The deadline is today.

In other news, I’m back from England and totally shaking in my boots at the giant backlog of biogerontological articles that have accumulated in my absence. (Not that I didn’t have a backlog before.)

I’ll be away until May 13th, attending the wedding of a dear friend. Posting should resume on the 14th or so. During my absence, comments will be closed.

Lots to look forward to — plenty of great new papers in the hopper, plus I’ve been invited to SciFoo 2008 (see here for a description of last year’s event), so I’ll also be noodling about how best to take advantage of that opportunity.

One thing I’d like to figure out when I get back is whether anyone might be willing to guest blog the Understanding Aging conference in June. I’d intended to head down there, but it turns out that I’ll be visiting family that weekend, so I can’t attend after all. If anyone is already planning to attend and would be interested in liveblogging and/or reviewing the conference, drop me an email and let me know. Strong writing skills a must; hyperactivity a plus; the rest negotiable.

OK, see you in a week.

I have two words for you: rat lipsuction.

One of the common features of aging throughout the Class Mammalia is the accumulation of body fat in specific deposits — specifically, the growth of visceral (or abdominal fat). We do it, monkeys do it, dogs do it, and rodents do it. Visceral fat (VF) has been implicated in a variety of age-related disorders, including metabolic syndrome and chronic inflammation, both of which have in turn been linked to frailty.

If VF produces a factor or factors that limits lifespan (either by promoting the aforementioned conditions or by another mechanism), then removing it should make those factors go away and concomitantly lengthen lifespan. (I suppose the alternative would be a parabiosis experiment in which a rat with lots of VF shared a blood supply with a rat with little VF, though (a) the results would be difficult to interpret due to myriad confounding factors; (b) I’m not sure what one would do if the fat rat died while the thin rat was still alive; and (c) the entire exercise would be a horrifying abomination.) Muzumdar et al. have collected just that sort of data: They removed the VF from rats consuming an ad libitum chow diet, and showed that the rats aged almost as successfully as calorie-restricted (CR) rats (which, by the way, never accumulate VF):

Visceral adipose tissue modulates mammalian longevity

Caloric restriction (CR) can delay many age-related diseases and extend lifespan, while an increase in adiposity is associated with enhanced disease risk and accelerated aging. Among the various fat depots, the accrual of visceral fat (VF) is a common feature of aging, and has been shown to be the most detrimental on metabolic syndrome of aging in humans. We have previously demonstrated that surgical removal of VF in rats improves insulin action; thus, we set out to determine if VF removal affects longevity. We prospectively studied lifespan in three groups of rats: ad libitum-fed (AL-fed), CR (Fed 60% of AL) and a group of AL-fed rats with selective removal of VF at 5 months of age (VF-removed rats). We demonstrate that compared to AL-fed rats, VF-removed rats had a significant increase in mean (p < 0.001) and maximum lifespan (p < 0.04) and significant reduction in the incidence of severe renal disease (p < 0.01). CR rats demonstrated the greatest mean and maximum lifespan (p < 0.001) and the lowest rate of death as compared to AL-fed rats (0.13). Taken together, these observations provide the most direct evidence to date that a reduction in fat mass, specifically VF, may be one of the possible underlying mechanisms of the anti-aging effect of CR.

The authors argue (a bit too strongly, in my opinion) that their experiment demonstrates that prevention of VF accumulation is a major mechanism of the lifespan extension due to CR. A skeptic could easily argue that it works the other way: VF represents a really large storehouse of energy, and its removal could force the rat to deplete other fat reserves and enter a state that mimics CR. The parabiosis experiment that I parenthetically described above (or some less repellent and [not entirely incidentally] more scientifically valuable version thereof, e.g., one in which candidate factors secreted by VF were introduced back into lipectomized rats) would go a long way toward bolstering the authors’ interpretation.

Regardless, it’s a good reminder not to skip yoga and jogging this weekend.

It is widely accepted that stem cells are involved in tissue regeneration. It is also widely accepted that (in most organs) stem cells are vanishingly rare. So: if there doesn’t happen to be a stem cell adjacent to a site of damage, how can stem cells be involved in the process of tissue repair?

One possible answers: There might be more stem cells than we think, because we’ve been missing them for some reason. This possibility is strongly supported by the recent findings of Zuba-Surma et al., who have discovered a population of tiny pluripotent cells (termed, appropriately, very small embryonic-like, or VSELs) scattered throughout the body.

Very small embryonic-like stem cells in adult tissues—Potential implications for aging
Recently our group identified in murine bone marrow (BM) and human cord blood (CB), a rare population of very small embryonic-like (VSEL) stem cells. We hypothesize that these cells are deposited during embryonic development in BM as a mobile pool of circulating pluripotent stem cells (PSC) that play a pivotal role in postnatal tissue turnover both of non-hematopoietic and hematopoietic tissues. During in vitro co-cultures with murine myoblastic C2C12 cells, VSELs form spheres that contain primitive stem cells. Cells isolated from these spheres may give rise to cells from all three germ layers when plated in tissue specific media. The number of murine VSELs and their ability to form spheres decreases with the age and is reduced in short-living murine strains. Thus, developmental deposition of VSELs in adult tissues may potentially play an underappreciated role in regulating the rejuvenation of senescent organs. We envision that the regenerative potential of these cells could be harnessed to decelerate aging processes.

Note that both VSEL number and potency diminish with age, consistent with the decrease in proliferative and regenerative capacity that we see in older animals. (And recall that diminishing stem cell potency is just one side of the story: over the course of aging, tissue microenvironments themselves grow more hostile to stem cell growth and function).

The small size of the VSELs, along with their dispersal throughout the body, might explain why they’d been missed up until now. It makes sense that cells devoted to long-term storage of regenerative potential would be very little: other than surviving and maintaining the ability to respond to proliferative signals, they wouldn’t really have much in the way of functional requirements, and wouldn’t need much more than a nucleus, a membrane, and extremely vigilant signal-transduction pathways — the latter ready to awaken the dormant cell when it’s time to turn into a proper stem cell, divide, and differentiate. In a sense, then, these VSELs are not so much progenitors as “progenitor progenitors”, the of regenerative capacity lying silent until they are needed.

(Extending this admitted over-interpretation — small size, after all, does not mean low metabolism, but I’m reasoning by analogy to spores and other very small totipotent cellular forms — another advantage of keeping stem cells metabolically inactive is that they would be less likely to suffer mutations or other damage that could convert them into cancer stem cells.)

Required skepticism: VSELs are both brand new and (so far as I can tell) idiosyncratic to a single group’s work. Before we get too worked up about this, I’d like to see the work reproduced by other labs and in other systems. Hopefully that sort of confirmation is already underway.

If you are interested in attending the “Understanding Aging” conference June 27-29, be aware that the registration deadline is rapidly approaching. From organizer Aubrey de Grey:

I am writing to remind you that the early registration and abstract submission deadlines for the conference “Understanding Aging: Biomedical and Bioengineering Approaches” are coming up on May 15th. This conference, to be held at UCLA, Los Angeles, California, USA on June 27th-29th 2008, is organised jointly by me, Irina Conboy of UC Berkeley, and Amy Wagers of Harvard. All details, including forms for abstract submission and online registration, are at the conference website:

http://www.methuselahfoundation.org/UABBA/

Please note that standard registration fees are fully inclusive of three nights’ accommodation and all meals. However, there is also a deeply discounted non-residential rate of just $150 for students and $300 for others.

http://www.methuselahfoundation.org/UABBA/tickets/

That non-residential rate is very attractive, especially if you’re already in the LA area.

Cellular senescence is regarded as a tumor suppressor mechanism: damaged cells permanently leave the cell cycle (preventing tumor initiation), and also secrete factors that trigger both tissue repair and inflammation in the vicinity. This is probably good at first but bad later on: persistent senescent cells also secrete growth factors and metalloproteases that degrade the tissue microenvironment and encourage nearby preneoplastic cells to progress into full-blown tumors. Thus, senescence has been implicated in late-life cancer and age-related decline in tissue function.

The “damage” in question is usually genotoxic in nature: telomere shortening, indicating that a cell has undergone many rounds of potentially mutagenic cell division, or high levels of DNA damage such as that resulting from ionizing radiation or exposure to chemical clastogens. Oncogene expression probably also induces senescence via DNA damage, by triggering over-firing of replication origins and generating broken ends and weird chromatin structures that are interpreted as damage.

Now it appears that falling cellular ATP levels may also result in cellular senescence. Unterluggauer et al. report that inhibition of glutaminolysis (preventing cells from generating ATP from glutamine, an unglamorous and occasionally overlooked pathway that is nonetheless an important energy source in many cellular lineages) results in increased senescence in human vascular endothelial cells (HUVECs):

Premature senescence of human endothelial cells induced by inhibition of glutaminase

Cellular senescence is now recognized as an important mechanism of tumor suppression, and the accumulation of senescent cells may contribute to the aging of various human tissues. Alterations of the cellular energy metabolism are considered key events in tumorigenesis and are also known to play an important role for aging processes in lower eukaryotic model systems. In this study, we addressed senescence-associated changes in the energy metabolism of human endothelial cells, using the HUVEC model of in vitro senescence. We observed a drastic reduction in cellular ATP levels in senescent endothelial cells. Although consumption of glucose and production of lactate significantly increased in senescent cells, no correlation was found between both metabolite conversion rates, neither in young endothelial cells nor in the senescent cells, which indicates that glycolysis is not the main energy source in HUVEC. On the other hand, glutamine consumption was increased in senescent HUVEC and inhibition of glutaminolysis by DON, a specific inhibitor of glutaminase, led to a significant reduction in the proliferative capacity of both early passage and late passage cells. Moreover, inhibition of glutaminase activity induced a senescent-like phenotype in young HUVEC within two passages. Together, the data indicate that glutaminolysis is an important energy source in endothelial cells and that alterations in this pathway play a role in endothelial cell senescence.

The authors provide good evidence that endothelial cells rely heavily on glutaminolysis, and that removal of this energy source both drastically reduces cellular ATP levels and results in a “senescent-like” growth arrest. They then show fairly convincingly that this arrest is very similar to the arrest induced by telomere shortening, DNA damage or oncogene expression (i.e., cellular senescence) — in particular, by demonstrating that the arrested HUVECs express a panoply of senescence-associated gene expression and cytological markers. No word, as far as I could tell, on the reversibility of the arrest upon resumption of glutaminolysis (irreversibility is a hallmark of senescence); I mention this because growth arrest is a fairly obviously sensible response to an energy deficit, but it’s not clear why it ought to be permanent.

The reason I’m interested in this paper is that it might point toward a unifying principle underlying two major subjects within the field of biogerontology — cellular senescence and sirtuins — which both receive a great deal of individual attention but so far have not been demonstrated to have much to do with one another. Sirtuins such as SIRT1 are regulated by cellular energy state (in particular, by the NAD+/NADH ratio); if it turns out that perturbations in the cellular energy budget are an important means of senescence induction, it might be interesting to take a closer look and see whether sirtuin signaling might influence the establishment of cellular senescence.

Increased expression of a metabolic enzyme, phosphoenolpyruvate carboxykinase (PEPCK, an enzyme that most of us learned about in freshman biology and then promptly forgot, reasoning that the descriptive name and the ability to look it up if necessary would suffice if it ever came up again) results in mice that are muscular, have lower body fat than a runway model, and able to run 25 times farther than a wildtype control.

Even more interesting, according to proud parents Hanson and Hakimi, the females of the PEPCK-C^mus strain mate and have normal-sized litters at 35 months, an age when the blood of wildtype mice has cooled substantially (and, indeed, the mice themselves are starting to check out). The implication is that aging is slowed, and longevity extended, as a result of the transgene.

It’s become reflexive to ask whether a long-lived mutant is living longer because it’s calorie-restricted for some reason, incidental to the main phenotype conferred by the mutation, but this is not the case here: In order to preserve their enviable bods, PEPCK-C^mus mice eat 60% more than controls — so they’re not extending their lifespan by dieting. If anything, they’re anti-dieting: their increased metabolic efficiency means they’re harvesting more calories per gram of carb or fat than normal animals. No word yet on what happens if you do try to calorie-restrict them; I can imagine it going either way but am holding out hope for tiny explosions.

The PEPCK-C^mus seem to have it all: great bodies, long lives, extended reproductive and sexual lifespans, and no need to limit their appetites. The down side? Apparently, they are complete assholes: the mutants are aggressive and hyperactive, traits heretofore unheard-of among muscular, fit humans (and, indeed, in the field of biogerontology).

Rigorous lifespan and aging studies in these animals are ongoing, but are not yet complete, so the authors are reserving final judgment on the question of whether PEPCK-C^mus transgenics are bona fide longevity mutants. Hopefully we’ll have an answer within a couple of years. In the meantime, I hope they’re busily cross-breeding the transgene into short-lived DNA repair mutants — recently shown to induce longevity-assurance pathways in a last-ditch effort to stave off progeria — both to accelerate the progress of research and to see whether the metabolic benefits of PEPCK-C^mus might be used to treat premature aging syndromes.

(Hat tip to Longevity Meme.)

Kinoshita and Clark announce Alzforum, an online community for Alzheimer’s disease (AD) researchers:

Alzforum: E-Science for Alzheimer Disease

The Alzheimer Research Forum Web site (http://www.alzforum.org) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. … In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.

It’s an ambitious mission and could use the support of the community, beginning with your participation.

In honor of the pending acquisition of Sirtris by GlaxoSmithKline — and the advent of truly big pharma getting into the biology of aging — I wanted to pay tribute to SIRT1, the principal target of the sirtuin activators under development.

SIRT1 plays a variety of roles in regulatory biology and lifespan determination, and the list is growing: it inhibits p53, blocks inflammatory signaling, extends the healthspan of mice, and improves exercise tolerance It slices, it dices, and that’s not all: SIRT1 also

• regulates energy metabolism and mediates lifespan extension in response to calorie restriction (CR);
• directs neurogenesis;
• suppresses tumorigenesis in the gut (and, in tumors that do form, may negatively regulate the oncogenic form of β-catenin);
• antagonizes cellular senescence (though, just as with inhibiting p53, this might not be a crazy good idea in in all tissues);
• gives Lenny Guarente something to write reviews about; and
• has some really interesting relatives, including SIRT6, which was recently shown to maintain telomeric chromatin in a healthy and functional state.

Watch for more functional news, as well as novel connections between SIRT1 functions and human disease, as industry starts generating more (and more specific) activators of this multi-talented protein and its relatives.

Following closely on news that products in their pipeline can decrease blood glucose and may have tumor suppressor potential, Sirtris Pharmaceuticals (SIRT) has been snapped up by GlaxoSmithKline (GSK).

Sirtris has focused on the commercial development of clinically useful sirtuin activators, which are predicted to be useful as anti-diabetic drugs. Data from academic labs have suggested they could be of even wider use, e.g., in increasing exercise tolerance or treating inflammatory disease. Underneath it all, of course, is the knowledge that the the sirtuins were initially identified as longevity assurance genes; the subtext of all discussions of sirtuin activators is that they may mediate their beneficial effects by slowing aspects of the aging process itself.

The acquisition of an small company at a large premium (the offer was more than 80% higher than Sirtris’ market cap) by a pharmaceutical giant is one of the first demonstrations that the drug industry is taking seriously the idea that there’s money to be made in treating aging per se rather than all of the associated conditions separately (link):

“Through the acquisition of Sirtris, GlaxoSmithKline will significantly enhance its metabolic, neurology, immunology and inflammation research efforts by establishing a presence in the field of sirtuins, a recently discovered class of enzymes that are believed to be involved in the aging process,” the companies said in a joint release.

Then again, even in the best case, those who take sirtuin activators will get age-related diseases eventually anyway, so the question of whether to treat aging or age-related disease isn’t really an either/or choice.

I am currently wondering whether recent findings that indiscriminate activation of SIRT1 might lead to cancer (e.g., when DBC1 is deleted) will temper the enthusiasm for these compounds.

For those who were intrigued by yesterday’s post about the reversal of dermal aging by blockade of NF-κB, I wanted to point our a few more interesting tidbits related to everyone’s favorite inflammatory transcription factor.

• Skin is not the only organ in which aging can be reversed by attacking NF-κB activity. In the immune system, Huang et al. report that pharmaceutical inhibition of NF-κB blocks age-related increases in inflammatory cytokine production. The study focuses on a class of helper T cells that have been implicated in both immune senescence and autoimmune pathologies.
• Mourkioti and Rosenthal review the role of NF-κB in muscle, and discuss several mechanisms by which the factor might influence age-related muscle disease.
• Finally, Li et al. demonstrate that the MULAN protein is a mitochondrial ubiquitin E3 ligase that regulates mitochondrial dynamics. Prior work had shown MULAN to be an activator of NF-κB, so this study may be the first step toward establishing a novel signaling pathway between the mitochondria and the nucleus. (Brainstorming topic: Under what conditions would the mitochondria want to instruct the nucleus to produce inflammatory cytokines?). Their paper is at PLoS ONE, so reader comments are welcomed.

Holy smokes! Over at the (relatively) new blog Ageing Research, Dominick Burton is engaged in nothing less than a comprehensive review of cellular senescence and its (putative) role in organismal aging. He started from first principles (with definitions of aging and a discussion of some early theories regarding the process), and has moved from there through a historical overview of senescence to a discussion of the modern understanding of senescence and aging. He’s now focusing on some of the molecular mechanisms underlying senescence in vitro.

It’s more than a blog — it’s more like a slowly evolving review that grows in bite-sized chunks. That’s a good thing for readers who want to learn about the most modern aspects of the field but might require additional background information to get up to full speed. Heck, it’s pretty great for us so-called “experts” — skimming over Dominick’s archives, I definitely found myself reminded of a few things I’d forgotten (and then forgotten that I’d forgotten).

So if you’re at all interested in theories of aging, cellular senescence, telomere biology, or just well-researched and well-written science blogging, click on over to Ageing Research and check it out. Belated welcome to the biogerontology blogosphere, Dominick!

The transcription factor NF-κB has been well studied in its role as an inflammatory signaling factor, and more recently in the context of aging. In the context of inflammatory lung disease, NF-κB is downregulated by SIRT1, a pro-longevity protein. Furthermore, a focused analyses of its role in inflammaging have revealed that NF-κB expression is regulated by FOXO transcription factors, which are also involved in longevity assurance.

Fine; we know what sorts of factors can prevent NF-κB from wreaking its havoc in the first place — but what about havoc that has already been wrought? Knowing what might have inhibited NF-κB in the past is all well and good, but it’s cold comfort for individuals whose bodies are already undergoing its inflammatory ravages.

Happy news, then, from Adler et al., who report that genetic knockdown of NF-κB can actually reverse inflammatory damage in the skin of aged mice:

Reversal of aging by NFκB blockade

Genetic studies in model organisms such as yeast, worms, flies, and mice leading to lifespan extension suggest that longevity is subject to regulation. In addition, various system-wide interventions in old animals can reverse features of aging. To better understand these processes, much effort has been put into the study of aging on a molecular level. In particular, genome-wide microarray analysis of differently aged individual organisms or tissues has been used to track the global expression changes that occur during normal aging. Although these studies consistently implicate specific pathways in aging processes, there is little conservation between the individual genes that change. To circumvent this problem, we have recently developed a novel computational approach to discover transcription factors that may be responsible for driving global expression changes with age. We identified the transcription factor NFκB as a candidate activator of aging-related transcriptional changes in multiple human and mouse tissues. Genetic blockade of NFκB in the skin of chronologically aged mice reversed the global gene expression program and tissue characteristics to those of young mice, demonstrating for the first time that disruption of a single gene is sufficient to reverse features of aging, at least for the short-term.

Could NFκB inhibitors be used to turn back the clock in age-damaged skin, or in other organs? At the moment, the state of the art is decidedly not up to the task. Our own lab uses a wide range of pharmaceutical NFκB inhibitors for a variety of purposes, and the consensus is that these compounds make cells very unhappy (though we don’t know whether that is because of a direct effect on NFκB signaling or some off-target effect on other pathways). Beyond that, NFκB is actually useful in contexts where inflammation is useful, as when the immune system is fighting off infections (and some tumors).

What would be nice is if we could specifically turn off the transcription of NFκB in cells or tissues of interest, perhaps using therapeutic small RNAs or some other approach — but this is pie-in-the-sky assumption of a can opener; if we could turn off specific genes in specific cells we could basically do anything in biology. Then again, even decades before the technology becomes available, it doesn’t hurt to start compiling a prioritized list of the things we’d do with it.

SIRT1, the most widely studied of the protein family known as sirtuins, is a histone deacetylase that has been implicated in regulation of aging in mammals. Activators of SIRT1, such as resveratrol, have been demonstrated to extend the lifespan as well as boost mitochondrial function in mice.

More recently, SIRT1 has been demonstrated to regulate p53 function: deacetylation by SIRT1 makes p53 less active, thereby decreasing apoptosis in response to specific types of DNA-damaging stress (e.g., ionizing radiation). This would be advantageous in some circumstances and deleterious in others, depending on the relative value placed on cellular survival vs. elimination of potentially neoplastic cells. Thus, this observation raises questions regarding how SIRT1 is itself regulated.

In back-to-back papers in Nature earlier this year, two labs report the discovery that the DBC1 (”deleted in breast cancer”) protein specifically inhibits SIRT1, in turn increasing p53 activity and thereby stimulating p53-mediated apoptosis in response to genotoxic stress. Of the two papers, Zhao et al. have the more elaborate abstract, reproduced below; Kim et al. reach similar conclusions:

Negative regulation of the deacetylase SIRT1 by DBC1

SIRT1 is an NAD-dependent deacetylase critically involved in stress responses, cellular metabolism and, possibly, ageing. The tumour suppressor p53 represents the first non-histone substrate functionally regulated by acetylation and deacetylation; we and others previously found that SIRT1 promotes cell survival by deacetylating p53. These results were further supported by the fact that p53 hyperacetylation and increased radiation-induced apoptosis were observed in Sirt1-deficient mice. Nevertheless, SIRT1-mediated deacetylase function is also implicated in p53-independent pathways under different cellular contexts, and its effects on transcriptional factors such as members of the FOXO family and PGC-1 directly modulate metabolic responses. These studies validate the importance of the deacetylase activity of SIRT1, but how SIRT1 activity is regulated in vivo is not well understood. Here we show that DBC1 (deleted in breast cancer 1) acts as a native inhibitor of SIRT1 in human cells. DBC1-mediated repression of SIRT1 leads to increasing levels of p53 acetylation and upregulation of p53-mediated function. In contrast, depletion of endogenous DBC1 by RNA interference (RNAi) stimulates SIRT1-mediated deacetylation of p53 and inhibits p53-dependent apoptosis. Notably, these effects can be reversed in cells by concomitant knockdown of endogenous SIRT1. Our study demonstrates that DBC1 promotes p53-mediated apoptosis through specific inhibition of SIRT1.

The fact that the DBC1 protein was originally identified as one that is frequently deleted in breast tumors suggests that there are indeed tissues in which unchecked SIRT1 deacetylation of p53 would be a bad thing (i.e., in which it makes sense to kill off damaged cells, even at a cost to regenerative capacity — another example of the evolutionary tradeoffs between regenerative capacity and tumor suppression).

One obvious question is whether DBC1 is also commonly deleted in other epithelial tumors; if so, is there a pattern in the tissue types that develop such tumors? e.g., perhaps DBC1 is particularly important in epithelial populations that, like the breast, lie dormant for much of the lifespan but possess the latent ability to proliferate rapidly in response to hormones — in cells like these, it makes sense to have a relatively “hair-trigger” apoptotic response to potentially carcinogenic insults. In less proliferative tissues, however, the system might be tuned quite differently, with DBC1 levels set relatively low in order to preserve self-renewal capacity even after a manageable level of genotoxic damage.

Next step, of course: What regulates DBC1?

Forty-five years ago, Aubrey David Nicholas Jasper de Grey was brought into the world. Today is his birthday, and it seems appropriate to briefly reflect on Aubrey’s achievements to date and what he represents to biogerontology.

At times brilliant, at times exasperating, Aubrey is unquestionably the world’s most energetic popularizer of the idea that there is something we can do about aging — and not just a little something, mind you, but a very big something: we can end it, once and for all. In particular, he argues, we can take an engineer’s approach to reversing or repairing several types of damage that characterize aging, and thereby eliminate the process of aging itself. Over the years, his vision has been refined into a detailed program of proposed research and development called Strategies for Engineered Negligible Senescence (SENS), elaborated in great (and accessible) detail in his 2007 book Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime (co-authored with Michael Rae).

To mildly understate the case, Aubrey’s core thesis is controversial, even (and sometimes especially) within the community of biogerontologists. In the process of promulgating his views, he has unquestionably raised hackles, and has at times been subjected to (usually well-meaning) satire — but he has also stimulated scholarly debate, in which even his most staunch critics often find themselves engaging the issue on his own grounds.

On his birthday, it is good and right that we appreciate Aubrey for his energetic efforts in pushing a radical idea — that aging might someday be vanquished — out of the fringes and into the mainstream of modern biological thinking. Despite his differences with individual scientists (and sometimes with large groups of them, waving torches) he remains biogerontology’s most prominent popularizer, and therefore in some sense the field’s biggest fan.

So, how will you celebrate Aubrey’s birthday? Perhaps you could take in one of his popular lectures, like this one at the prestigious TED conference; if you’re intrigued, share it with a friend. (If you’re looking for something lighter, there’s always his stint on the Colbert Report.) To learn more, you could buy his book. While you’re at it, check out the Methuselah Foundation, maybe even make a donation. Those with the means might consider attending the upcoming conference he is organizing, Understanding Aging. Through the miracle of modern technology, you can even become Aubrey’s friend.

Regardless of what you do, I hope you’ll join me today in celebrating the vision, energy, fearlessness and enthusiasm that Aubrey brings to this greatest of causes.

Happy birthday, Aubrey. Many, many happy returns.

Two recent reviews discuss the evidence that mitochondria (specifically, age- and damage-related dysfunction in these organelles) are responsible for age-related degenerative conditions. Both reviews focus on oxidative stress as a primary mechanism underlying the connections, but depending on the disease in question, they reach rather different conclusions about the significance of mitochondrial damage.

Kim et al. describe the role for mitochondria (in particular, reactive oxygen species [ROS] produced by damaged mitos and the concomitant inflammation) in the etiology of late-life insulin resistance. The authors conclude that the balance of evidence supports a role for mitochondrial damage in late-onset diabetes, and I think their arguments are reasonable (though I’m hard pressed to think of a phenomenon that doesn’t play some role in diabetes).

Meanwhile, Fukui and Moraes critically evaluate the idea that ROS-induced damage causing further ROS production, and the possibility that such a “vicious cycle” could participate in the development of neurodegenerative diseases. Their conclusion is that the field has been led astray by results of in vitro experiments that don’t accurately model the situation in vivo.

The soluble protein Klotho appears to be an anti-aging factor, since mice deficient in the Klotho gene show signs of premature aging. However, the validity of Klotho^-/- mutants as a model of progeria is controversial: many of the pathological features of the mutant phenotype can be attributed to hypervitaminosis D, and can be reversed by eliminating vitamin D from the diet. (Biogerontologists are generally more skeptical of progeria than increased longevity, since there are lots of ways to shorten lifespan that don’t involve bona fide accelerating of the aging process, whereas there are far fewer ways to lengthen lifespan without slowing that process down.)

Another blow against the idea of Klotho as a regulator of lifespan comes from Brownstein et al., who show that increased circulating levels of Klotho protein (pursuant to a chromosomal translocation that activates the gene) are associated with hyperparathyroidism and rickets (n.b. that the latter is a classic symptom of, wait for it, vitamin D deficiency).

This is interesting from an endocrinological standpoint because rickets is often the result of hypophosphatemia (low phosphate –> weak bones), whereas hyperparathyroidism is usually associated with hyperphosphatemia.

But from a biogerontological perspective, it’s both interesting and sad: Specifically, it’s a strike against the idea that we might be able to supplement aging mammals (like ourselves) with increased levels of Klotho in order to forestall aging. Of course, it’s possible that the very elevated levels of the protein seen in this study are totally off the charts, and that more modest doses might have a salubrious effect — but more and more, the most reasonable interpretation of the data is that Klotho is involved in mineral and vitamin metabolism in a way that doesn’t have much to do with lifespan; that the levels of Klotho are already more or less optimized (since a syndrome results from either deficiency or elevation relative to wildtype); and that the “progeria” of Klotho^-/- is simply a compelling mimic of accelerated aging rather than a legitimate model of the process.

In evolutionary biology, much is made of the tiny sequence difference between humans and chimpanzees. Our two species differ, on average, by only 1 out of 100 nucleotides — and in these small differences much lie the whole explanation for the phenotypic differences between H. sapiens and P. troglodytes. Fair enough, though I think the “1 out of 100″ statistic is a little bit misleading: the differences are not evenly distributed throughout the genome; besides, any modern biologist worth their pipet tips knows that small changes in regulatory regions can have dramatic, disproportionate effects on phenotype.

By this logic, sequence divergence between humans and chimps should also help explain the (small) difference in our two species’ lifespans, and the (somewhat larger) differences in how we acquire and manifest age-related disease. To the extent that these phenotypic differences are guided by evolutionary pressures (e.g., grandmother selection), we should see evidence of adaptive change at the sequence level.

Uddin et al. looked for such evidence (cleverly, they searched not only in comparisons between humans and chimps, but more comprehensively throughout the mammalian lineage). They find that there is indeed evidence of adaptive evolution in aging-related pathways, but that the history of these changes is much more ancient than the divergence between the great apes:

Distinct genomic signatures of adaptation in pre- and postnatal environments during human evolution

The human genome evolution project seeks to reveal the genetic underpinnings of key phenotypic features that are distinctive of humans, such as a greatly enlarged cerebral cortex, slow development, and long life spans. This project has focused predominantly on genotypic changes during the 6-million-year descent from the last common ancestor (LCA) of humans and chimpanzees. Here, we argue that adaptive genotypic changes during earlier periods of evolutionary history also helped shape the distinctive human phenotype. Using comparative genome sequence data from 10 vertebrate species, we find a signature of human ancestry-specific adaptive evolution in 1,240 genes during their descent from the LCA with rodents. We also find that the signature of adaptive evolution is significantly different for highly expressed genes in human fetal and adult-stage tissues. Functional annotation clustering shows that on the ape stem lineage, an especially evident adaptively evolved biological pathway contains genes that function in mitochondria, are crucially involved in aerobic energy production, and are highly expressed in two energy-demanding tissues, heart and brain. Also, on this ape stem lineage, there was adaptive evolution among genes associated with human autoimmune and aging-related diseases. During more recent human descent, the adaptively evolving, highly expressed genes in fetal brain are involved in mediating neuronal connectivity. Comparing adaptively evolving genes from pre- and postnatal-stage tissues suggests that different selective pressures act on the development vs. the maintenance of the human phenotype.

That they observe prominent changes in brain genes is perhaps unsurprising, since we flatter ourselves with the idea that our brains are very different from those of our closest extant relatives. From a biogerontologist’s perspective, however, the brain is not only the seat of major behavioral and cognitive differences between species, but also the site of a great deal of aging-related action (developmental, neurodegenerative, and “normal” aging).

Star Trek fans know that Klingons prefer to eat their worms while they are still alive. It therefore seems fitting that biogerontologist’s favorite worm, C. elegans, in turn prefer their own food alive. Lenaerts et al. report that C. elegans has a nutritional requirement for some component of metabolically live microbes. This compound (or set of compounds) remains to be identified.

These findings may make it necessary to re-interpret a number of calorie restriction (CR) studies performed in axenic (bacteria-free) media — which deprives the worm of this required factor. Thus worms in axenic media may be undergoing not only CR but nutritional deficiency. If the required compound is diffusible, it might also go some way toward explaining why olfactory cues can influence health and lifespan. (The authors demonstrate that the component in question is probably not even soluble, but then again, many odorants aren’t.)

(More analysis and discussion of this article can be found at PharmacoNutrition Reviewed).

Per yesterday’s discussion of mitochondrial deletion mutations, Baste Schaffer (of PharmacoNutrition Reviewed) points us to an upcoming review (of which he is a co-author) that answers some of the questions we raised:

The mitochondrial free radical theory of ageing – Where do we stand?

Understanding the molecular mechanisms underlying the ageing process may provide the best strategy for addressing the challenges posed by ageing populations worldwide. One theory proposing such molecular mechanisms was formulated 50 years ago. Harman et al. suggested that ageing might be mediated by macromolecular damage through reactions involving reactive oxygen species (ROS). Today, a version of the free radical theory of ageing, focusing on mitochondria as source as well as target of ROS, is one of the most popular theories of ageing. Here we critically review the status of key principles and concepts on which this theory is based. We find that the evidence to date shows that many of the original assumptions are questionable, while on some critical issues further refinements in techniques are required. Even so, it is becoming evident that mitochondria and mtDNA integrity may indeed be crucial determinants of organismal ageing. Implications for the prospect of successful interventions as well as evidence for and against efficacy of current therapeutic approaches are discussed.

The review will be printed in the May issue of Frontiers in Bioscience, and is currently available in PDF form here.

Another semicentennial reflection of the free radical theory of aging is discussed here.