I’ll never be like you: Daughter cells send toxic aggregates back to mom

Cells tend to produce unwanted protein aggregates and other molecular refuse slightly faster than they can get rid of it, resulting in a time-dependent accumulation of potentially toxic cellular garbage. This, in turn, can cause an age-dependent loss of cellular viability, which is (in certain contexts) a fair operational definition of aging.

How can cells deal with their garbage? Protein aggregates are both sticky and insoluble, making it hard for cellular machinery to deal with them at an enzymatic level. If the gunk can’t be eliminated, however, it might still be possible to move it around in a useful way. Specifically, at mitosis, the cell could make sure that all the potentially toxic aggregates stay in one of the progeny. To illustrate the argument I’ll turn to the words of the estimable Alex Palazzo:

One approach is to distribute everything equally amongst your two offspring. …

A second approach is to give all the crap to one of the two new cells and keep the other one pristine. Lets call these two cells the crap cell and the pristine cell. What’s the result of this second strategy? Using our crap metric from above, the first cell accumulates 10 units of garbage over its lifetime and then gives it all to one offspring, the crap cell, and none to the other offspring, the pristine cell. Those cells then grow and by the time they divide each second generation cells have made 10 units of additional crap each. The crap cell has 20 units the pristine cell 10. The two cells divide and dump all their garbage on one of their offsprings. One cell starts with 20 units of crap, one cell with 10 units and two cells are again crap free. The end result of this strategy? Part of your descendents will become more and more decrepit as they fill up with crap, while others remain pristine.

The crap cell (I love this nomenclature) will become inviable sooner under this strategy, but the alternative would be a symmetric division strategy in which all descendants accumulate garbage, ultimately causing the extinction of the entire lineage. The idea here is that assuming certain values for adjustable parameters re: the rate of garbage accumulation and the effect of garbage level on reproductive fitness, this can be an advantageous strategy to ensure reproductive success. Both single-celled yeast and mammalian stem cells employ this asymmetric strategy in order to preserve the viability of an indefinitely dividing lineage.

In yeast, the crap cell is called the “mother”; the pristine cell is called the “daughter” — mom accumulates garbage of various kinds, both protein aggregates and rDNA circles. When the mother is ready to divide, a bud forms at a specific site on her cell wall, defined by a set of macromolecular complexes that determine cellular polarity. Liu et al. have demonstrated that the daughter cell is using some of the same polarity-determining machinery (the “polarisome”) to actively transport protein aggregates back into the mother:

The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates

The paradigm sirtuin, Sir2p, of budding yeast is required for establishing cellular age asymmetry, which includes the retention of damaged and aggregated proteins in mother cells. By establishing the global genetic interaction network of SIR2 we identified the polarisome, the formin Bni1p, and myosin motor protein Myo2p as essential components of the machinery segregating protein aggregates during mitotic cytokinesis. Moreover, we found that daughter cells can clear themselves of damage by a polarisome- and tropomyosin-dependent polarized flow of aggregates into the mother cell compartment. The role of Sir2p in cytoskeletal functions and polarity is linked to the CCT chaperonin in sir2Δ cells being compromised in folding actin. We discuss the findings in view of recent models hypothesizing that polarity may have evolved to avoid clonal senescence by establishing an aging (soma-like) and rejuvenated (germ-like) lineage.

Note the role for Sir2p, the founding member of the sirtuin family of longevity assurance genes: Sir2p is required, via another protein’s activity, for the normal folding of actin, the cytoskeletal protein from which the daughter-mother transport cable is built. It’s an indirect interaction, and more complex than I’m making it out to be here. Nonetheless, it is satisfying for those of us looking for unifying theories in aging that one of the most widely studied proteins in lifespan regulation is involved in the deep connection between polarity and aging.

I’ll close with a few questions:

• Why can’t the mother cell export the aggregates? One of our initial premises was that aggregates are biochemically hard to handle, which is why they accumulate rather than being degraded. But now we know that cells can bundle aggregates onto actin cables and move them around — why not sort the aggregates into vesicles or membrane blebs and dispose of them? Granted, in order to export an aggregate out of the cell, it would have to cross a membrane, but this would be no more difficult topologically than mitophagy. The obvious (and trivial) answer to this question is “because it didn’t evolve that way,” but I’m curious to know whether there’s some compelling reason why it couldn’t have evolved that way.

• How do symmetrically dividing cells overcome this problem? In order to exploit asymmetric division, one must first establish polarity. The argument above about the rate of garbage accumulation would seem to apply equally well to non-polarized cells like bacteria – why, then, do clonal lineages of symmetrically dividing cells not invariably go extinct? Maybe the cells that we think are symmetric are secretly asymmetric, with a crap/pristine segregation that has yet to be uncovered. Or maybe the symmetric cells know something about garbage disposal that we don’t. In either case, there’s something important to learn that might help us keep mammalian cells youthful.

Liu, B., Larsson, L., Caballero, A., Hao, X., Öling, D., Grantham, J., & Nyström, T. (2010). The Polarisome Is Required for Segregation and Retrograde Transport of Protein Aggregates Cell, 140 (2), 257-267 DOI: 10.1016/j.cell.2009.12.031

 

Mazel tov! You should have such long telomeres

A study of Ashkenazi Jewish centenarians by Atzmon et al. has revealed that telomere length is correlated with longer lifespan and slower biological aging (reflected in measurements of several biomarkers of aging). Both lifespan and telomere length are, in turn, correlated with polymorphisms at the hTERT and hTERC loci, two genes that respectively encode the major protein and RNA component of telomerase.

Recently we learned that telomere length is a biomarker of chronological age – in other words, that younger people have longer telomeres in general. This correlation is imperfect, unsurprisingly, and probably for lots of reasons, including individual variations in lifestyle, outlook, stress levels, and other factors. This new study demonstrates that there some of the difference between individuals in the rate of telomere shortening over time is under genetic control.

Atzmon, G., Cho, M., Cawthon, R., Budagov, T., Katz, M., Yang, X., Siegel, G., Bergman, A., Huffman, D., Schechter, C., Wright, W., Shay, J., Barzilai, N., Govindaraju, D., & Suh, Y. (2009). Evolution in Health and Medicine Sackler Colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians Proceedings of the National Academy of Sciences, 107 (suppl_1), 1710-1717 DOI: 10.1073/pnas.0906191106

Related articles elsewhere:

• TERC, telomerase, and rate of aging (The Longevity Meme)
• Common variants near TERC are associated with mean telomere length (Nature Genetics)

 

Now we are six

A somewhat belated happy birthday to Fight Aging!, an important resource for lifespan extension advocates that also has some of the best (and constantly improving) scientific coverage in the field. Fight Aging! (and its older companion effort The Longevity Meme) are two fine websites that this humble blog is proud to count as friends. We might not agree on everything, but then again, who does?

If you’re not reading Fight Aging!, you should be.

Congratulations to FA’s proprietor, Reason. Happy sixth blogiversary, and many (many, many…) happy returns!

 

Corpsicles in The New Yorker

No science today, I’m afraid, but I did want to point anyone who’s behind on their back issues of The New Yorker toward a nice piece on cryonics (on the movement in general and the Cryonics Institute in particular).

I mention this here because while scholars of biogerontology don’t generally study cryonics, the latter subject seems to orbit the former like a dim moon. I tend to get questions about cryonics when I make public appearances to talk about longevity research. That isn’t surprising, since both subjects share a common goal, if not methodology or standards for intellectual rigor. Consequently, my ears tend to prick up whenever I see it mentioned in the mainstream popular literature.

I’m a cryonics skeptic of the “extraordinary claims require extraordinary evidence” flavor. As I’ve said before, I suspect that long-term preservation of the potential for life by freezing or other means is physically possible, but at present I don’t think we’re making any significant progress in that direction. Part of the problem is that there’s very little serious initiative within the mainstream of academia or industry to build the many, many necessary precursor technologies. Another part is that the problem is really, really hard – harder than the comparatively simple but still unsolved problem of maintaining cellular viability within tissues at low temperatures. In the New Yorker article, they hit the nail on the head:

“Neuropreservation” has a scientific attitude, but that doesn’t make it science. Credentialled laboratory scientists don’t generally think the dead will one day awaken. The consensus appears to be that when you try to defrost a frozen corpse you get mush. And even if, in the future, scientists could repair the damage done to cells by freezing and thawing, what they would have, at best, is a cadaver.

Got that? In order for cryonics to work, we have to be able to do a lot of hard things:

1. Preserve cells at ~100% viability.99% just ain’t gonna cut it, especially in tissues like the heart and brain, and we’re barely there even in ideal situations like loose cells in rich media loaded with antifreeze compounds
2. Cure the disease or other condition that (would have) killed the subject. I’ve never been clear on whether that would happen in the frozen state, or the inanimate and presumably further deteriorating thawed corpse. Both pose formidable technical hurdles.
3. Bring people back from the dead. Literally resurrect them.

That last step is, as they say, a doozy: Let’s imagine that you’ve got a dead person on the table: their cells are viable, you cured whatever ailed them – but not only are their brain and heart silent, but the metabolism of every cell is at best restarting from an inactive state, and I suspect that your handy defibrillator is not going to do the job. Cryonics advocates tend to elide the distinction between “thawed” and “revived”.

Granted, our definition of “dead” has changed a lot over the past century. Once upon a time, you were dead if your heart stopped – now we routinely bring people in cardiac arrest “back from the dead” in that sense. Now we define death by reference to brain activity, but I suspect even those definitions are already in flux.

Still, I would submit that someone who has died or ended their own life; frozen or otherwise preserved their bodies; been subjected to radical molecular or cellular processing sufficient to reverse a lethal illness, along with any damage incidental to the preservation procedure; and thawed themselves out (either before or after the aforementioned processing), is – by any definition we can imagine at present – really really quite very dead. It behooves any would-be cryonaut to give this issue serious thought in any evaluation of one’s chances for revival.

Lest if I sound closed-minded, allow me to reiterate my ultimate position: Extraordinary claims require extraordinary evidence. In the face of such evidence, I’ll gleefully change my view. In other words, show me the (figurative) money. I’m waiting for someone to take the tools of modern biology and take a few steps in the right direction: The viable freezing, preservation, and thawing of (at first) individual tissues, then organ systems, and (eventually) an intact small mammal. Start with skin! If we can’t do skin, we can’t do a whole body, so we might as well start small (and thin). Skin sounds downright easy.

The field could take a lesson from the dawn of modern biogerontology back in the early 1990s: Acknowledge the mind-bending complexity of the challenge. Create model systems for cryonics, using the best tools from the vast edifice of modern biological knowledge. Break down the problem into feasible steps. And then, by all means, full steam ahead.

 

Resveratrol and rapamycin as therapeutics vs. aging and cancer

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.

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

 

Rapamycin reviewed

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:

• Late-Life Administration of Rapamycin Extends Life in Mice (Fight Aging!)
• Aging – Lost in translation? (NEJM)
• What Does Life-Extending Drug Mean for Humans? (TIME)

 

Back from the dead, hopefully for real this time

I’m trying to claw my way back from a long period of inactivity. In late 2009, experiments and other work prevented me from devoting time to this project, and even after some of those obligations lightened, I was finding it difficult to get back in the saddle. My last moment of inspiration turned out to be a false alarm, and rumors of my resurrection had been greatly exaggerated. Most of the posts in the final quarter of last year were made by one of our other writers (turritopsis’ excellent coverage of the SENS4 conference).

There are a number of forces conspiring against my blogging actively. Most have to do with tradeoffs: I have a limited amount of time (less than I used to, now that I’m commuting from Oakland to Novato every day) and energy, and – especially given how long I’ve been a postdoc – it’s hard to justify spending time on a project that doesn’t create new data. Also I have some ambivalence about the value of blogging as a filter for the literature.

But I’ve decided that this is important to me, for a variety of reasons, both selfish and other-centered. I like the way that Ouroboros helps me keep on top of the literature – even if I’m deciding not to write about an article, I’m thinking about it – and I’ve been missing that. I also liked the small but growing sense that I was doing something that other people enjoyed, and that benefited the field as a whole. On the careerist side: Knowing the field helps me choose the best experiments to do in my own work. Beyond that, as my generation gradually takes over the reigns of academic science, more and more people will appreciate the value of activities like blogging – so hopefully there will be no ultimate career tradeoff between time spent blogging and time spent on research activities.

So as of tomorrow, I’ll be back, in some form. I’ve decided to give the project a certain amount of time every day, and get done what I can in that time, and not worry so much about the absolute amount of writing I get done. Hopefully those of you who are interested will have something new to read (almost) every day.

Baby steps back into active blogging, then. Which is not to say that I don’t have ambitions. Over the next month or so, I plan on moving Ouroboros off of wordpress.com to another server – I’ll still use the WordPress software, but I want to have more control over the site’s structure and content. Also I want to open the door to monetizing the site in some way (probably not through ads, but possibly using a donation-based system like Kachingle, whenever that opens up); one of the things that takes me away from blogging is my consulting work, and it would be easier to rationalize spending more time on the blog if I weren’t paying as much of an opportunity cost when I spent time working on it.

Wow. TMI, probably. I’d better go read a paper. See you tomorrow.

 

Conference: “New Insights into Healthspan and Diseases of Aging: From Molecular to Functional Senescence”

There’s a Keystone Symposium on this subject Jan 31-Feb 5 2010:

Aging can be defined as the gradual loss of the ability of the organism to maintain homeostasis. Our aim will be to focus on the molecular and cellular mechanisms by which tissue and organ function deteriorate and homeostasis fails rather than on longevity itself, which has been the theme of previous Keystone Symposia meetings on aging. Work from a variety of models is recognizing that organisms, especially humans, are complicated systems in which interventions that extend lifespan might not necessarily block the aging and loss of function in specific organs or tissues and vice versa. Continuing this approach will help us gain an understanding and appreciation of the complexity that underlies aging in humans. The aim of this meeting is to reveal the integration and communication between pathways and systems during functional aging and their relationship with longevity. This meeting will highlight important questions to address in future research. Most importantly, what are the common and disparate causes underlying the cellular and physiological mechanisms responsible for human senescent phenotypes?

It’s at Granlibakken, an adorable Tahoe resort where my old department used to go on retreat every autumn. I’ve never been in the winter, but I hear it’s nice.

Registration information is can be found here. Early registration deadline is November 30, but you can continue to register for full price up until January 31 (or until the conference fills up).

 

Sí se puede

Just to follow up on that last post asking you to help the SENS Foundation win $5000 — it worked! SENS came in first, and won the grand prize. The margins were pretty narrow — well below the number of people who visited the contest page from Ouroboros alone — so it can truly be said that every vote counted.

Thanks to the readers of Ouroboros and everyone else who helped SENS over the top.

The amount of money raised is, in the grand scheme, rather small, but it’s possible that the victory for SENS in what amounts to a popularity contest will help increase awareness of the life extension cause.

“I’m immensely grateful to 3banana for involving us in this great opportunity, and to all the SENSF supporters who took the time to leave comments at the site,” said SENS Foundation CSO, Dr Aubrey de Grey. “These supporters have recognised that a public and eloquent expression of broad-based support for our mission has the potential to raise the profile and perceived legitimacy of our work and thereby greatly amplify the impact of the competition itself.”

 

Help raise $5000 for SENS – by leaving an online comment

The SENS Foundation (which organizes the Strategies for Engineered Negligible Senescence conferences) is in the running for the $5000 grand prize in 3banana’s Share to Win event. The contest seeks to raise money “for causes serving unmet needs in health, education and environment.”

And you can help. It’s pretty simple: All you have to do is leave a comment on this page. (The award goes to the cause with the most comments.) You can sign on using a Google account if you already have one of those, or register for a free one-off account. It’s painless and takes about thirty seconds.

Your comment/vote makes a difference! Right now, SENS is neck-and-neck with the competition — as of this post, they’re 17 votes behind first place. (Well, sixteen, since I just commented.) So don’t just sit there — this is your opportunity to help send real money to a very important cause, at no cost to yourself.

Post your comment now.

There are only four days left in the contest, so time is of the essence.

(For all you social media users, feel free to spread the word via blogs and Twitter. If you’re interested in regular updates from the SENS Foundation, there’s a Facebook page as well.)

UPDATE: The push yesterday put SENS into the lead — thanks to all Ouroboros readers who took the time to comment! But the current lead is tenuous, and it could still be lost. If you haven’t commented yet: it doesn’t take much time, and with margins like these your vote really makes a difference. Would you really want to find out that SENS had lost by a single vote? Please consider taking a minute or so and leaving a comment on the contest page.