As I said yesterday, today and tomorrow I’ll be attending the annual meeting of the Larry L. Hillblom Foundation.

This morning is devoted to presentations from the leaders and directors of the LLHF’s big “network” and “center” grants, and it appears that a good deal of each speaker’s time will be spent enumerating how many students, fellows, papers, and additional grants they’ve trained, written or garnered over the course of the past year. I’m not expecting very much in the way of data. Still, I’ll try to hit the highlights, mostly from a biogerontology-centric perspective:

  • Peter Butler (UCLA) opened his talk with a letter from a parent whose daughter was recently diagnosed with type I diabetes; the author of the letter was distraught about the decrease in quality (and quantity) of life that would result. Pete made the provocative comment that in five years, this letter would be considered “a historical document,” and closed with a confident statement that we’re seeing the “light at the end of the tunnel.”
  • Dale Bredesen (Buck Institute) described the mission of the LLHF Center for Integrative Studies of Aging, which opened last year: to bring together scientists with disparate specialties to approach geroscience from multiple angles. He gave credit to prion biologist Stan Prusiner, saying that the organization of Stan’s (gargantuan) laboratory inspired the multidisciplinary approach adopted by the Center. He closed with a quote from Fabricius that struck me as an odd choice during a conference about aging research: “Death comes to all/But great achievements raise a monument/Which shall endure until the sun grows old.”
  • Gal Bitan (UCLA) discussed recent progress in creating drugs that inhibit amyloid beta (Aß) oligomerization and toxicity, currently believed to play a major role in the onset of Alzheimer’s disease (AD) pathology. He began with a concise description of the challenge (it’s difficult to use small molecules to prevent protein-protein interactions mediated by very large, flat contact areas) and went on to describe his lab’s efforts to use structural data to rationally design peptide inhibitors. Bitan also reported that his group has developed an efficiacious small molecule drug as well, but he couldn’t tell us more about it because of intellectual property concerns.
  • Alberto Hayek and colleagues (UCSD) talked about the challenges of using stem cells to rebuild pancreatic beta cells in vivo. They presented quite a bit of data, but I’m afraid that diabetes + developmental biology = my personal scientific kryptonite, so I got a little bit distracted. The work is very good, I’m sure, and it represents the most likely application of stem cell therapy in large populations in the near-term future.
  • Bob Hughes, , Pankaj Kapahi, Simon Melov and Gordon Lithgow (Buck Institute) gave a group talk under the umbrella topic “Chemical biology of aging” (we heard a bit about this at last year’s meeting). Bob introduced a screen for small molecules that extend lifespan in simple model system; the goal is to screen 100,000 compounds, identify drugs that increase longevity in both yeast and worms, and then test these molecules in mice. Pankaj focused on a longevity-related pathway for which small-molecule inhibitors are already known: TOR, which we’ve talked about recently here; he continued with a discussion of differential control of translation during dietary restriction. Simon showed some data from a study of a anti-aging compounds and their effects on mitochondrial oxidative stress in the mouse, and Gordon capped off the hour with data demonstrating a role for endocannabinoids in responding to nutritional status.

Random thought: If a corner café can provide free wireless internet to its customers, shouldn’t a luxury hotel that charges in excess of $200 a night and advertises itself as a venue for “critical corporate summits” also be able to provide the same service for a reasonable price? I just paid $12.95 for 24 hours of what appears to be wireless dialup, or possibly telegraph; blogging is frustrating enough that I feel a little bit like crying. Thus far I am not so impressed by the modern electronic comforts provided by the Balboa Bay Club in Newport Beach — conference organizers, take note.

(Coverage of the morning session continues here.)



Sometimes I feel like our field produces review articles faster than it produces good ideas. Certainly, biogerontology generates more reviews in a given week than truly significant papers, but the same might be said of any discipline.

I’ve been ambivalent about how to deal with reviews — I’ve considered ignoring them altogether, only covering the “important ones,” link-dumping a bunch of them whenever I was too lazy to write a real post, and various other hybrid strategies. Ignoring them seemed most attractive, since our main mission at Ouroboros is to review the primary literature, so reviewing reviews seemed pointless and derivative.

But a recent reader inquiry (from one of our junior colleagues who basically wanted me to do some of their homework for them; my response was basically “read a review and make up your own mind”) reminded me of the importance of review articles: They’re a great way for scientists who aren’t already expert in a field to figure out where the important questions are. The best ones also juxtapose the most current efforts in creative and interesting ways, adding value by pointing out non-obvious connections between subfields. If read closely and attentively, reviews can be the source of great inspiration.

So rather than treating the elements of the secondary literature like second-class citizens, I’m going to start a quasi-regular feature wherein I (or one of the other writers) compile a list of the most important and interesting reviews of the last couple of weeks, and link to them without much further comment (thereby avoiding the vaguely ridiculous feeling of reviewing reviews, which would make one — what? — the “tertiary literature”?). You, the reader, can do what you wish with them. This new feature of Ouroboros begins…NOW!



DNA damage & gene expression:





TOR signaling:


Like I said, I’ll do something like this every couple of weeks, or whenever the review folder gets full. That way we’ll never fall too far behind.

According to a recent study by Lanza et al., endurance exercise increases mitochondrial protein levels, metabolic enzyme activity, and expression of SIRT3 (a sirtuin thought to be involved in longevity assurance). At the organismal level, insulin sensitivity goes up (this is good: insulin resistance leads to type II diabetes) and gluconeogenesis goes down.

So far, so good, but hardly surprising: file under “exercise is good for you, item #68232”. The interesting bit is that the mitochondrial and other changes are very similar to the physiological consequences of calorie restriction (CR), an intervention that is known to extend lifespan in model organisms and to delay age-related disease in humans. The authors argue that exercise may promote longevity through the same pathways as CR.

This fits in nicely with recent observations connecting exercise and CR: for example, resveratrol, thought to be a CR mimetic, improves exercise tolerance in mice, consistent with the idea that exercise and CR have something in common.

The next obvious question: Do exercise mimetics also promote longevity, and if so, do they do so by the same mechanism as CR?

A new and as-yet-unpublished study proposes a causative link between advanced glycation endproducts (AGEs) and DNA damage, potentially explaining the link between diabetes (where frequent blood glucose spikes cause accelerated formation of AGEs) and male infertility. The authors of the study focus on sperm, but the result suggests that AGEs may play a role DNA damage in other tissues as well. Since DNA damage is widely believed to play a causative role in the aging process, follow-up experiments could provide the long-awaited smoking gun connecting AGEs to fundamental mechanisms of aging — and breathe new life into the longstanding search for a clinical use for AGE-breaking compounds like Synvista‘s alagebrium.

(Hat tip to Longevity Meme.)

We usually discuss advanced glycation endproducts (AGEs) in the context of slow, lifelong accumulation of nonenzymatic reaction between protein and sugars. Until recently, I hadn’t realized that the diet is also a major source of AGE and AGE-related damage. I learned about the extrinsic source of AGEs from a recent study that showed diets lower in AGE (i.e., products of the Maillard reaction — outside the body, usually the heat-catalyzed reaction of hexose and pentoses with muscle proteins in cooked meat) alleviate both cardiac and kidney fibrosis.

On a related note, it turns out that most renoprotective measures taken to prevent damage to diabetic kidneys have something in common — surprisingly, it’s not that they lower blood sugar, rather but that they retard or prevent the formation of AGEs in the kidney, suggesting a causative role for AGEs at least in diabetes-related nephropathy.

How might AGEs cause age-related damage in the kidney and other tissues? One mechanism might involve AGE-induced production of matrix metallproteases (MMPs) by fibroblasts. MMPs are known to break down the extracellular matrix, weakening the structural integrity of a tissue and also promoting metastatic invasion by cancer cells.

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.

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.

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