Rebalancing proteins in the blood is the single most promising strategy for age reversal in the present environment. There are two competing schools for how to approach this. I’m calling on both to put their heads together and develop a strategy that combines their insights.
Please forgive me while I rant for a paragraph before beginning this column in earnest. Len Hayflick demonstrated that senescence in many animal species, probably including humans, is promoted by lack of a simple, cheap enzyme (telomerase) that every cell knows how to produce. To anyone who hasn’t been indoctrinated into the selfish gene dogma, this would be a sure indication that the body is trying to kill itself. But fifty years on, Len is still saying that aging = entropy catching up to a body’s chemistry. An equally powerful discovery came from Irina and Mike Conboy, who have been at the forefront of experiments demonstrating that aging is centrally coordinated through signal molecules in the blood. In every context but this one, the Conboys will acknowledge that these molecules are subject to directional selection and are tightly regulated in the metabolism. But when the blood plasma fills up with pro-inflammatory cytokines during aging, the Conboys insist that this is an accident. The body made a mistake. They call it “deregulation”. And in case anyone misses the point, they add in parentheses, “(noise)”. These are exactly analogous to the directed changes that cause growth, puberty, cessation of growth, onset of menopause, etc. In those other context, the change in balance of plasma proteins are signals, but in the context of aging, they must be “noise”.
And even more incomprehensibly, the “noise” to which they refer always goes in one direction, and that is producing too much of some signal molecules, and the “noise” always manages to emphasize exactly those signals that bring the body down in a hailstorm of inflammation.
Evolution is a many-splendored thing, and natural selection is perfectly capable of producing well-regulated, interdependent communities. This has meant selection for Goldilocks rates of reproduction balanced artfully against death rates that are also well regulated under evolutionary control.
And YES, it does matter whether you think of aging as signal or noise. (I apologize again as my rant spills into its fourth paragraph.) It matters because if aging comes from a set of signals, we know well how to block those signals, e.g., with drugs that jam their receptors. But if it’s noise, the task is so much more difficult because it unfolds differently in every individual.
It’s no secret to readers of this column that I think altering the balance of signal molecules in blood plasma is the most promising road to anti-aging in humans. There are now two competing approaches to this project. The Katcher school says that there are youthful factors missing in the blood of old animals, while the Conboy school says that there is an excess of pro-aging factors. Both are quick to say that yes, it is a balance of pro-aging and anti-aging factors in the blood that ultimately determines the animal’s fate. But Katcher says that if you deliver the right combination of youthful factors, they will reprogram the epigenetics so that the pro-aging factors retreat as a side-effect; while the Conboys claim that if you dilute the blood, removing equal proportions of pro-aging and anti-aging factors, that dilution is sufficient to reset the aging clock, and stimulate new production of the youthful factors.
Problems with the Katcher protocol
Until last week, Katcher had the more compelling data (IMHO), because he demonstrated dramatic epigenetic age reversal in rats. But last spring, the disappointing results in a small lifespan trial (8 rats) makes us wonder if his protocol needs a lot of fine tuning before it’s ready for prime time. And another weakness in his protocol is that he doesn’t know what is in the blood-derived E5 elixir that does its magic. He tells me there are efforts underway to identify the active components of E5. I think this determination is a high priority with global implications for health, so, by my lights, the analytic work on E5 should be a top priority. But there is a financial incentive not to know what are the active components of E5. This is because Katcher’s Yuvan Research has a patent on the process of extraction, but the components themselves are natural proteins, and thus they cannot be patented. So as soon as the information about the active components of E5 become public, his process patent risks becoming worthless. Other, larger laboratories than Yuvan will be able to synthesize the chemicals and sell them. I fear that research is being held back, and for what? I don’t even believe that the strategy of secrecy can secure the patent rights for Yuvan, because the knowledge will inevitably leak out, and Yuvan doesn’t have the resources to pursue multi-million dollar court battles over patent rights.
Human trials of plasma dilution
Now there is a new article from the Conboys analyzing results of plasma dilution in three human subjects. They show improvements suggestive of rejuvenation in several biomarkers. They do not report methylation age. They do begin the analysis process, and offer suggestions about what may be the most important pro-aging components of blood plasma that must be removed or inactivated.
Why don’t they measure methylation age using any of the available clock algorithms? There is a short statement why they don’t believe in methylation clocks, and they express the opinion that another biomarker of aging, one not based on “machine learning or large data sets” is urgently needed by the community. I believe that methylation clocks are the best means we have at present to evaluate the effects of anti-aging interventions, and in this one respect I find myself (for a change) aligned with the majority view in the field. The Conboys owe us a better explanation why they have gone to such great lengths to report other biomarkers of aging, but they don’t offer us the simple one that most researchers rely on.
It’s a popular theory aging that DNA damage is an important driver of aging , but I don’t believe it.
Interestingly, the procedure of small animal plasma exchange to dilute the circulating factors in plasma effectively reset the age-elevated systemic proteome and restored youthful healthy maintenance and repair of muscle, liver, and brain, without any added young blood, young plasma, or young factors [15–17].
This is a crucial point. How strong is the evidence? The three references are all previous publications from the Conboy lab. Ref 15 describes results of delivering young blood into old mice, an experiment which cannot tell us whether dilution alone rejuvenates gene expression. Ref 16 is about plasma dilution in mice and humans. This study establishes that something in old blood inhibits satellite (stem cell) growth, necessary for healing and repair, and that dilution is sufficient to restore youthful activity of these cells. Some evidence is noted of changes in the global proteome toward a more youthful state. Ref 17 establishes that plasma dilution is sufficient to enhance cognitive performance and reduce inflammation in old mice.
There is a section of the paper documenting “proteome noise”, which the Conboys propose as an important biomarker of aging. I disagree, of course. I see the directed changes in gene expression as the important drivers of aging, and the random changes are secondary. Much of the Conboys’ paper is devoted to analyzing noise in the proteome of subjects, and interpreting this as an aging biomarker which moves in the direction of youthfulness after plasma dilution. I admit much of the biochemistry is above my pay grade. I can’t comment on the merits of their proposed components of a new proteomic clock. But from the vantage of scientific methodology, developing appropriate biomarkers of aging should be a separate endeavor, done in advance. Criteria for successful rejuvenation should be established ahead of time, and not developed on the fly with results of the experiment already in hand.
I would have liked to see methylation age before and after treatment. I understand that the Conboys have reasons for not giving credence to the methylation algorithms. But how about A1C or CRP? These are measures of insulin resistance and inflammation, respectively, that are standard blood tests, but are not mentioned in the Conboy paper. How about any measures of cognitive or physical performance? There are no phenotypic aging markers in the Conboy paper.
Breaking new ground
The Conboys identify two proteins, TDP43 and TLR4, that were previously unfamiliar to me, but are markers of an aging proteome. The former is associated with cancer, the latter with dementia, and both increase with age. Both are attenuated with the Conboys’ plasma dilution protocol. I recognize that it is labor-intensive work to identify specific protein targets and test them individually, but this is the kind of work I think is most valuable going forward.
How I think about aging
My (tentative) model: “Old” and “young” are always in the body’s repertoire of behaviors, and the body will choose according to the signals it receives. The age state of the body is stored in the epigenetic state of cells, and communicated through hormones and other signal molecules in the blood. Some of these molecules also act as transcription factors, and they can feed back to affect the epigenetic state of dispersed cells. This is the reason for hope that a younger environment in the blood can effect long-lasting rejuvenation.
The great task before the Conboys and Katcher and other researchers in plasma rejuvenation is to identify which of the hundreds of proteins that change with age are the few transcription factors that are capable of reprogramming expression of the rest.
- There is no guarantee that a small subset of proteins exists that can do the job, but we won’t know until we look.
- And there remains the possibility that a central clock in the hypothalamus is able to override records of biological age in the epigenetics of dispersed cells. If this turns out to be the case, then we have to find ways to breach the blood-brain barrier and reprogram the hypothalamus.
A modest proposal
Harold Katcher, Mike and Irina Conboy are at the forefront of anti-aging technologies today. Both labs are very close to having an effective treatment for humans, close in the sense that there remain no conceptual hurdles, but only the predictable quotidien work of expert lab biochemists. In other words, a lot of work remains to be done, but the map is drawn.
Aging is not a cell-autonomous function, but happens under system-level control, with information about the body’s age communicated by signal molecules in the blood. This is the key insight on which Katcher and the Conboys agree.
To those of us watching from the outside, it is clear that a rebalancing of young and old plasma components will have a dramatic effect on health and lifespan. The remaining task is to identify a minimal set of those factors that must be removed (or neutralized) and those that must be added to the blood of an old person in order to trigger a global resetting of the epigenome toward full youthful gene expression.
We, the consuming public, would benefit greatly if the Conboys would hire Katcher to come work in their lab. Their two conceptions need not be antithetical. Let’s call on them to work together to identify that minimal set of blood factors, resetting of which can accomplish robust rejuvenation.
The importance to humanity of this research agenda must override the personality differences, the philosophical differences, the legal and IP problems that must be overcome to make this collaboration possible.