The Alzheimer’s Project, produced by HBO and the National Institute on Aging, is a new website on Alzheimer’s disease. The site contains information on Alzheimer’s for the general public as well as resources for those suffering from the disease.

The center of the collaboration is a four part documentary, which is now streaming on the project’s website. Although you may feel the need to jump to the film about the science of Alzheimer’s (and its supplemental videos), the real power of this series lies in the other sections.

Grandpa, do you know who I am? features interviews with the grandchildren of Alzheimer’s patients, and Caregivers provides a look at lives of those who care for Alzheimer’s patients. Both of these films are worth watching, especially if someone you know has Alzheimer’s.

For scientists, though, The Memory Loss Tapes is a must see. This section profiles seven people with Alzheimer’s, each at different stages of the disease. As basic scientists, we are often too far removed from those actually suffering from the diseases we study. This film gives us an up-close view of what it is like living with Alzheimer’s, and is a wonderful reminder of why we do what we do.


Protein degradation is an essential longevity assurance pathway. Maintaining high levels of autophagy can delay age-related decline in liver function. Obstacles to protein degradation tend to shorten the lifespan: blocking autophagy causes hypersensitivity to stress, and inhibiting the ubiquitin/proteasome pathway damages the mitochondria; both of these treatments kill neurons.

Conversely, longevity enhancement tends to enhance disposal of cellular garbage: In a worm model of Alzheimer’s disease, long-lived daf-2 mutants exhibit slower protein aggregation and decreased proteotoxicity, probably as a result of higher rates of protein degradation.

Despite the overall importance of protein degradation in delaying aging, the destruction of individual proteins is not always a good thing. During a screen of worm E3 ubiquitin ligases, Mehta et al. discovered that blocking the degradation of the HIF-1 protein dramatically increases lifespan and blocked the toxicity of pathogenic, aggregation-prone proteins.

Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans

The Caenorhabditis elegans von Hippel-Lindau tumor suppressor homolog VHL-1 is a cullin E3 ubiquitin ligase that negatively regulates the hypoxic response by promoting ubiquitination and degradation of the hypoxic response transcription factor HIF-1. Here, we report that loss of VHL-1 significantly increased life span and enhanced resistance to polyglutamine and amyloid beta toxicity. Deletion of HIF-1 was epistatic to VHL-1, indicating that HIF-1 acts downstream of VHL-1 to modulate aging and proteotoxicity. VHL-1 and HIF-1 control longevity by a mechanism distinct from both dietary restriction and insulin/IGF-1-like signaling. These findings define VHL-1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

The initial finding was that knockdowns of the E3 ligase VHL-1 were long-lived. VHL-1 is known to degrade HIF-1, the transcription factor involved in the hypoxic response. To rule out the possibility that another substrate of VHL-1 was important in the longevity enhancement, the authors used fairly straightforward genetic analysis: Mutating EGL-9, another gene required for HIF-1 degradation, also confers the lifespan extension, but neither vhl-1 not egl- mutants could live long in the absence of HIF-1.

The VHL-1/EGL-9/HIF-1 pathway is distinct from other means of lifespan extension: both daf-2 mutants and calorie restricted animals could extend the lifespan of hif-1 mutants, and conversely vhl-1 mutations could further extend the lifespan of daf-2 animals. This distinction may exist only at the level of the more upstream signaling events, however: DAF-16, the longevity assurance transcription factor that is disinhibited by daf-2 mutation, shares many target genes with HIF-1, so it is possible that the longevity enhancements rely on the same stable of stress-resistance and repair genes.

Will boosting HIF-1 levels also influence lifespan in mammals? Probably not, at least not in any simple way: the proteins involved are highly conserved — but VHL-1 is a tumor suppressor in humans, so targeting it with a drug is almost definitely a bad idea. Since suppression of the hypoxic response (especially angiogenesis) is likely to be important to the mechanism of tumor suppression by VHL-1, the same goes for HIF-1. It wouldn’t be incredibly surprising if this particular mechanism of lifespan regulation weren’t conserved between worms and mammals: worms don’t like oxygen as much as we do, so even if the machinery is conserved, the physiological consequences of activating that machinery might not be.

Still, as the authors point out, there might be some value in exploring manipulations of the hypoxic response in post-mitotic tissue – like brain — where the risk of tumorigenesis would presumably be smaller.

ResearchBlogging.orgMehta, R., Steinkraus, K., Sutphin, G., Ramos, F., Shamieh, L., Huh, A., Davis, C., Chandler-Brown, D., & Kaeberlein, M. (2009). Proteasomal Regulation of the Hypoxic Response Modulates Aging in C. elegans Science DOI: 10.1126/science.1173507

Most Alzheimer’s disease (AD) is sporadic, i.e., not the result of inheritance. Familial AD is relatively quite rare, but by studying heritable AD we’ve learned a disproportionately large amount about the genetic risk factors that predispose an individual to contract the disease.

One of the major risk factors for AD is mutation in the amyloid precursor protein (APP) gene. Mutant APP is more likely to be proteolytically cleaved into the β-amyloid (Aβ) form, which generates the amyloid fibrils and plaques that characterize AD pathology. Production of the toxic protein form is, genetically, speaking, a gain of function — so these APP mutations cause dominant inheritance of familial AD, i.e., a patient only needs one copy of the gene in order to have a very high risk of early-onset AD, and they’re 50% likely to pass this phenotype on to their children.

A newly discovered mutation, however, turns that inheritance pattern on its head. The A673V mutation in APP is associated with AD, but the inheritance pattern is recessive, i.e., a patient needs two mutant alleles in order to acquire the disease risk. In combination with wildtype allele, A673V doesn’t cause AD. Furthermore, the presence of the mutant protein prevents the wildtype protein from forming amyloid fibrils, even under very favorable in vitro conditions. Di Fede et al.:

A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis

β-Amyloid precursor protein (APP) mutations cause familial Alzheimer’s disease with nearly complete penetrance. We found an APP mutation [alanine-673valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer’s disease.

The basis of this effect is unknown — why would an amyloidogenic peptide fail to form fibrils simply because a non-amyloidogenic peptide is present? It’s tempting to speculate that is has to do with some aspect of the way in which Aβ proteins assemble into oligomers. Crystals form only from assemblies of like objects; by analogy, perhaps there are flavors of APP that can only form oligomers with their own kind — oligomers that are disrupted by the presence of other similar, but non-identical, monomers. At present we’ve got very little information to inform hypothesis building: amyloid fibrils are poor subjects for the standard techniques of structural biology, so their molecular details — and any clue about how this unusual mutant behaves — remain a mystery.

One experiment I’m dying to see: Do the A673V mutant proteins prevent other APP mutant proteins (the ones associated with the dominant form of familial AD) from forming fibrils?

Here is the next in what will likely be a long series of semi-regular review roundups — links, without extensive further comment, to the reviews I found most intriguing over the past few weeks months (I went on hiatus during the winter holidays). For the previous foray into the secondary literature, see here.


Apoptosis & cancer:

Calorie restriction:




Stem cells:


(continued from our coverage of yesterday’s sessions: A B)

This session was devoted to presentations by postdoctoral fellows and recipients of faculty startup grants — talks tended to be more data-intensive than the network-grant talks yesterday morning. Here are some of the highlights:

  • The cortex experiences significant synaptic loss in AD; Josh Trachtenberg (UCLA) has developed a method for imaging this loss as well as its repair in vivo in a mouse model of Alzheimer’s disease. This technology will be important in future studies of AD under the emerging paradigm of AD as a disease of neuronal connectivity (as opposed to cytotoxicity); more about this in yesterday’s coverage.
  • Speaking of connectivity in AD: Beth Stevens (Harvard Medical School) has asked whether Alzheimer’s is caused by re-activation of a developmental mechanism of synapse elimination. She is studying the effect of astrocytes (non-neuronal cells in the brain, each of which can ensheath and contact up to 100,000 synapses) on developing synapses, and observed that the complement protein C1q — involved in opsonization and clearance of foreign bodies in the blood — is expressed at synapses during the time period in early deveopment when “pruning” of superfluous connections is taking place. (In C1q knockout mice, pruning doesn’t occur efficiently.) Stevens hypothesizes that this process may be reactivated in AD (as well as other diseases that involve synapse loss), resulting in the targeting and destruction of (desirable) synapses.
  • I spoke during this session, partly about a paper about senescence-associated protein secretion that our lab has coming out in December and partly about my own studies of the relationship between micro-RNAs and cellular senescence. Oddly for an aging conference, my talk was one of only two about cancer and the only one about senescence.
  • Sun Hur (UCSF) spoke about the relationship between RNA modification and the human progeroid syndrome dyskeratosis congenita. The dyskerin protein is required for covalent modifications to a number of RNAs, including the telomerase RNA (aka TERC). Hur has crystallized several protein-RNA complexes, and is using their crystallographic structures to learn about the functional importance of RNA modification in the cell.
  • Ken Nakamura (UCSF) is studying Parkinson’s disease in a refreshingly original way: he has developed ways to monitor alpha-synuclein multimers in live cells, using fusion with fluorescent proteins. The pathological protein aggregates end up associating with membranes, including mitochondria — which then fragment, potentially contributing to cytotoxicity.

(continued from our coverage of the earlier session)

I’m going to cover just one talk from this session, from Charlie Glabe, who gave two of the more exciting talks at the last two LLHF meetings (see my review of the 2006 and 2007 meetings).

Glabe’s group (including several other PIs joined by a LLHF network grant) has been developing anti-amyloid antibodies, some of which are conformation-specific but not necessarily sequence-specific; in other words, antibodies that recognize common features of amyloid aggregates formed by many different types of protein (e.g., Aß but also alpha-synuclein, IAPP, and other peptides involved in aggregation-based diseases). These reagents will be useful in research but also potentially as therapies against multiple age-related illnesses.

Since last year, the group has been attempting to determine the structure of amyloid oligomers. Problem: amyloids don’t crystallize, so the current strategy is to form co-crystals between anti-amyloid antibodies and prefibrillar oligomers — or, failing that, crystallize the antibody alone and make inferences about the amyloid structure (which should be the ‘negative space’ of the antibody Fab fragment — assuming, of course, that the antibody doesn’t have to undergo a dramatic structural rearrangement in order to bind). Another member of the collaboration has been trying to understand the folded and unfolded states of amyloidogenic proteins, using solution-based techniques (EPR, NMR) rather than crystallography.

Another new direction in this project: studying the effect of amyloid oligomers on membrane conductance. Amyloid oligomers, which are toxic to cells, have a significant effect on the electrical properties of lipid bilayers: specifically, they increase the rate of depolarization. Novel, and this will be especially relevant to the emerging idea that AD is a disease of neuronal connectivity (i.e., interfering with membrane conductance) as well as cell toxicity.

Not a whole lot of new stuff on the therapeutic angle this time around, but you can’t win the lottery every year.

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.)


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