Lifespan extension


Subhash Katewa (Kapahi lab, Buck Institute) talked about the metabolic adaptations that occur in flies whose lifespan is being extended by dietary restriction (DR). Katewa is studying translational control in DR using a method called translational profiling, which uses the number of ribosomes bound to each mRNA as an index of translational activity (more ribosomes = more translation). He found that DR increases translation of messages that encode a variety of mitochondrial functions; this observation led to some interesting findings about the differential turnover of triglycerides in DR vs ad libitum flies.

Adam Freund (Campisi lab, Buck Institute) spoke about the sources of age-related inflammation, focusing on the senescence-associated secretory phenotype (SASP). Freund has elucidated mechanisms of SASP control that intermediate between the most upstream events in senescence (DNA damage) and its downstream effects (secretion of inflammatory factors). I have it on good authority that he has a completed manuscript on the subject, hopefully to be publshed soon, so I won’t say more about his story here. (Mr. Freund happens to be my baymate.)

Dario Valenzano (Brunet lab, Stanford University) is studying the genetic architecture of longevity in a short-lived fish Nothobranchius furzeri, the shortest-living vertebrate that can be reared in captivity. As a graduate student, Valenzano developed a system of biomarkers for tracking the progress of aging in skin, brain and other tissues – not only physical markers like the senescence-associated beta-galactosidase but also behavioral markers that change over the lifespan. He is now proceeding to map the longevity-associated genes in N. furzeri and testing the sufficiency of the genes he finds. Early results indicate that short-lived and long-lived fish are dying from different causes, as evidenced by a bimodal distribution of death rate vs. age.

Adolfo Sánchez-Blanco (Kim lab, Stanford University Medical School) described the “molecular odometer” for aging in the worm C. elegans. He began with the observation that lifespan is variable, even among clonally identical individuals kept under identical conditions. With genetics and environment taken out of the picture, what makes some individuals live longer than others? In order to address this question, SB had to develop a molecular marker (e.g., promoter activity of some gene) that measures physiological age (as opposed to chronological age), and then determine whether the expression level of that marker in individual worms is predictive of lifespan. SB has identified several such genes whose expression at middle age strongly predicts remaining lifespan. He is now actively looking for interventions that abolish the correlation between marker expression and longevity: if the marker gene’s activity is serving to overcome the life-shortening effect of some stress, then removing that stress will not necessarily abolish the variability in the marker, but will eliminate the correlation between marker levels and lifespan. (This is a subtle but important logical issue; I would have thought that one should look for interventions that drove the population distribution of marker levels toward the favorable side of the distribution. It was clear from questions that a lot of audience members had trouble with this logic, and I’m still not sure I understand it myself.)

(next session)

We know that exercise is good for us, and increasingly we’re understanding how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress; it also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our knowledge is sophisticated enough that we can identify and develop small-molecule exercise mimetics and drugs that improve exercise tolerance.

Overall, then, exercise and its molecular/cellular consequences are consistent with longevity assurance pathways and life extension interventions. However, there are complications emerging.

One of the results of exercise is increased activity of anabolic pathways, especially in muscle. Building up tissues require new protein synthesis, and new protein synthesis requires activity of the TOR pathway. TOR is increasingly thought to be a pro-aging or gerontogenic pathway: rapamycin, a drug that inhibits TOR, blocks senescence and extends lifespan in mice (we already knew that TOR inhibition increased longevity in worms and yeast).

Until recently, we’d believed that exercise modulated TOR in the “right” direction for longevity assurance (i.e., down). For instance, AMPK, a target of exercise mimetics, appears to downregulate TOR signaling.

But it would appear that the above result, obtained using exercise mimetics, may not be generally applicable to all exercise — in particular, it does not extend to a specific regimen of exercise designed to stimulate anabolism and muscle growth. In blood flow restriction (BFR) exercise, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle; it increases protein synthesis in muscle cells and activates the TOR pathway. Now, Fry et al. have shown that in older men (who don’t increase muscle mass in response to ordinary resistance training), BFR activates TOR.

Superficially, this would seem to represent a contradiction: a lifespan-extending intervention (exercise) activates a lifespan-shortening biochemical signaling pathway (TOR). How might this seeming paradox be resolved?

  • TOR activity in the muscle might be irrelevant to lifespan control. Testing this hypothesis is a special case of a broader question, which is the determination of the key tissues responsible for the lifespan extension by rapamycin. This will probably require tissue-specific conditional knockdowns of either TOR or downstream pathways (e.g., S6K), and will take a while.
  • Not all exercise is lifespan-extending. Perhaps exercise regimens specifically optimized to stimulate anabolism might be gerontogenic, while those that create acute stress and activate hormetic pathways might extend lifespan.

It’s also worth mentioning that BFR exercise may be uniquely bad vis-a-vis longevity control. In worms, one of the targets of TOR is HIF-1, the hypoxia inducible factor. HIF-1 is a gerontogene: knocking it down extends longevity, so its wildtype function must shorten lifespan. I wonder whether the blood flow restriction in BFR exercise might create low-grade hypoxia in the muscle tissue, inducing HIF-1 activity and incurring some gerontogenic effect. It certainly wouldn’t be the first time that an intervention that helped older men increase muscle mass ended up being bad for them in the long run (e.g., hGH).

ResearchBlogging.orgFry, C., Glynn, E., Drummond, M., Timmerman, K., Fujita, S., Abe, T., Dhanani, S., Volpi, E., & Rasmussen, B. (2010). Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men Journal of Applied Physiology DOI: 10.1152/japplphysiol.01266.2009

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SNPedia is a wiki-style index of genetic variants that have interesting phenotypic associations in human beings. The name comes from the acronym for “single nucleotide polymorphisms,” i.e., one-letter variations among different individuals’ genomes.

In honor of the new year, one of the proprietors has posted SNPedia’s Top 10 SNPs of the Year, based on an admittedly “subjective combination of medical importance, statistical believability, and overall general interest.” The variants that made the list are associated with a wide range of phenotypes, but they fall into a few categories:

  • benefits of major drugs (e.g., effect of Plavix on heart disease risk);
  • likelihood of drug side effects (e.g., myopathy in response to statins);
  • risk for specific diseases (CVD, periodontitis, cancers)

The list, especially the items regarding drug efficacy and adverse reactions, got me thinking about anti-aging medicine.

Any hypothetical longevity-enhancing therapies will be more or less effective, and be subject to more or less severe side effects, as a function of individual genetic variation. One consequence of pharmacogenetic variability is that small or insufficiently diverse trial populations (in which specific genetic variants might be underrepresented) can result in misleading results about a therapy’s potential efficacy in the general population. And it’s hard to know, in advance of preliminary results, what the relevant variants might be.

This logic is general to a wide variety of therapies. Drugs are just molecules of varying shapes and sizes, and molecules of all shapes and sizes mediate cell-cell interactions, so it’s likely that pharmacogenetics will influence cellular therapies as well as more conventional pharmaceutical approaches. I suspect that cellular therapies might even be more vulnerable to genetic variation, since cell-cell interactions rely on proteins and other molecules produced by multiple genetic loci – e.g., not just a receptor or a ligand but both the receptor and the ligand acting together – and these pairwise interactions will be even more difficult to tease out than phenotypes that rely on a single locus.

It’s already going to be hard to determine over short intervals whether a given anti-aging therapeutic is effective, since we don’t (yet) have biomarkers that allow us to measure the rate of aging. Most of the best biomarkers are most convincing at the population level, and it’s hard to use them to compare the rate of physiological vs. chronological aging in a single individual. Therefore, proof of efficacy of longevity-enhancing treatments will rely on long studies and sizable populations of subjects – and the existence of unresponsive genotypes in the population will further confound that analysis.

Granted, we already know that building an anti-aging pharmacopeia will be challenging, and I’m not suggesting that this line of reasoning means we should pack up and go home. I mention it mostly because genetic variations will almost certainly play an important role in determining the efficacy of any given therapy, and we had best be prepared for that.

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A review I should have cited yesterday addresses the promise and challenges of the two most prominent natural-product candidates for longevity-enhancing therapeutics. The author is prominent biogerontologist and all-around bright feller Matt Kaeberlein (see here for earlier posts on his group’s work).

Resveratrol and rapamycin: are they anti-aging drugs?

Studies of the basic biology of aging have advanced to the point where anti-aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age-associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti-cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age-related diseases by modulating the molecular causes of aging.

Note that resveratrol has been taking a bit of a thrashing of late, with recently released studies calling into question its ability to directly activate sirtuins. Briefly, the critics posit that the early data may have been misinterpreted due to artifacts in a fluorescence-based system used to detect protein-drug interactions — but check comment #32 on that post for David Sinclair’s personal response on this issue.

ResearchBlogging.orgKaeberlein, M. (2010). Resveratrol and rapamycin: are they anti-aging drugs? BioEssays, 32 (2), 96-99 DOI: 10.1002/bies.200900171

One of 2009’s most significant breakthroughs in biogerontology (or in any field; q.v. Science, WIRED) last year was the announcement that the macrolide drug rapamycin can extend longevity in mice.

More specifically, rapamycin can accomplish this when administered to adult, wildtype mice. In other words, no genetic modification or early-life intervention is necessary, making rapamycin one of the first compounds that meets the criteria for an anti-aging drug that could be used for people who are already alive and well down the road toward aging themselves.

The lifespan extension achieved is modest (~10%), but this is more impressive in light of the fact that the mice were quite old at the time treatment began, and the study used only a single dose rate. Future studies will undoubtedly seek to optimize the dose and regimen with the goal of achieving greater enhancement of lifespan.

How does it work? As the saying goes, further study is required, and at multiple levels.

• Organism: It is possible that rapamycin acts by delaying the onset of cancer, frankly slowing the aging process, or a combination of both. (This issue could be addressed by using genetically engineered mouse strains that exhibit very little cancer.)

• Tissue: Rapamycin might decelerate cellular senescence, which could fight aging in two ways: by maintaining cells in a division-competent state (and thereby increasing the pool of cells available to regenerate tissues), and by ameliorating the damaging effects of deleterious inflammatory secretion by senescent cells. This is complicated by the fact that senescence is itself a tumor-suppressor pathway; in the absence of data to the contrary, one might have expected the drug to have a modest oncogenic effect, but that doesn’t seem to be the case in the mouse studies. (It’s worth mentioning that the author of that first senescence study prognosticated the efficacy of rapamycin as an anti-aging drug several years ago).

• Cell: With respect to cellular and molecular mechanisms, all eyes are on the TOR pathway (“target of rapamycin”; the protein is inhibited by rapamycin) . The TOR kinase, which has been implicated in lifespan control in smaller organisms, regulates translation by modulating the activity of ribosomal proteins and elongation factors. Deleting the S6 kinase gene (a target of TOR; eliminating S6K is like selectively turning off a specific arm of the TOR pathway) extends lifespan in rodents – consistent with the idea that TOR exerts its effects on aging by controlling translation.

There’s a good deal left to discover about the rapamycin’s effects on aging in general — and regarding the specific mechanistic relationship between translational control, senescence, and organismal aging — but I have it on good authority that there’s a great deal of effort being exerted in that direction. Watch this space for future developments.

If you’re interested in reading more, there’s a nice post on the issue over at Fight Aging!

Oh, I almost forgot – impending pun alert – in the “cruel irony” department, rapamycin may inhibit the formation, consolidation and preservation of long-term memory; it’s even been proposed as a treatment for PTSD. (To make a very long story short, protein translation is required for establishment and maintenance of memories.) It’s not yet clear whether the doses of rapamycin that extend lifespan will have an effect on memory, but it’s clearly crucial to figure that out. It would be a damn shame to live an extra ten or twenty years at the cost of slowly forgetting one’s past. I’ll be following that emerging story with interest.

More elsewhere:

We are all descendents of an unbroken line of cell divisions, dating back to the last common ancestor of all life on Earth. At some point, long after our lineage had acquired features like nuclei and mitochondria, a less distant ancestor stumbled on a major innovation: it grew a body, bringing with it the advantages of cell and tissue specialization.

For many multicellular organisms, this specialization included a distinction between the mortal cells (the “soma”) and the potentially immortal cells (the “germ line”) that are capable of participating in the creation of new organisms. When you look at us, most of what you see is soma — the germ line is safely tucked away in the gonad, which is (usually) itself tucked away someplace safe.

But both the germ line and soma are made of cells. How is it that the soma is mortal while the germ line is, for practical purposes, immortal?

The disposable soma theory of aging begins from the premise that an organism has access to a finite amount of resources (broadly, energy and matter), and that it must distribute these resources in a way that maximizes reproductive fitness. First dibs goes to the germ line (without which it doesn’t matter, in a fitness sense, what becomes of the rest of the organism) and the rest gets divided among the cells of the soma.

For the moment, all we really need to take away from this model is that the germ line and soma are maintained in different ways, either in quality or extent. The germ line is doing something differently than the soma, the upshot of which is that the germ line is immortal. (A strict interpreter of the theory would presume that this “something” is resource-intensive, so that it wouldn’t be possible to apply the strategy to the soma. It’s also possible, however, that it’s simply inconsistent with optimal somatic functions — e.g., that making a muscle the best muscle it can be requires that myocytes not partake of the germ line strategy for immortality, for some structural reason that has nothing to do with resource allocation per se.)

One oh-wow corollary of this model is that if somatic cells could be made more like germ line cells, they would live longer. This prediction has a deliciously outrageous quality — yet is so simple that upon first hearing it, I reached for the nearest journal with the intention of rolling it up and smacking myself repeatedly on the forehead. Fortunately, there was a copy of Nature handy.

To be honest, it didn’t really happen that way. That copy of Nature contained the very article that introduced me to this concept: Curran et al. have shown that in long-lived mutants of the worm C. elegans, somatic tissues start acting like germ line cells:

A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants

Unlike the soma, which ages during the lifespan of multicellular organisms, the germ line traces an essentially immortal lineage. Genomic instability in somatic cells increases with age, and this decline in somatic maintenance might be regulated to facilitate resource reallocation towards reproduction at the expense of cellular senescence. Here we show that Caenorhabditis elegans mutants with increased longevity exhibit a soma-to-germline transformation of gene expression programs normally limited to the germ line. Decreased insulin-like signalling causes the somatic misexpression of the germline-limited pie-1 and pgl family of genes in intestinal and ectodermal tissues. The forkhead boxO1A (FOXO) transcription factor DAF-16, the major transcriptional effector of insulin-like signalling, regulates pie-1 expression by directly binding to the pie-1 promoter. The somatic tissues of insulin-like mutants are more germline-like and protected from genotoxic stress. Gene inactivation of components of the cytosolic chaperonin complex that induce increased longevity also causes somatic misexpression of PGL-1. These results indicate that the acquisition of germline characteristics by the somatic cells of C. elegans mutants with increased longevity contributes to their increased health and survival.

Just to be clear: the somatic tissues of the long-lived mutants had not actually transformed into germ line cells as such, nor were the mutant worms festooned with extra gonads (though admittedly, that would be totally awesome). Rather, the somatic tissues exhibited gene expression patterns ordinarily found only in the germ line.

On the correlation vs. causation issue: The authors showed, using RNAi knockdowns, that the germ line-restricted genes were required for the longevity enhancement due to the mutation in daf-2 (worm insulin/IGF). There’s a bit of a wrinkle: in wildtype animals, blocking these same genes actually resulted in an increase in lifespan. How to explain that? The proffered rationale is that in the wildtype, germ line-restricted genes are only present in the germ line. Knocking them down has no effect on somatic tissue, but might reduce the activity of germ line cells; it’s been known for some time that ablating part of the gonad has life-extending consequences in wildtype animals.

The critical observation, in any case, is that the germ line genes are turned on in daf-2 mutants, and this activation is necessary in order for daf-2 mutation to extend lifespan.

Next questions, in rough order of difficulty:

  1. Does the soma-to-germ line transition occur in other long-lived mutants, or in calorie restricted animals?
  2. By what mechanisms are the germ line-restricted genes extending the somatic lifespan?
  3. Will this finding generalize to other metazoans?
  4. Do the germ line genes expressed in daf-2 soma contribute to germ line immortality?

ResearchBlogging.orgCurran, S., Wu, X., Riedel, C., & Ruvkun, G. (2009). A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants Nature DOI: 10.1038/nature08106

Welcome to the tenth edition of Hourglass, our blog carnival about the biology of aging. This month, the carnival has returned home to Ouroboros. In this issue, we have submissions from six bloggers, including a nice mix of veterans and new participants. Several of the posts are united by common themes: we have heavy representation from the neuroscience community, and multiple discussions of the clinical and social payoffs that are likely to result from progress in lifespan extension.

At psique (which hosted Hourglass IX), Laura Kilarski describes an important, evolving online tool for biogerontologists: the Human Aging Genomics Resources:

As I was reading a paper earlier about chromosomal region 11.5p and its putative association with aging (Lescai et al, 2009) I came across an interesting sounding url, namely http://genomics.senescence.info. Turns out that the website is home to HAGR, an interdisciplinary project devoted to the genetic study of aging … GenAge constitutes a major part of the site, and is a manually curated database of genes which could possibly be associated with human aging, largely based on studies done on the usual suspects: Mr. Mouse, Drosophila, C. elegans, and yeast. … The AnAge database on the other hand contains entries for over 4000 animals and some basic life-span-related facts. … And then there’s the ‘Δ Project’, the aim of which is to figure out transcriptional differences between young and old organisms.

Laura describes HAGR in depth and also provides some of her own analysis of the available resources.

On another age-related subject, neurodegeneration, Laura discusses the potential value of regular brain scans for early ascertainment of diseases such as Parkinson’s. Free brain scans for all! It’s a moving piece, which underscores the human cost of neurodegenerative illness and describes the author’s personal reactions on the subject, while also addressing important clinical and scientific issues.

As we age, we all suffer from some level of neurodegeneration, though in most cases this falls below the threshold of a clinical pathology. Slow chronic change isn’t the only form of age-related brain damage: let’s not forget about strokes, which can wipe out otherwise healthy neurons in macroscopic regions of the brain. While the risk factors for stroke and neurodegeneration are distinct, therapies might ultimately be quite similar — since in both cases, the goal is to regrow neurons to replace those that have been lost. At Brain Stimulant, Mike tell us about a clinical trial that will use stem cells to treat stroke:

The company Reneuron has just recently gotten the go ahead to commence a new trial that will use stem cells to treat patients with stroke damage. The trial will use stem cells to replace missing brain matter in those who have had stroke brain trauma. They are injecting doses of approximately 20 million stem cells into the stroke patients brain. Interestingly these ReN001 stem cells will not require a patient to have immunosuppression therapy.

He goes on to discuss the future challenges posed by the prospect for brain engineering: precise cell delivery, control of axon sprouting and pathfinding, and the possibility of using non-invasive methods to encourage the growth of new cells.

Also coming from a neuroscience perspective, Christopher Harris of Best Before Yesterday writes about What we need to accelerate biomedical research and fight aging.

A few hundred years ago I could not have been born. I was massive – 5.5kg – and the birth eventually turned caesarean and took many long hours. I owe my life to medical science. One day, 11 years later, I was out biking and realized for the first time that the annihilation following my death would be infinite. Now, 25 years after my complicated birth, I think a lot about whether medical science, rejuvenation research of the SENS variety in particular, will save me a second time.

What do we need? According to Harris: (1) Safe and inexpensive brain surgery (to install devices that can manipulate the reward circuitry of the brain); (2) Widespread use of enhanced motivation through deep brain stimulation (specifically to encourage exercise and healthy living); and (3) Rewarding brain stimulation for research centers (to accelerate scientific progress).

One of my favorite new sites, the Science of Aging Timeline, has a new entry about the Sinclair lab’s discovery of sirtuin-activating compounds:

Working off a model of calorie restriction via sirtuins David Sinclair et al. worked to find molecules which could modulate sitruins activity, and thus longevity.

They accomplished this by screening a number of small molecule libraries, which included analogues of epsilon-acetyl lysine, NAD+, NAD+ precursors, nucleotides and purinergic ligands. Results from the screening where assayed against human SIRT1 to identify potential inhibitors, and the following molecules where found: Resveratrol, Butein, Piceatannol, Isoliquiritigenin, Fisetin, and Quercetin. Of all of these, resveratrol proved to be the most potent …

In the copious spare time left when he’s not working on the comprehensive history of biogerontology, timeline curator Paul House has started another ambitious project: a catalog of all the labs working on aging. It’s early days yet, and only a few labs are listed, but I’ve already seen Paul take one great idea (the timeline) from seed to oak, so I have every confidence that this page will grow substantially in the weeks and months to come. Those who are interested in having their labs listed on the page can send Paul an email.

Over at Fight Aging!, Reason continues excellent coverage of recent papers in biogerontology; I daresay that the detail of coverage on primary scientific literature has improved even further in the past month or so, concomitant with the site’s participation in the ResearchBlogging tracking system for blog posts about journal articles. For this edition of Hourglass, Reason has submitted two excellent analyses of recent papers, and a third piece of a more philosophical bent:

It is from the last piece that I’ve chosen an excerpt:

Wouldn’t it be nice to wake up and find that we were all immortal? That would save a whole lot of work, uncertainty, and existential angst – and we humans are nothing if not motivated to do less work. The best of us toil endlessly in search of saving a few minutes here and a few minutes there. So it happens that there exist a range of metaphysical lines of thought – outside the bounds of theology – that suggest we humans are immortal. We should cast a suspicious eye upon any line of philosophy that would be extraordinarily convenient if true, human nature being what it is.

Moving on from a philosophical post written by a scientifically minded life-extension advocate, our next posts are scientific posts written about life extension from a political philosopher. Colin Farrelly of In Search of Enlightenment has submitted two long, thoughtful articles, the first about the clinical and social importance of tackling aging, the second about the cognitive biases that affect the way we think about risk and the significance of aging as a cause of mortality:

The “availability heuristic” was a new one on me. Here’s an operational definition as it applies to our thinking about aging:

In a rational world, aging research would be at the forefront of a global collaborative initiative to improve the health and economic prospects of today’s aging populations (and all future generations).

But humans are not rational. We suffer many cognitive biases. One prominent bias is the availability heuristic. Risks that are easily brought to mind are given a higher probability; and conversely, the less vivid a risk, the more likely we are to underestimate the probability of their occurring.

The two tests above reveal how prominent this heuristic is in your own comprehension of the risks facing yourself, your loved ones and humanity. Because death by aging is not something that is vivid is most people’s minds (though it is in the minds of the scientists who study the biology of aging and thus know all too well how it affects a species functional capacities), odds are you probably underestimated it as a risk of mortality.

The benefits of lifespan extension, both with regard to human health and society as a whole is sometimes called the Longevity Dividend. Alvaro Fernandez from SharpBrains sent in a long piece about the Longevity Dividend (written by a contributor from the Kronos Longevity Research Institute). Ever heard of the Longevity Dividend? Perhaps Gray is the New Gold:

The Longevity Dividend is a theory that says we hope to intervene scientifically to slow the aging process, which will also delay the onset of age-related diseases. Delaying aging just seven years would slash rates of conditions like cancer, diabetes, Alzheimer’s disease and heart disease in half. That’s the longevity part. … The dividend comes from the social, economic, and health bonuses that would then be available to spend on schools, energy, jobs, infrastructure—trillions of dollars that today we spend on healthcare services. In fact, at the rate we’re going, by the year 2020 one out of every $5 spent in this country will be spent on healthcare. Obviously, something has to change.

Alvaro, the editor of SharpBrains and founder of the parent website, has recently published a book, The SharpBrains Guide to Brain Fitness, which is the subject of this recent (and quite favoriable) review. If you’re interested in learning more, here’s list of cognitive fitness references, based on the authors’ research for the book.

That’s all for now. If you’d like to host a future installation of Hourglass, please email me.

In 2008 I was involved in an April Fool’s Day prank: a horde of science bloggers, under the sway of a charismatic yet psychotic leader, all conspired to publish the same fake story: that the NIH and European science funding bodies had decided to ban the use of grant funds by scientists who engage in “brain doping”, i.e., mental performance enhancement through the use of pharmaceuticals.

The prank was relatively successful — enough so that mastermind Jon Eisen got calls from reporters pursuing it as a legitimate story — but we can’t take all the credit. The fake story was believable in large part because it was so close to the truth: “brain doping” is actually very widespread, enough so that several entities in the mainstream media had already pondered its potential effects on the “level playing field” of academic science (see the list in the original prank post).

Margaret Talbot’s recent New Yorker piece is probably the longest and most comprehensive treatment of the subject I’ve seen so far. It starts with a discussion of brain doping by students but also considers their role in the workplace and the medical, ethical and sociological implications of cognitive enhancement (though, happily, it doesn’t spend very much energy hand-wringing over worst-case scenarios resulting from use and abuse of such approaches). There’s even a connection to lifespan extension (link):

BRAIN GAIN: The underground world of “neuroenhancing” drugs

And on Internet forums such as ImmInst, whose members share a nerdy passion for tweaking their cognitive function through drugs and supplements, people trade advice about dosages and “stacks”—improvised combinations—of neuroenhancers. …

Seltzer considers himself a “transhumanist,” in the mold of the Oxford philosopher Nick Bostrom and the futurist writer and inventor Ray Kurzweil. Transhumanists are interested in robots, cryogenics, and living a really, really long time; they consider biological limitations that the rest of us might accept, or even appreciate, as creaky obstacles to be aggressively surmounted. On the ImmInst forums—“ImmInst” stands for “Immortality Institute”—Seltzer and other members discuss life-extension strategies and the potential benefits of cognitive enhancers.

I’ve argued before that there are profound similarities between some of the ethical issues raised by cognitive enhancement and those raised by lifespan extension, especially in the structure of the arguments underlying opposition to these kinds of intervention. For those of us interested in expanding human longevity, it will be wise to keep abreast of the discussion.

One of the central precepts of biogerontology is that meaningful lifespan extension will be concomitant with extension of the “healthspan”, i.e., the vigorous part of life — life that is, for lack of a better phrase, worth living.

This relationship is borne out both in nature (where longer-lived organisms also have longer healthspans) and in the laboratory, where genetic and pharmaceutical manipulations increase longevity also increase the duration of healthy life (q.v. Apfeld and Kenyon‘s study of the worm daf-2 mutant, which is still active and visually “young” at a time when most of its wildtype cohorts are moribund).

A related point is essentially the converse: We screen for longevity genes by looking for mutants that confer extended lifespan, rather than those that shorten it. It’s very easy to decrease longevity by making an animal sick. Genetic changes that derange or destroy vital functions are likely to hasten death but are unlikely to teach us anything about the fundamental mechanisms of aging.

In addition to being a unifying theme in academic biogerontology, this idea is also an important aspect of the way that those of us in the life extension movement answer an oft-encountered objection to longevity enhancement, which I will now state in the most charitable way I can: We’ve seen our parents and grandparents age and become frail, slowly stripped of their mental acuity and physical dignity. People aren’t so much living longer as “dying longer.” Why, then, would we want to add ten or twenty years to that painful process? (This line of thinking has been termed the Tithonus Error, after the Greek myth of the man whose immortal lover wished for him eternal life but forgot to add a clause for eternal youth; Tithonus ended up shrinking into a cricket, which the goddess kept in her pocket.)

The answer to this objection is that we don’t want to simply add years to life, but life to years — and, based on what we know from decades of biogerontological research, we expect lifespan extension to necessarily entail healthspan extension. In order for us to consider the Tithonus error to be an error, we must believe this is so. (There are those who would argue that conscious life at any cost is worthwhile, regardless of physical health, and I’m not sure they’re wrong, but that’s a subject for another time. The point here is that the “twenty more years in the ICU” objection is an important part of the larger public debate on the issue of longevity research, and it needs to be answered — and we feel like we have done so.)

Because of the importance of this assumption, we need to be on the lookout for counterexamples, such as the one provided by a recent study from Avanesian et al.. The authors show that lamotrigine, an anticonvulsant medication already shown to extend lifespan in the worm C. elegans, also has longevity benefits in the fly — but at an apparent cost to healthspan:

Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster

he discovery of life extension in Caenorhabditis elegans treated with anticonvulsant medications has raised the question whether these drugs are prospective anti-aging candidate compounds. The impact of these compounds on neural modulation suggests that they might influence the chronic diseases of aging as well. Lamotrigine is a commonly used anticonvulsant with a relatively good adverse-effects profile. In this study, we evaluated the interaction between the impacts of lamotrigine on mortality rate, lifespan, metabolic rate and locomotion. It has been proposed in a wide range of animal models that there is an inverse relationship between longevity, metabolic rate, and locomotion. We hypothesized that the survival benefits displayed by this compound would be associated with deleterious effects on health span, such as depression of locomotion. Using Drosophila as our model system, we found that lamotrigine decreased mortality and increased lifespan in parallel with a reduction in locomotor activity and a trend towards metabolic rate depression. Our findings underscore the view that assessing health span is critical in the pursuit of useful anti-aging compounds.

In short, lamotrigine extends life but decreases metabolism and locomotor activity. The conclusions are a bit confounded by the nature of the drug used. Lamotrigine is an anticonvulsant; it’s not surprising that long-term depression of neuromuscular activity would diminish locomotor activity. Still, the paper represents a clear counterexample to the positive association between healthspan and lifespan.

Let me be clear: I do not think that this study represents a serious blow against the idea that lifespan extension will entail healthspan extension — the idea is well supported in both nature and the laboratory. Rather, as the authors point out, the existence of exceptions to the general case underscores the importance of vetting each candidate longevity enhancement therapy for its effects on healthspan, before rushing into further development.

This raises a further question: We believe that lifespan is regulated, at least in part, by processes that have been conserved across evolution — this is the fundamental justification for studying aging in model organisms. When leads are generated in model organisms like worms and flies, however, should negative outcomes/side effects rule out further study and development in models that are evolutionarily closer to humans, such as mice? Or should any promising longevity enhancement therapy in the smaller metazoans be vetted in mice before conclusions are drawn?

ResearchBlogging.orgAvanesian, A., Khodayari, B., Felgner, J., & Jafari, M. (2009). Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster Biogerontology DOI: 10.1007/s10522-009-9227-1

Fasting (intermittent, IF, or alternate day, ADF) may be the newest diet craze rivaling calorie restriction (CR) to increase longevity and improve health. Recent reports have shown that fasting diets can confer health benefits similar to (or even greater than) those of chronic calorie restriction (CR), without reducing the number of calories consumed relative to an ad libitum diet. The molecular mechanisms underlying the IF diet induced longevity are not well understood.

Honjoh et. al. established a fasting diet regimen in C. elegans to study molecular pathways involved in fasting induced longevity. They found that alternate day fasting (ADF) had a 40.4% increase in lifespan, and intermittent fasting (IF: every two days) had a 56.6% increase in lifespan over ad libitum fed worms. In contrast, chronic CR only increased lifespan by an average of 13.2%.

CR and IF may have similar effects on lifespan, but results reported in this paper indicate that signals in each of these processes are distinct. skn-1 and pha-4 have been shown to be essential genes in the CR longevity phenotype, but are dispensable in IF longevity.

Two proteins that were found to be important in this model of IF induced longevity are RHEB-1 (Ras homologue enriched in brain) and it’s downstream target, TOR (target of rapamycin). Inactivating either of these genes suppressed the longevity of worms on the IF diet, adding support to the role RHEB and TOR proteins play in influencing lifespan. Interestingly, inactivation of RHEB-1 did not mimic IF longevity, instead it recapitulated CR in lifespan increase and target gene activation. Thus, the authors conclude that RHEB-1 has a dual role in lifespan regulation.

Signaling through RHEB-1 mediates intermittent fasting-induced longevity in C. elegans.

RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signaling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signaling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signaling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signaling pathway.

The authors performed a microarray on fasted worms with or without RHEB-1 or TOR RNAi to identify gene expression changes. They found that the majority of genes that were upregulated as a result of fasting were dependent on RHEB-1 and TOR (100 out of 112 genes and 94 out of 112, respectively). RNAi of either RHEB-1 or TOR suppressed the induction of these genes in fasting. Through further analyses, hsp-12.6 (the C. elegans orthologue of αB-crytallin) and ins-7 (insulin-like peptide 7) were identified as downstream targets of RHEB-1 and TOR and are critical for mediating the IF-induced longevity phenotype.

It will be important to follow up on these findings, which elucidate the molecular pathways behind longevity diets, to determine how different diets overlap (or are distinguished) at the molecular level – especially considering that it seems improbable that people will willingly embrace a lifelong restricted diet to improve their health and lifespan. Understanding these pathways and factors involved will hopefully advance our ability to develop pharmaceuticals to mimic the benefits observed in these longevity diets.

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