Gone fishin’

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.

 

Your pot belly is trying to kill you

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.

 

Widdle biddy stem cells

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.

 

Registration deadline for “Understanding Aging: Biomedical and Bioengineering Approaches”

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.

 

A glutamine a day keeps senescence away

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.

 

A candle that burns twice as bright and twice as long: the PEPCK-Cmus transgenic mouse

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.)

 

Alzheimer Research Forum on the web

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.

 

Is there anything SIRT1 can’t do?

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.

 

Sirtris to be acquired by GlaxoSmithKline

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.

 

NF-κB’s role in aging is not just skin deep

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.