Thursday, January 29, 2015

The Fountain of Youth, or, Monkey Glands Revisited?

Remember Serge Voronoff?  No?  He was the guy who wanted to use surgery to mimic a slurp from the Fountain of Youth.  At around the turn of the 20th century the idea became very popular among those socialites with resources to burn and not enough religion to really believe they were going somewhere after death (or, speaking of burning, perhaps given their wealth that that 'somewhere' might be rather warm), that you could extend youthful life by receiving a transplant of 'glands', that is, testicles from some other animal.  This would give you a hormonal boost that would put hair back on your chest (I don't know if women were ever privileged to have xenografts of, say, goat or chimp ovaries).

Voronoff (1866-1951)  Source: Wikipedia

Voronoff tried such xenografts among various domestic animal species, and for humans it became 'monkey glands' that were in demand by those in their idle dotage, or who wanted to avoid such dotage.  Here shown is a before and after (taken from the Voronoff book How to restore youth and live longer published in 1928).  Note the difference?  It seems less than miraculous to us, not that different from the fake youthfulizing miracle creams or treatments advertised in Parade Magazine.  But never mind.

Before and after a 'glandsplant', from Voronoff's 1928 book

I don't happen to know if Voronoff had himself rejuvenated by this means, or not, but it's beside our point here.  In the end, the idea proved rather useless, unless there was a placebo effect, and today we know about such things as tissue rejection and that this isn't the kind of transplant likely to work without a lot of remodeling of the recipients immune system.  But the idea of transplant of healthy tissue to replace diseased tissue is very much alive and well.  Fortunately, the problems have to a great extent since been worked out, as many thousands of people with kidney, heart, bone marrow, or other organ transplants have lived to be able to attest.

In a sense, putting a younger, healthy heart or kidney into you to replace your worn-out one is a clever, focussed and almost miraculously wonderful way to rejuvenate.  It doesn't make you younger over all, the way the monkey gland craze promised, but it gives you longer, stronger life.  That's very good and the transplant industry seems to be thriving as a result of understanding many different aspects of the body's responses to non-self tissue.  And there is no reason this success can't be extended in open-ended ways.

Naturally, the dream of staying frisky past sixty attracted a lot of attention in Voronoff's day, where the objective was not to replace a single decaying organ but to reverse the aging process more generally.  Just as naturally, it didn't work, but could more generic rejuvenation now be in the offing?

Modern 'parabiosis'
A recent Nature review describes the history of studies of pairs of mice, one young, one old, that have had a bloodline connection made between them (see figure).  This is known as parabiosis, and is like reverse-engineering conjoined twins!  The young mouse's blood goes into the older mouse, and then the scientists check what they wish to look at in the recipient's tissues.  The article summarizes findings suggesting that many different tissues appear in a sense to be 'younger' than the recipients calendar age.

The method summarized in a figure (with credits) in the Nature commentary
The effects were measured on trait after trait and various organ systems, with the basically consistent finding that the youthful blood made the tissues more youthful-appearing.  We say 'appearing' because the authors of these various experiments don't claim that there will be an overall longevity increase, though that would not be surprising.

The investigators are not claiming an actual fountain of youth, but make the reasonable inference that constituents of the blood change in a senescing way with age. They have identified a few components and clearly there are more to be found.

There may be many people with specific debilities for which such blood-borne treatment would work, though doing it by getting Sonny to be grafted onto Granny may be a tad of a problem (especially if Granny doesn't like to watch football games every weekend or Sonny doesn't like to watch Lawrence Welk).

However, instead of that rather draconian treatment, and it's not clear whether Sonny or Granny would resent it more, one can imagine extended sorts of allografts from at least compatible people, or homo-grafts (storing blood when young for use later on oneself....somewhat like cryopreservation!), or more likely the purifying or synthesizing of individual factors found differently in younger vs older blood.  Again, this is the appropriate sort of thing that is being investigated.

Those who themselves or whose relatives are 'losing it' with age, will likely welcome some such therapies.  But one will have to be careful.  Allografting tissue to ameliorate mental deterioration, one clear objective in principle, might not be so unquestionably good if the mentally rejuvenated recipient still can't walk, or hear, or see, etc., or if the treatment just stalls off death long enough for cancer, stroke, or renal failure to arise.

An ethical aside
At this juncture we can't refrain from remarking that we find the approval of these Frankenstein experiments on living mice to be thoroughly immoral and should not have been allowed.  The history of animal research reveals some of the gruesome things IRBs will sign off on. The investigators apparently reassured their doubting IRBs that they would carefully 'reduce animal discomfort', such is the euphemistic language usually used to avoid saying honestly, the victims' terror and agony.  Of course, as the article says, the investigators held 'long discussions with our animal-care committee', quoting one.  The animals remained joined for many months.  This seems a horrible thing to do to the animals.

One can argue about who should make the call about what constitutes 'torture', but we think surely there must be other ways to do blood or blood extract transfusions to achieve similar ends.  Of course investigators always defend what they want do as 'necessary'.  Were such studies ever really needed or justified?  Those who did them will of course vehemently say yes, essentially invoking human exceptionalism and the dismissal of the quality of life of their laboratory victims.  Things will have to rest at that.

We must acknowledge that we did IRB-approved research on normal and abnormal mouse development for 25 years, and that, while we did not knowingly torture them, we did kill them.  The whole subject of animal research, and what IRBs will sign off on, is not an easy one.

The current situation: plenty of positive possibilities
Anyway, if we can somehow put these ethics issues aside, it seems that many investigators who are following up these basic findings are, as the story reports, taking the modern more focused or specific approaches one would expect, such as to identify all compounds circulating more in young than old blood from isogenic individuals (e.g., inbred lab strains), finding various plausible signaling and other similar factors, and then attempting ingredient-specific infusion therapies.  The paper reports a number of these attempts and specific factors (growth factors, and the like) that are found in the younger blood that could be useful in this context in addressing human senescent diseases.  At this stage, with the factors identified, one doesn't even need isogenic individuals, and older to younger human parabiotic transfers are in trials in the university and private sectors.

In principle, given these kinds of circulating factors, one might not need to be specific to genotype of young donor or old host persons, if it be sufficiently accurate that there is no reason to think that the major aspects of the effect, or the detailed molecular structure of the youthful donor's circulating factors themselves, need to be genotype-specific.

One might wonder why it is that these factors' concentrations in blood diminish with age in the first place, because the complex mix and relative proportions of circulating factors may be genotype specific (especially if the widely claimed importance of genotype-based causation is accurate).  Thus, a good scientific question might be to ask how to reverse the normal decline of factor concentration with age, so an individual can resume making his/her own mix, rather than thinking that single-factor transfusion is the best approach.  On the other hand, if the decline in natural production is due to somatic mutation or local epigenetic changes, re-stimulating the person's own mix might be worse than using exogenous, purified, single-factor therapy, because the result might re-stimulate damaged molecular structure or relative concentrations. These things would be worth knowing both for basic biology and to understand aging better.

Additional more likely and important cautions exist because, as the Nature review notes, by stimulating cell division in the elderly one might generate cancers that would otherwise arise much later or not at all.  The same would be true of stimulating endogenous production of the same cytokines.  That is because, if understanding of cancer as largely a somatic mutational problem (see Tuesday's post) is correct, the cells in elderly recipients contain many mutational changes acquired by somatic mutation during life, making them closer to final transformation.  Stimulating a quiescent carcinogenic cell, or many cells that are but one mutational step away from transformation, could very quickly lead to a tumor.

It is relevant, we think, that the natural increase in age-specific cancer incidence generally tapers off in the elderly.  The presumed reason is simply that cell division slows down as tissues restore themselves more slowly.  So, making elderly cells divide could be playing with dynamite.

Nonetheless, identifying what is in young blood but diminishes with age is a useful idea with potentially major importance.  Some of this applied work, according to the Nature story, is already in the private sector.  Of course, with a cynical gleam in our eye, we can imagine that company offices are surely being set up somewhere in Florida, where the hordes of well-heeled snowbird customers are a ready-made sitting-duck clientele.  If they go for the skin creams and so on, think how they'll go for the new advanced rejuvenation therapy!

One could set up shop anywhere near Miami, say, but any shopping mall in the Sunshine State will probably do. Fortunately, with these new tools it will not be necessary to find an actual fountain, where the miracles of youth will be dispensed. As with old-fashioned monkey gland treatments, who, who is nearing his Maker, who can afford the treatment, would have the courage to say 'no'?  Still, if you want this new-style rejuvenation regimen, you will have to stand in line.  Ponce de Leon and his crew got there first, and they've been waiting for a very long time.

Ponce de Leon makes a point (from Wikipedia images. public domain)

By the end of his life, Serge Voronoff  had generally been judged to have been a quack. We can't say if that's fair or not.  There are always snake oil salesmen around, including 'respectable' scientists enthused by their idea, often who believe their over-stated or premature claims, hastily taking a research finding to the private world.  Brand it, say, 23andAgain!

At least, Voronoff's general idea wasn't completely whacko, even if the technology and its knowledge-underpinning were simply far from adequate for the task. The rich no longer demand monkey glands, but the basic yearning for extended youth is understandable, and isn't likely to go away, given the alternative.

But, while reveling in the many exciting, positive things that may be available in the near future, think about sparing a thought for the helpless and hapless mice whose slaveowners decided that doing this to them was an acceptable thing.

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