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Reverse Ageing Hype

There are a number of annoying clichés of science reporting, prime among them being the need to make a connection from any research to a specific application. It must be deeply embedded in the journalism culture, or written in a handbook somewhere.

In medicine this means that any study that involves viruses or the immune system’s ability to fight off infection might lead to a cure for the common cold. Any study that has anything to do with cell function might lead to a cure for cancer. Almost any study of the brain might one day cure Alzheimer’s disease.

Add to this – any study that alters a metabolic parameter that changes with age might, of course, reverse the ageing process.

Such were the headlines about a recent study in Cell looking at mitrochondrial function in mice. Here is the summary:

Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD+ and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.

They used the magic word, “reversible” – that means to the media, apparently, the fountain of youth.

The research itself is very interesting. Mitochondria certainly are vitally important to cell function and are implicated in a number of disease processes. The more we learn about the function, regulation, and ageing of mitochondria, the better.

One thing we have certainly learned over the last couple of centuries is that biochemistry and physiology are complex webs of interactions. Our bodies are Rube Goldberg machines, evolved over millions of years to work well enough. Our biology is like code that has been patched, upgraded, and expanded millions of times – it’s a mess.

Another meta-lesson from medical science is that pulling on one thread in the complex biological web rarely has simple or predictable outcomes. If one small change has a clear positive outcome without any downsides, we probably would have evolved that solution long ago. Rather, biological interventions tend to have complex outcomes with many side effects.

What the researchers have found here is one tiny slice of the regulation of mitochondrial function – lower levels of NAD+ with ageing contribute to the decline in mitochondrial function, and artificially raising NAD+ levels restores certain measured aspects of mitochondrial function.

Here is what we do not know – what are the net effects on cell function of prolonged increase in NAD+, what are the net health effects on the organism, are such effects sustained, what are the negative effects?

The researchers, of course, acknowledge this. Reporting on this news item, however, focuses on the potential to “reverse the ageing process” in gushing terms, before finally adding the usual caveats – far enough down that most people probably won’t read that far. The BBC writes:

Experiments showed that boosting NAD levels, by giving mice a chemical which they naturally convert into NAD, could reverse the sands of time.

One week of youth-medication in two-year-old mice meant their muscles became akin to those of a six-month-old in terms of mitochondrial function, muscle wastage, inflammation and insulin resistance.

The words “reverse the sands of time,” or “youth medication” did not appear in the study publication.

The researchers note that the mice did not demonstrate any change with the treatment. Their muscle strength did not increase, despite the reported changes to the muscle cells. In the final paragraph to the BBC article they quote Dr. Ali Tavassoli, from the University of Southampton:

This could be for one of two reasons. Either they need to treat for longer so that the changes occurring in the cells have time to affect the whole organism, or alternatively, the biochemical changes by themselves are not sufficient to reverse the physical changes associated with ageing in the mouse.

More experiments are necessary to see which of these cases are true.

Which do you think is more likely? I certainly hope that increasing NAD+ levels turns out to be an elixir of youth, but I won’t hold my breath. Whenever a study of an intervention fails to find an effect it appears to be obligatory for someone to point out that the lack of effect could be because the dose was too low or the duration of treatment too short. This is, of course, generically true, but doesn’t change the fact that no effect was seen.

Take a look at this headline from The Guardian:

Harvard scientists reverse the ageing process in mice – now for humans.

This article is not about the current research – it is from 2010 and refers to a study in mice involving telomeres. The study looked at mice who lacked the gene for telomerase, which cause premature ageing and organ damage. Some of this damage was reversed when these mice were given injections to reactivate telomerase. Restoring mice to something closer to normal physiology is hardly reversing ageing.

Again, deep in the bowels of the article they discuss the fact that humans are different from mice in important ways regarding telomerase. The enzyme is suppressed as we get older to help prevent cancer from forming and spreading. Reactivating telomerase to reverse aging would likely result in rampant cancer. That is what we call a non-trivial problem.

To be clear, I am not against research into life extension or methods for limiting senescence. These are likely to be useful avenues of medical research. When reporting on such research, however, I would prefer if it were put into a more realistic context.

Ageing is not one process – it is many complex processes. No single intervention is likely to have a significant impact on overall ageing. Interventions are likely to have unwanted consequences, and overall risk-benefit will need to be carefully studied (just like with all medical interventions).

The difference here is that we are not talking about compensating for a dysfunction, but enhancing normal physiological function. This is a much trickier game.

Posted in: Basic Science

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26 thoughts on “Reverse Ageing Hype

  1. I actually have some tangential connections to this…at least, my face is up against the glass (so to speak). One of the study authors, David Sinclair of Harvard, is IMHO partially to be blame. He’s been mining the sirtuin pathway for the last several years; his work on resveratrol generated similar hype but ultimately led to a dead end (look up the Sirtris/GSK fiasco). I fault him for intentionally stirring up the media with every stepping stone uncovered by bench scientists (trying to cultivate funding, perhaps, in a world where research dollars have dried up), *but* I don’t fault him for finding things out and seeing where they go.

    Biology is a mess, but so is science; textbooks make everything so neat and tidy for college students, but the reality is that there were many, many dead ends, heated arguments, bruised egos while pop media for the lay public has always played the dual role of carnival barker/cheerleader and heckler.

    “I am not against research into life extension or methods for limiting senescence.”
    I agree. Another aspect of the messy scientific process is the grumpy derision of old men who hold the purse strings of institutional investment; they’ve become blase about efforts at the bleeding edge of science. Aging research has traditionally been one of those efforts, but it seems that the tide has turned in recent years.

    In fact, Dana Goldman of USC and David Cutler of Harvard put out an interesting paper a little while ago on the potential ROI of interventions that successfully produce only the most modest delay of aging (the returns as a whole are dramatic).
    http://content.healthaffairs.org/content/32/10/1698.abstract

    1. windriven says:

      The Health Affairs piece was interesting but I think it’s economic assumptions were pretty rosy. The US economy is having a difficult time providing employment for the current working age population, especially those without highly specialized skills. Simply extending the working lifetime of individuals does not automatically translate into an expansion of the economy to accommodate the enlarged labor pool.

      A related issue that has not gotten much ink is that our needs for a wide array of goods and services are provided by a much smaller domestic labor force than has historically been required. Some of this has come through automation (agriculture, automotive), some has come from off-shoring (electronics, call centers). This leads to a conundrum: household final consumption accounts for 70% of GDP. But households can’t consume without income and income can’t be generated without jobs.

  2. windriven says:

    “deeply embedded in the journalism culture, or written in a handbook somewhere.”

    Journalism, sadly, has become a degree in selling groceries and furniture. Factual reportage, where it occurs, is secondary. Mass market media are paid for their ability to attract volumes of listeners/readers/watchers in particular demographics. Content is used to attract those eyes and ears which then become the products that media sell to advertisers. I’m not suggesting that Robbie Reporter wakes up each morning thinking about how he can deliver more readers to Safeway. But the publisher that he works for does. And that shapes how content is collected, processed and presented.

    The study that Dr. Novella reports is interesting for those interested in the molecular biology of mitochondria. Not so much for the guy flipping through the paper looking for yesterday’s box scores. So you slip the story into a sheer skirt and spike heels and sprinkle it with the magic dust of credulity, Now you have something that people will talk about at the water cooler. Look, Robbie Reporter is being paid to write science news. He has to write about something. From his perspective he has to come up with a story sexy enough that his editor doesn’t transfer him to writing obits.

    The moral of the story is: don’t get your science information from NPR or The Daily Jabber.

    But the larger story is that expectations often drive results. We have political discourse that resembles a never ending WWF grudge match. We have reporting that rarely just informs, it more often panders to the prejudices of its perceived audience (Fox, MSNBC). We have a stupid body politic because we expect a stupid body politic. We require nothing more from them than allegiance to the team.

    The same holds true with science. People believe all manner of nonsense because few leaders or institutions demand more – even from themselves. If we don’t want people to believe in magic then why do we countenance major medical schools and medical centers teaching and selling bullsh*t? In this regard and on that level perhaps the charge actually can be made that those doctors are “Only Out to Make Money.” No other possibility seems obvious to me.

    Anyone who has raised kids understands that what you get is largely what you expect and what you incentivize. The political class is happy to incentivize rote adherence to one or the other political dogma. And apparently the medical class is happy to incentivize belief in woo. It isn’t difficult to understand the motivations of the political class, but …

    1. disappointed says:

      “So you slip the story into a sheer skirt and spike heels ”

      Really? Yeah, you went there. Somehow I expected better of you. Alas.

      1. windriven says:

        @disappointed

        Yeah, pretty cheesy analogy. I expect better of myself too. But sometimes stuff leaks out of my mouth before my brain has time to stuff a rag in it.

        1. redeemed says:

          Haha, then I’ll forgive you. Just this once. ;)

    2. AlisonM says:

      I actually wonder how much of this is countenanced by the researchers doing the work. Surely it happens, but really, it happens so much that one would think that no actual science is being done. I’ve found some individual cases (after a lot of digging) where authors have protested the misrepresentation of their work by journalists. My assumptions are that 1. They don’t have time to combat every misrepresentation because there are so many, and 2. Even if they tried, their explanations won’t be as appealing to the public.

      You can actually play a Google game with this. Pick an article that shows up in your newsfeed under a Health or Medicine category. Google the article that has the most hits when you search it. Find the original research and look at the abstract – you don’t even need journal access! Compare what the abstract says and then see how many pages it takes for the titles in the search to come even a tiny bit close to what the research was actually looking at. Each time you search, the number of pages with ridiculous assumptions in the titles increases until the next big thing comes along.

      It’s depressing.

    3. Rokujolady says:

      I would like to report that it has always been like this in journalism. I collect old AP photos associated with archaeology. The slugs are almost always unrelated, wrong, or trying to somehow associate the find to the Bible. My conclusion is that journalism has always been a mixed bag of real reporting, hearsay, marketing, and phoning it in .

  3. Stephen H says:

    I have to say that increasing NAD+ levels is clearly the wrong approach. Instead, the research team should consider adding water. After this is done, shake, then repeat seven times – pouring out any excess after each dilution.

    This method is bound to work.

    /s

  4. Andrey Pavlov says:

    One of my undergrad degrees was in evolutionary biology and I did much coursework with Dr. Michael Rose using Drosophila as our model species. He is also very interested in senescence research and my post-grad research in molecular pharmacognosy was under Dr. Mahtab Jafari specifically in the area of anti-senescence research. I was able to get in and start working in the lab because of my experience with flies as an undergrad. Dr. Rose has a one hour talk on the topic of senescence and he views the new age of biology in terms of the Big Data on genomes having ushered in a paradigm shift in senescence research. He likens it to Einstein and later quantum mechanics further refining Newtonian mechanics and inducing a different way of studying the topic of physics. If you are interested, I highly suggest watching the video. It is very enlightening and done in a sort of James Lipton-esque manner that I find entertaining. And yes, Dr. Rose is a quirky guy, but awesome in his field.

    The big thing to realize is that, as Dr. Novella said, this is a complex interaction with senescence having been deeply rooted in our fundamental evolutionary history. We don’t know precisely why this is the case, but we do know it is the case and that it is not a single gene, gene product, regulatory element, or anything else in isolation but a very complex array of interactions at the cellular AND organismal level that lead to senescence. What is particularly interesting is that all animals investigated demonstrate a stopping of senescence at some point late in their lives. This includes humans. The process begins and then stops at some point (95-105 years of age in humans). Of course this doesn’t mean if you live long enough you will live forever. The accrued damage to your cells and continued environmental assaults will eventually do you in. But it does jibe nicely with the observation that otherwise very healthy individuals who reach centenarian status tend to continue being very healthy and functional until they are done in by some sort of accident – usually a fall or an infection.

    The point is that most of the stuff we are looking at – telomere length, mitochondrial function, and now NAD+ – are surrogate markers for the larger and vastly complex process going on to produce aging (strangely I prefer the non-British spelling of that one). They are not themselves the aging process nor the drivers of senescence, but a product (either directly or indirectly) of the actual process that is going on. It is for these reasons (and others) that reversing these processes has failed to produce a measurable change in the aging process.

    Additionally, as Dr. Novella points out, we don’t know what the side effects will be of stopping or reversing this process. It evolved for some reason or reasons. It may be that those reasons no longer apply to our current biological interactions with the environment. I feel that is unlikely. A simplistic way to think about it is that there is something worse than aging that is being prevented by the process of aging. At least, that seems likely to be the case.

    What is particularly interesting is that the research done by Rose and others demonstrates a senescence curve. Essentially we anti-age as we grow into adulthood, then age until 95-105 years old, and then stop. It seems not only biologically implausible but also a bad idea to simply STOP the process. It is there for some physiological reason. What makes more sense is to find a way to decrease the slope of that curve to extend out our senescence such that we age the same “amount” but it takes us a lot longer to do so.

    None of this precludes the need for medical science to keep us healthy and alive during that time and in fact would likely mean more of it as we increase our exposures and lifetime risks.

    1. RealityEngineer says:

      re: “what the side effects will be of stopping or reversing this process. It evolved for some reason or reasons”

      The reason it evolved may be because it benefits the species, even if it is detrimental to individuals. Since individuals die eventually (from accidents or predators, etc), evolution is a species level process. It is survival of the most fit species, not the most fit individuals. Fit individuals usually in aggregate lead the species to be more fit, however individuals dying off allow for newer generations that may be more fit than prior generations to take their place.

      Individuals need to be healthy through the period in which they produce offspring, but after that they use up resources which could be used by newer generations. So having them weaken and die off makes sense from a species evolution perspective. The tradeoffs involved might have been bit different once the precursors of humans evolved to the point where they learned about the world and those with more experience helped the survival odds of a group. Of course the benefit was likely limited when the pool of potential knowledge that might be of benefit was small through most of history and likely most of it was acquired by the time they had the next generation of children.

      It may be that the leveling out of changes due to aging is simply an accident of evolution, since few people survived to that point so it wasn’t really selected for one way or another. The processes that helped thin the herd of elderly to make way for the new likely functioned well enough that new processes to continue age degradation didn’t need to evolve. Those few that survived despite the usual age weakening were likely both rare, and in groups successful enough for other reasons that there was no selection pressure for a process to arise to kill them off.

      1. Andrey Pavlov says:

        @realityengineer:

        Indeed those are some valid hypotheses. I think there are some tweaks that the data show us doesn’t quite jibe with some aspects of what you wrote, but overall seems reasonable. There are, of course, more reasons why and we haven’t quite sussed them out yet.

        1. RealityEngineer says:

          re: “tweaks that the data show us doesn’t quite jibe”

          I would be curious as to what those are, I haven’t delved into the issue in detail. I figured it was implied, but perhaps I should have noted that my comments were merely speculative hypotheses and weren’t driven by detailed research.

          1. Andrey Pavlov says:

            @RE:

            Indeed – I took your post exactly as intended. I apologize for the brevity and not being clear in that when I commented before. Dr. Rose’s wiki page can give you a little bit more information on the topic (at least a starting point).

            Fit individuals usually in aggregate lead the species to be more fit, however individuals dying off allow for newer generations that may be more fit than prior generations to take their place.

            The nuance here is that you needn’t necessarily die off in order to remove yourself from the gene pool and allow the F1 generation to supplant the F0 and lead to population level evolution. Menopause would be an example. Additionally the key here is that aging – senescence, more accurately – seems to actually STOP at a certain point and is non-existent (or at least very uncommon or undetectable) in species with asexual reproduction. This indicates that the process itself is more than just a means by which to cull off the older population in order to leave more resources for the younger. This is where protagonistic pleiotropy and/or polyphenism would come into play. The same process which allows for maturation and growth of young individuals could lead to senescence in older individuals by any number of mechanisms.

            Individuals need to be healthy through the period in which they produce offspring, but after that they use up resources which could be used by newer generations. So having them weaken and die off makes sense from a species evolution perspective.

            True, except that would need to be counterbalanced by the fact that fitness is measured in how many progeny you create that can themselves reproduce. A viable strategy would be to live longer and have a longer viable breeding time. This plays into K vs R selected species in terms of reproductive habits and would likely be a negative selection pressure against senescence.

            It may be that the leveling out of changes due to aging is simply an accident of evolution, since few people survived to that point so it wasn’t really selected for one way or another.

            This is true but needs a little bit further elaboration. You are correct that end-of-life and post-reproductive selection pressure would be very low thus allowing deleterious genomes to exist (cancer would be a good example of this). However the fact that senescence seems to stop at some point indicates that this lack of selective pressure is unlikely to have merely allowed it to happen by accident and then get fixed in populations. It must have evolved positively somehow on the front end and then there was simply no back end pressure to mitigate the later consequences of the process of senescence. In other words, it fits better with the pleiotropy and polyphenism hypothesis rather than being able to be ascribed just to genetic drift. (Hopefully that makes sense – happy to clarify if needed).

  5. Angora Rabbit says:

    Regarding the hype, given that every NIH proposal now requires us to describe and critique the Significance of our work, can you blame biomedical researchers for placing our work in a futuristic context? (disclaimer: I know David and respect his work.)

    I’ll read the paper tomorrow (promised self that today is sewing day) but the journalists’ idea that one can “raise” NAD is naive. We went through this several years back with the hangover “treatments”. One doesn’t increase cellular reducing power by feeding niacin (the NAD precursor) or even tryptophan (converted to niacin 1:60 ratio). I now predict (using my Randi crystal ball) a flood of “anti-aging” crapola featuring niacin and riboflavin.

    Cells work hard to maintain NAD at level X and the NADH/NAD ratio even more tightly. Which is why some readers feel so miserable this New Year’s morning. :) Raising NAD per se won’t increase ox phos or expression of proteins that participate in ox phos. I think the point of David’s paper (looking only at abstract so far) is that it identifies HIF1a signaling as an important coordinator nuclear/mito regulation of ox phos capacity, distinct from PGC1a. Which is pretty cool, actually, but is hard to explain to the laity. I don’t know what the solution is.

  6. gippgig says:

    Here’s the paper that might really lead to reversing aging:
    Pluripotent Stem Cells Induced from Mouse Somatic Cells by Small-Molecule Compounds (Science 341 651; doi: 10.1126/science.1239278)
    They showed that introducing the induced stem cells into mice had no harmful effects. They didn’t show that it had any effects on aging, but there will undoubtedly be people who are sufficiently desperate to try this on themselves and I’d sure like to know what the result is.

    #2.1: You CAN have income without jobs. People own shares of businesses. The businesses make profits. People get dividends. That may be where we’re heading. Just as it no longer made sense for most people to produce their own food once agriculture became established, we are reaching the point where it no longer makes sense for most people to earn a living. Everyone needs to realize this and plan for a future where most people don’t work (there are plenty of other worthwhile things to do such as creating, helping others, & discovering).

  7. JoshP says:

    Just a tangential thought about “Their muscle strength did not increase, despite the reported changes to the muscle cells”: well, maybe the potential is there but they need to do some resistance exercise in order to materialize it.

    I did not read the research article so maybe this avenue of thought was followed, in which case I apologize for your time.

  8. Dr Robert peers says:

    It is just so easy, dudes…nature has this hormone called igf one, that makes us grow, reach reproductive age, then…thanks it igf,s effects on stem cells ..we age and die……to stop this scenario, all we have to do is suppress igf signalling…I have identified, in the diets of centenarians, the molecule myo inositol, which suppresses the above growth and ageing pathway…bang, this turns on two key longevity transcription factors…foxo and nrf two…which in turn switch on a bunch of very ancient cytoprotective genes, for detoxification, oxidation resistance, protein damage control, and enhanced immunity…wow, and the immunity benefits include better t memory cell pool, plus more naive T cells, to supply regulatory and other T cells, throughout life…foxo also drives the expression of Oct four, a stem cell factor..which may explain partial soma to germ line transformation in long lived worm mutants…wow, that includes precision DNA repair and high velocity anti viral response…uniquely germ line functions, now seen in mortal somatic cells….wow….all done with grains, beans, nuts and citrus !!!!!!!!

    1. windriven says:

      Do you have some nice peer reviewed citations supporting this?

  9. I found a company selling a supplement containing NAD (www.zaoreset.com) and am thinking of trying it. Has anyone any else tried this product yet?

    1. Harriet Hall says:

      @Melissa,
      “Has anyone any else tried this product yet?”

      The question you ask is the wrong one for this website. If someone tries NAD and thinks it has helped them, they might be wrong. If someone tries it and thinks it doesn’t help, they might be wrong. Testimonial “evidence” is unreliable. A much better question is: has it been tested, and is there credible scientific evidence supporting its use? The Natural Medicines Comprehensive Database rates it as “possibly safe,” “Possibly ineffective” in dementia, and “insufficient evidence to rate” for other uses.

    2. Andrey Pavlov says:

      You should read Angora Rabbit’s comment above. Just in case, here it is:

      I’ll read the paper tomorrow (promised self that today is sewing day) but the journalists’ idea that one can “raise” NAD is naive. We went through this several years back with the hangover “treatments”. One doesn’t increase cellular reducing power by feeding niacin (the NAD precursor) or even tryptophan (converted to niacin 1:60 ratio). I now predict (using my Randi crystal ball) a flood of “anti-aging” crapola featuring niacin and riboflavin.

      Cells work hard to maintain NAD at level X and the NADH/NAD ratio even more tightly. Which is why some readers feel so miserable this New Year’s morning. :) Raising NAD per se won’t increase ox phos or expression of proteins that participate in ox phos. I think the point of David’s paper (looking only at abstract so far) is that it identifies HIF1a signaling as an important coordinator nuclear/mito regulation of ox phos capacity, distinct from PGC1a. Which is pretty cool, actually, but is hard to explain to the laity. I don’t know what the solution is.

      In other words, not only is Dr. Hall’s point very valid, but the idea that an NAD supplement could actually do anything is a bit of a stretch, to say the least.

    3. Sawyer says:

      You’re being to patient, Andrey and Harriet. This is clearly a spam account. Check the facebook link.

      She’s from Clearwater though, so maybe Scientologists are getting in on the supplement business. We have to reverse aging to resurrect L. Ron!

      1. Andrey Pavlov says:

        I try and be patient as much as I can. Sadly (or happily) I am still human and lose it from time to time, but in general it seems to me a better approach to maintain patience if not for the sake of the conversant but for others reading it. I – and you and many others here I imagine – will wade through vitriolic prose to glean the useful information. Many won’t.

        Plus, Angora Rabbit did 99% of the work on that comment for me :-D

    4. gippgig says:

      NAD should be broken down in the digestive tract so it is probably just a very expensive way to get niacin.

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