Ambitious New Anti-aging Trial in Humans

Pre-announcement Announcement

Life Extension Foundation has just announced that next week they are going to announce a partnership with the Young Blood Institute for what is perhaps the most ambitious human trial of anti-aging medicine ever.  It’s a daring project, with what is IMO a most promising target.  But I find details of their protocol puzzling, and haven’t been able to get satisfying answers from LEF or from YBI about why they’ve made the choices they have, and how they will be able to learn from the project.

  • The principal treatment consists in 6 plasma transfusions scheduled over 4 weeks.
  • Extensive testing is planned, including telomere age and methylation age in addition to a full battery of standard blood tests like lipids and inflammation markers.
  • The program is self-funded by research subjects, with projected cost ~ $50,000 per participant.
  • In each transfusion procedure, red and white blood cells will be separated and cycled back into the subject.  Blood plasma with dissolved blood chemicals will be removed.  It will be replaced not by full plasma from a donor but by albumin and gamma globulin only.

“Rescue Elders” project of LEF

Last year, Life Extension Foundation announced a new and ambitious program of human experimentation at the edge of medical science, sponsoring high-risk trials to prospect for anti-aging breakthroughs in the near term.  (The project’s name, Society for the Rescue of our Elders, was taken from an 18th Century group in Amsterdam, Society for Recovery of Drowned Persons, that was formed after the efficacy of artificial respiration was first discovered.)  Their first project was a clinical trial of rapamycin, now ongoing.  This present program of plasma transfusions is their second project.


Target: Epigenetics

It’s my belief that the body’s primary aging clock is epigenetic.  That is to say, different combinations of genes are expressed at different times in life, and in old age the constellation of genes that is turned on causes inflammation, auto-immunity, and a preponderance of anabolism over catabolism.  The master’s tools are deployed in old age to dismantle the master’s house.

As a general concept, I think this is the best working hypothesis we have.  But if it is correct, it doesn’t offer an immediate key to rejuvenating the body.  The problem is that epigenetics is enormously complicated.  (The genetic code, in contrast, is as simple as it can be—a code of correspondence between triples of nucleic bases in the DNA with the 20 amino acids that are linked together, then folded to form proteins.)

Methylation of chromosomes is the best-known and first-discovered mechnism by which genes are turned on and off.  In addition to methylation, there are dozens of other epigenetic markers and signals that are applied directly to DNA or indirectly to the histone spools, beads of protein that around which DNA is coiled.

Different genes are turned on in different parts of the body.  This is the primary way that the body differentiates one kind of cell from another—they all have the same genes, but different combinations of genes are turned on in a nerve cell or a muscle cell or a skin cell.  Overlayed on these differences from one cell type to another, genes are turned on and off with age. This effect is reliable and consistent enough that Steve Horvath was able to construct a methylation clock based on 353 methylation sites that change consistently with age across all cell types in the body.

The connection to blood signals was supplied by research from Stanford, Berkeley and Harvard, in which blood from a young mouse is introduced into an old mouse, and is shown to rejuvenate its tissues, stimulate new growth, and promote healing.  With a small conceptual leap, I imagine that there is a self-regulating epigenetic clock distributed through the body.  On the one hand, epigenetic markers in each cell give each cell its characteristic age.  On the other hand, these same cells are sending signals though the blood (transcription factors) that are continually updating the epigenetic program and keeping it in sync throughout the body.  The hope is that (even if we don’t understand in detail how the epigenetics is programmed) the substitution of a young blood environment for an older blood environment will reprogram epigenetics in the distributed cells, and after a few cycles it will be self-sustaining.  That is, once the cells are reprogrammed to be younger, they will themselves send signals into the blood that maintain the younger state.

Criticism of the protocol

Here is a description of the proposed YBI protocol.  Six times over a period of 4-6 weeks, patients will be hooked up to a plasmapheresis machine.  Whole blood is removed from one arm, and a mixture is returned to a vein in the other arm.  The mixture that is returned will include all the patient’s own red and white blood cells.  But the blood plasma, clear liquid with all the dissolved signal molecules, will be removed.  The plasma will not be replaced by blood plasma from a younger patient, as in a standard plasma transfusion.  Instead, the return side will contain only albumin and gamma globulin.  These are the hydrostatic and immune components of the plasma (antibodies).  The theory is that auto-immune aspects of aging will be addressed in this way…but the antibodies are generated continually by white blood cells, so that the treatment will not last long.  Hence the rationale for frequent repetitions of the treatment, less than a week between treatments.

My principal fear is that the planned YBI protocol may be able to do only half the job.  My conjecture is that it is the signal molecules that actually maintain the epigenetic program.  The proposed protocol will remove the bad ones, and that’s half the job.  It may be that there are transcription factors from young blood that are deficient in the old and need to be replenished.  Full plasma transfusions from young donors would do both, fully replacing the blood environment of an old person with the blood environment of a young person.  But it is expensive and requires many donors for each patient.  It is to control expense that YBI has chosen to do do the removal, but not replacement of blood signal molecules.

Just last year, Tony Wyss-Coray headed a Stanford trial for AD, through a for-profit spinoff called Alkahest.  Alzheimer’s patients were given four doses of young blood plasma.  But the dose was small, a total of 1.5 liters of plasma, and the bad actors weren’t being removed.  Results were disappointing, but perhaps this is because the procedure was not bold enough.


Promising Precedent

Beginning in 1924, a Soviet Bolshevik named Alexander Bogdanov experimented on himself, receiving a series of 10 blood transfusions from younger donors.  He was 51 years old at the start of the experiment, and contemporaries report that he appeared physically ten years younger in the course of the procedures.  He self-reported prodigious health benefits and return of youthful vigor.  The experiment ended tragically in 1928, when he received blood from a student who had been infected with malaria, and died of the infection.  

Harold Katcher has been thinking about the rejuvenation potential of plasma transfusions for a long while, and here is the protocol he suggested five years ago.  He does not speculate about what schedule would be ideal, and he cautions us that extensive experimentation with mice and even in cell cultures would be useful before beginning human trials.

Unpromising Precedent

Two years ago, I spoke via skype with Jesse Karmazin (Stanford University and Ambrosia).  He told me that as a med student he had done an analysis of historic data from transfusions performed at Stanford University Hospital, and found that those who had received blood from young donors had better outcomes and better long-term survival rates than those whose blood had come from older donors.  I was very interested in this claim, and asked him for the data that supported it.  He told me it could not be released for reasons of patient privacy.  I never did get to see that data, and he never published his analysis.

Last year, a published study claimed the opposite:  that in a large database of Swedish and Danish patients transfused between 1995 and 2012, they were unable to detect any survival difference between those who received blood from young donors and a matched group of patients whose transfused blood came froun old donors.



Ideally we would like to learn many details from a trial of HPE (heterochronic plasma exchange).  Fundamentally, we would test the basic question whether circulating factors in the blood are indeed able to reprogram the epigenetics of cells throughout the body, and whether this will have a salubrious effect on vitality, appearance, metabolism and the immune system.  A well-designed trial might also teach us more

  • Which chemical components (proteins and RNAs) are most important to be removed from the blood of older people?
  • Which chemical components (proteins and RNAs) from young donors are most effective to be added back?
  • How long does the young plasma profile remain in the bloodstream before the body’s old cells take over and drag the proportions back down to where they were?  (At this point, the next infusion would be appropriate.)
  • How many transfusions are required before the body’s cells are reprogrammed, and the young plasma profile becomes self-sustaining?

Transfusions from young donors are a good place to start, but obviously not a practical solution for rejuvenating large numbers of people in the long term.  But if we can learn which chemical constituents need to be removed and which need to be added, it is possible that a core handful of such factors might be discovered.  Those that need to be added can be manufactured in bulk by vats of genetically modified E coli.  Those that need to be removed can be targeted with antibodies and removed in a simplified blood filtering procedure.  This is a promising research path—perhaps the most promising that is visible from where we are now.  But we’ll never know if it can work until we do an expensive and time-consuming series of experiments.

How many transcription factors need to be regulated in order to the job?  This is the biggest unknown.  When I spoke with Irina Conboy four years ago, she was optimistic that the number may be less than ten, but last year, she was less optimistic.  I take heart from the fact that just four Yamanaka factors can turn a differentiated cell into a zero-age stem cell.


Toward the future

Plasma transfusions are a safe, approved medical procedure, used for decades as treatment for (especially) auto-immune diseases.  No FDA approval would be needed for a clinical trial, using transfusions “off-label” to test rejuvenation potential.  However this is not a project likely to be picked up by venture capitalists looking to make a quick buck.  The first reason is that the process will be expensive and time-consuming, with a great deal of trial and error.  The second reason is that when it is all over, everyone will know what are the best schedules and procedures, and the most important transcription factors in our blood—but it is doubtful that this will be patentable intellectual property, or that the investors would be able to maintain a trade secret.  What we need is a substantial public investment or a middle-aged billionaire angel investor who is thinking clearly about his own destiny a decade or two down the road.

Marriage, Sex and Longevity

Like you, dear Readers, I tend to be focused on the biochemistry, and have to remind myself again and again that the mind and body are intertwined.  I came out last week with my core belief about biology: Mechanistic physics explains only half of what we are.  Life has its own laws which we will discover only if we admit they exist.

In fact, the most powerful thing we can do to prolong life expectancy is to have robust connections to other humans.  The best-documented effects are for empowering relationships with community (especially cooperative action for change) and intimate relations of love.  Together, these factors contribute more to life expectancy than any diet or exercise program, or any supplements you can take.  The difference is comparable to life expectancy difference between heavy smokers and non-smokers.  (I wrote about these topics 2 years ago: [1. Social status and depression, activism vs powerlessness, 2. Family]

Elissa Epel is famous for having elucidated the connection between stress and eroding telomeres.  But she has also brought us positive messages: Meditation is associated with telomerase expression and longer telomeres.  Altruism breeds telomerase.  Loving-kindness is associated with longer telomeres.  In a publication last summer, she and co-authors documented the benefits of sex.  Women (all subjects were partnered females) who had sex at least once in the week surveyed had longer telomeres than women who did not.

The result added to evidence that goes back at least 20 years.  The Caerphilly study showed that frequency of sex correlated with lower all-cause mortality in men.  The conclusion extends to women.  The tendency of medical professionals to interpret the result in terms of the biochemistry of orgasm has been tempered, as it became clear that sex with a partner, with or without orgasm, has benefits above masturbation [ref].  Intimacy without sex has its health rewards, as does the strength of one’s community fabric.

So, in this context, the headline result from the newest study is no surprise.  The puzzle is that, even though powerful connections between social relations and health are confirmed again and again, the details keep changing, and consistency is elusive.

For example, the study just cited found that subjects who reported more sexual activity had longer telomeres, but they didn’t have more telomerase activity.  In fact, they had (almost statistically significant) less telomerase activity.  This was a short-term study.  Telomerase activity is a short-term variable, and telomere length is supposed to respond in the longer term to telomerase activity.  We should not have been surprised if an increase in telomerase had been observed, without a significant difference in telomerelength.  The opposite finding suggests a missing link in the causal chain.  (The Discussion text in the article is very open about this mystery.)

The study included only women.  Women have been found to be more sensitive to the quality of loving attention and the depth of their connections in love, while men tend to respond to the cruder quantitative variable of sexual activity [ref].  But for women in this study, telomere length was related only to the frequency of sex, and not to the quality of relationship, or to relationship satisfaction.  In fact, they found no significant association with any of the subjective questions asked concerning satisfaction with the relationship, or feelings of closeness.  Again, the investigators themselves were surprised.

Paradoxical results from other studies:  Men (>57yo) who had frequent sex (more than once per week) and men who self-reported that sex was “extremely satisfying” had twice as many heart attacks in the ensuing five years [ref].  In the same study, results for women were not strong enough to be statistically significant, but were strange enough to be puzzling.  Women (>57yo) who reported sexual relations that were highly satisfying had higher risk of cardiovascular disease, but women who reported most intense pleasure from sex had lower risk. “These findings challenge the assumption that sex brings uniform health benefits to everyone.”

This classic study found that marriage offers substantial benefits in life expectancy for both men and women, but that the benfits for men are far larger.  The relative risk in mortality rate, unmarried vs married, is 1.5 for women but 3.5 for men. The large disparity has not held up in more recent studies.

This is the most comprehensive recent review of the relationship between social variables and all-cause mortality, but it is confusingly written (I believe the verbal interpretation of statistics is incorrect).  The message comes through loud and strong, that social integration accounts for a large benefit in decreased all-cause mortality, accounting for 5 to 10 years of life expectancy.  But even more than in other fields of social science, there are contradictory results and inconsistencies that thwart anyone trying to tell a neat story.


Why is social connection so important to health

“Two main types of models have been proposed to explain how social support influences physical health. In main-effect models, high levels of social integration are health promoting, regardless of whether one is under stress [ref, ref]. Greater integration into one’s social network gives an individual identity, purpose, and control, a perceived sense of security and embeddedness, and a source of reinforcement for health-promoting behaviors or punishment for health-compromising behaviors, all of which can promote health [ref]. In the stress-buffering model [ref], the negative effects of stress occurring outside of one’s social relationships (e.g., at work) are diminished by the presence of strong social support, which can mitigate stressful events directly (e.g., intervening on a friend’s behalf) or through reducing stress appraisals [ref].”  [quoted from Robles, 2004]

Bert Uchino distinguishes between “perceived support” and “received support”.  The correlation of the former with health and mortality variables is robust.  But the latter is sometimes found to be inversely correlated with health.  This seems to say that if people are helping you and you don’t appreciate it, you’re worse off than if you had been on your own.  If you think you’re embedded in a caring and supportive community, you’ll live longer.  If you’re actually embedded in a caring community, but you devalue what you’ve got or if you isolate yourself because you’re more comfortable that way, your life expectancy is shortened.  This is a morality tale if I ever heard one.

Conflictual interactions in the context of marriage (as in Western culture generally) contribute to higher levels of systemic inflammation [ref].  But this study found no relationship between job stress in men and measures of chronic inflammation.  Maybe it depends on what is meant by “stress”.  This study suggests that feeling out of control (powerlessness, low status) is associated with markers of inflammation.


Why do we care about this?  Many of us are fanatical about following the best evidence when designing exercise and supplement regimens for ourselves.  But is there anyone out there who is waiting for the latest correlation with telomere length before deciding whether to fall in love?  (I didn’t think so.)  

No, the reason we care about this subject is that it reminds us that aging is a social process almost as much as it is a biological process, even if the social correlates of longevity confound our best intuitions about how to live well.

And perhaps it reminds us, indirectly, that in the “rationalization” of our health care system, we have made a bad bargain.  Over the course of my lifetime, medical practice in America has gone from a model of individualized care by family doctors to impersonal care by specialists.  Medical care has become more evidence-based, and there is a much better chance that the doctor who treats your condition has a deep knowledge and experience of that condition.  But what we’ve lost along the way is the doctor-patient relationship—both because you see a different specialist for each condition, and also because as doctors’ time is squeezed to optimize profit, the time for listening and empathizing has been eliminated.  Despite the accumulation of studies showing that doctor-patient relationship has an outsized effect on prognosis, our present health care system is systemically deficient in human caring.