, it’s called glycotoxicity. Hemoglobin A1c is glycated hemoglobin, and it is commonly measured blood tests to assess the extent to which glycation is a problem more generally.

Note: Symptoms for all Types 1, 1.5, and 2 are memory loss, particularly short-term memory.

If your fasting insulin is >4.5 or your A1c >5.5 or your fasting glucose >93, you have insulin resistance, which is the most common, most important, and most treatable condition leading to AD.

“Ketoflex 12/3” is a mnemonic for Bredesen’s basic diet program: (1) mild ketosis, ongoing (2) flexible vegetarian diet, treating meat as a condiment (3) 12 hours of fasting every night, beginning 3 hours before bedtime.

Vegetarian is fine. If adding meat, it should be grass-fed beef or free-range fowl. If fish, the best fish are Salmon, Mackerel, Anchovies, Sardines, Herring (mnemonic: “SMASH”) to maximize omega-3s and minimize mercury.

Beta hydroxybutyrate (BHB) When the body is fasting or deprived of carbohydrates, it switches over to ketones for fuel. BHB is one of the ketones the body burns, and it also signals the body to alter gene expression in a beneficial way.

Bredesen recommends 70% of calories from fat. This is really on the edge of an extreme keto diet, best achieved with a nut-based diet supplemented by salad oil.

% calories from fat
Walnuts 83%
Sesame Tahini 77%
Avocado 77%
Chocolate unsweetened 74%
Peanuts 72%
Almonds 72%
Sunflower seeds 72%
Egg 64%
Tofu 57%
Chicken drumstick 53%
Salmon 49%
Milk, whole 47%
Ground Beef 44%
High-fat yoghurt 31%
Kale 30%
Brown Rice 15%
Broccoli 8%
Whole Wheat 5%
Oranges 4%
Lentils 3%
Apples 0%

The chart gives you a rough idea of what Keto-flex looks like in practice.  Salads with oily dressing are a good staple, since the greens provide fiber and phytonutrients but few calories, and most of the calories are from the oil in the dressing. Nuts are a tasty protein source that keeps the fat intake high. Fruits are bad news. If you eat an apple (0% of calories from fat), you have to expiate the sin with 1½ Tablespoons of salad oil.

It takes a few weeks to switch over from a sugar-burning metabolism to a ketone-burning metabolism. If you try to do it too quickly, you end up with the “keto flu”, headaches, nausea and low energy.

MCT=Medium-chain triglycerides, such as coconut oil, are the best oils for inducing ketosis. They are good for APOε4 negative people, but with APOε4 positive they pose a long-term risk of “bad cholesterol” in the blood. APOε4 positive people should jump-start a ketogenic diet with MCTs, then switch to olive, sunflower, or walnut oil.

During fasting, the body clears out waste outside cells (glymphatic system) and digests waste within cells (autophagy). For people who are APOε4 negative, 12-14 hours fasting each day is sufficient, APOε4 positive 15-16 hours is better.

Type 3 AD is cortical/toxicity

Derives from toxic build-up, heavy metals, pesticides, environmental toxins. Type 3 tends to present with high ratio of copper to zinc in the blood (generally a bad thing) and low triglycerides (generally a good thing).

Copper and zinc compete in the body, and many factors contribute to an excess of copper in modern Western environments (copper water pipes, low stomach acidity). This is one more reason not to take PPIs for common gastric distress or GERD*.

* PPIs include Prilosec and Nexium. Never take PPIs. If you must take PPIs, get off them after a few weeks.  This advice is from Mitteldorf, not from Bredesen.

Zinc is a component of many enzymes and hormones in the body, and contributes to neurogenesis and to a healthy immune system. Low zinc is also a risk factor for type 2 diabetes. High copper:zinc ratio increases inflammation. There are many good reasons to keep your zinc levels high, from male sexual function to enhanced immune response.

Note: Presenting symptoms for Type 3 are more often problems with disorientation, calculations, visual perception, reasoning and word-finding. Type 3 is more common in younger patients, in females, and in people without the APOε4 allele.

Look up more information about Type 3 under Posterior Cortical Atrophy (PCA).

Damp or water-damaged buildings can lead to toxic mold exposure. Aflatoxin is common in our diet.  It comes from grains or nuts that have been improperly stored, and especially from peanuts. Different people can have very different sensititivies to aflatoxin.

Mold contributes to both inflammation and toxicity. You can test your home for mold spores, or test your urine for mold toxins in the body.

Type 4 AD is vascular

The causes and risk factors are the same as for cardiovascular disease, but arterial blockage can affect the brain as well as the heart.  Multiple small strokes lead to loss of function in specific brain areas, inducing idiopathic forms of dementia.

Type 5 AD Traumatic

The same kinds of cognitive symptoms can derive from trauma to the brain, most often from a car accident or sports injury.

 

From the Discussion between Patrick and Bredesen

Herpes virus is a risk factor for AD, possibly because of its inflammatory effect.

Saunas are protective against AD. This is because of heat shock protein, but also because sweating helps the body to eliminate heavy metals. Wash immediately after sweating with a non-oily soap to assure that the toxins are not re-absorbed.

Homocysteine is a risk factor for faster brain atrophy and worsening cognitive decline. The old standard was <13, but Bredesen likes to see <7. How to lower your homocysteine? Eat raw vegetables, take folate supplements = vitamin B9. Caffeine, metformin, and niacin=vitamin B3 can all raise homocysteine levels. The MTHFR gene variant increases homocysteine levels. The amino acid methionine tends to raise homocysteine, but (the chemical relationship) there is no evidence that supplementing with SAMe increases homocysteine.  Betaine is a supplement that decreases homocysteine directly.  (Betaine also increases stomach acid, so it’s appropriate for some stomachs and not others.)

 

RECODE in My Experience

For a new drug or a specific diagnostic test, translation from the laboratory to the field is straightforward. What Bredesen has is something else.  It is a program of diagnostics, leading (through expert analysis and personal counseling) to an individualized program tailored to the patient. Though in principle it should be scalable, it’s a system that resists mass production. This year, Bredesen has partnered with Apollo Health to train a diaspora of specialized doctors, and begin to offer his program for Alzheimer’s nationwide. The program is called RECODE, for REversal of COgnitive DEcline.

Last fall, I enrolled in the RECODE program to learn more about it, and to help formulate an Alzheimer’s prevention program for myself (age then=69). I was frustrated by the unresponsiveness of the Apollo team. They seemed well-intentioned, but overwhelmed by expansion that was faster than they could keep up with. This summer, I tried again, and I also enrolled Ben (85), a relative who has recently moved with his wife to a Continuing Care facility because of early stage AD.

I found that the dysfunctional system had become functional, and that there is now a network of doctors trained in RECODE, including several near my home in Philadelphia. My personal experience has been good. Dr Reina Marino, who worked with me, was attentive and knowledgable and patient with the technical details that I imagine I was the only patient to ask about. In the months that she has been practicing RECODE, she has already seen some patients significantly improved, though no dramatic recoveries to report yet. She hinted that some patients didn’t follow through with the multi-faceted protocols for changes in life syle, diet, and environment. Indeed, I was disappointed to learn that Ben decided that his memory was “not that bad”, and he couldn’t be bothered with the program. On the other end, Dr Marino has been too busy to follow through with me.  My sample of one may or may not indicate that individualized medicine is time-consuming and expensive. On the subject of “expensive”, Medicare won’t pay for RECODE treatment, and my Medicare Advantage plan only covers a small part of the cost.

The RECODE web site for patients is not as friendly as it ought to be. I’m a computer professional, and I still had to get a RECODE staff person on the phone to tell me what needed to be filled out before I could download my test results and find a practitioner. The interface should be re-designed as soon as is practical to be navigated easily by older people who may be uncomfortable with computer systems.

Two more causes for concern

Ben scored 11 out of 30 on the standard MOCA paper-and-pencil test for cognitive impairment. That’s low even for an Alzheimer’s patient (though, to speak with him, one might have the impression that he was functioning at a high level). I was surprised to see that Ben’s blood test scores were better than mine in most areas. Comparing our two test results, it was not at all obvious why Ben should be impaired while I am not. If these tests are designed to pinpoint an individual cause for individual symptoms, then it seemed to me that they did not distinguish well between Ben’s condition and mine.

Link to my personal RECODE report

The initial report scores patients in five areas:

  • Toxicity–mercury, lead, arsenic, mold, pesticides, toxins that build up in the body
  • Glycotoxicity–accumulated damage from too much sugar in the blood
  • Trophic loss–micronutrients and minerals insufficient in the bloodstream
  • Inflammation–from leaky gut or chornic disease burden or autoimmunity or just aging
  • Vasculature–stiff or clogged arteries depriving the brain of sufficient oxygen

In four of these areas, Ben’s score was better than mine (meaning lower risk); only in glycotoxicity did I do a bit better than Ben. The risks are individually ranked for each patient, and both Ben and I were found to be at highest risk for toxicity, associated with Type 3 AD. But Ben’s toxicity was well below my own.

“This is not a one-size-fits-all program. Everyone’s version of RECODE is personalized, based on their test results.”

This has been a hallmark of the Bredesen protocol from the beginning, based on the premise that AD has very different causes in different individuals. It is, of course, the most difficult thing to achieve while the program is moving from the laboratory into the health care system. Differential diagnosis depends on, first, a computer algorithm, and then, the human intelligence of a doctor or other practitioner who has been trained by the RECODE core team.

Despite our very different profiles and different diagnoses (Type 3 for me, Type 1.5 for Ben), the first three steps in our computer-generated recommendations were identical. The section labeled “Your Suggested Plan” was identical for Ben and myself. The greatest risk factor identified for both of us was toxicity, yet the #1 recommendation for both of us was the keto-flex diet. This is congruent with the paradigm promoted by Mayo Clinic and elsewhere that AD is a kind of “type 3 diabetes”. Bredesen endorses this as one piece of a more complex story, so I had hoped for a more nuanced prescription from RECODE.

Reducing homocysteine was the #2 recommendation for both Ben and myself. The medical establishment recommends keeping homocysteine levels under 15, but Bredesen wants us to cut that in half. I have read the section on homocysteine from Bredesen’s book, and it is not clear whether homocysteine is important because of its direct neurotoxicity or because it is a marker of inflammation. After my RECODE interview, I left the Marcus Institute for Integrative Health with a bottle of a supplement formula designed to lower my homocysteine levels by direct and indirect action. Principal ingredients are B vitamins, N-Acetyl Cysteine (NAC) and (this one was new to me) betaine-HCl=trimethyl glycine (TMG). TMG reacts directly with homocysteine, pulling it out of the bloodstream. Are we fooling ourselves if we pull homocysteine out of the blood without reducing inflammation? David Quig says that betaine works great in the liver, but it doesn’t affect homocysteine levels on the other side of the blood-brain barrier. A better alternative for the brain is 5-methyl tetrahydrofolate, a fancier folate supplement than the common and cheap synthetic folic acid. (Note also that folic acid is toxic to people with the MTHFR allele.)

The bottom line

Last year, Bredesen published an account of replicated success in 100 patients that was, if anything, more impressive than the original. Under his close supervision, the Bredesen lab is able to reverse AD with a rate of success well beyond any treatments in the past. The Bredesen system depends on individualized diagnosis and individualized treatment plans, so scaling his methodology for wide application presents daunting challenges.