(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.

Aging is one of the most complex biological processes we know of, and the human brain the most complex biological system. Unsurprisingly, that makes figuring out how aging affects our brains – affects those processes we really care about like learning, behaviour, and memory – enormously difficult.

A whole host of gross-level neuroanatomical changes take place as we get older, but it’s unclear to what extent these can explain the cognitive deficits that characterize normal aging and diseases of age like Alzheimer’s. For example, while some parts of the hippocampus (a brain structure crucial for the formation of new memories, and linked to dementia) lose neurons as we age, other parts only grow more and more synaptic connections.

To get the complete picture, we need more detail – we need to know what is going at the level of individual genes. In recent years, two groups (Lu et al. and Erraji-Benchekroun et al.) have published microarray expression studies of the aging human brain. However, in both studies there is no control for gender – female and male brains are all lumped into one group –  and this adds substantial noise to their results. Male and female brains are known to develop differently, and even to age differently at the neuroanatomical level – for instance, men experience more (and earlier-onset) brain atrophy and a greater increase in cerebrospinal fluid.

Last month, Berchtold et al. published a gene expression study of aging in four areas of the human brain, and for the first time looked at gender differences in brain aging:

Gene expression changes in the course of normal brain aging are sexually dimorphic
Gene expression profiles were assessed in the hippocampus, entorhinal cortex, superior-frontal gyrus, and postcentral gyrus across the lifespan of 55 cognitively intact individuals aged 20–99 years. Perspectives on global gene changes that are associated with brain aging emerged, revealing two overarching concepts. First, different regions of the forebrain exhibited substantially different gene profile changes with age. For example, comparing equally powered groups, 5,029 probe sets were significantly altered with age in the superior-frontal gyrus, compared with 1,110 in the entorhinal cortex. Prominent change occurred in the sixth to seventh decades across cortical regions, suggesting that this period is a critical transition point in brain aging, particularly in males. Second, clear gender differences in brain aging were evident, suggesting that the brain undergoes sexually dimorphic changes in gene expression not only in development but also in later life. Globally across all brain regions, males showed more gene change than females. Further, Gene Ontology analysis revealed that different categories of genes were predominantly affected in males vs. females. Notably, the male brain was characterized by global decreased catabolic and anabolic capacity with aging, with down-regulated genes heavily enriched in energy production and protein synthesis/transport categories. Increased immune activation was a prominent feature of aging in both sexes, with proportionally greater activation in the female brain. These data open opportunities to explore age-dependent changes in gene expression that set the balance between neurodegeneration and compensatory mechanisms in the brain and suggest that this balance is set differently in males and females, an intriguing idea.

Before controlling for gender, Berchtold et al. examined the entire set of brain samples to see if there were any general trends across brain regions. Surprisingly, they found that the superior-frontal gyrus and the postcentral gyrus consistently showed the most aging-related changes. This is unexpected, because it’s the other two brain regions – the hippocampus and the entorhinal cortex – that are most associated with age-related brain diseases and cognitive decline.

Berchtold et al. then sorted brain samples by gender. They found that between young (20-59yrs) and old age (60-99yrs), the male brain undergoes three times as many changes in gene expression as the female brain. Also, men exhibit significantly higher levels of change in all areas save the hippocampus, where men and women experience roughly the same number of gene changes.

To get a more detailed picture, Berchtold et al. classified brains into four age groups: 20-39yrs, 40-59yrs, 60-79yrs and 80-99yrs. For men, the largest number of gene expression changes (about 5000) was observed between the age categories of 40-59yrs and 60-79yrs, and there were few changes in subsequent decades, i.e., the male brain seemed to stabilize. In contrast, the female brain showed substantially fewer changes (about 1000) between those age categories, and showed the most changes (about 3500) between later age categories 60-79yrs and 80-99yrs. The authors take this as evidence that the aging female brain never stabilizes in the way that the aging male brain does; it would be interesting to divide the final female age category into two finer categories (80-89yrs and 90-99yrs) to verify that stabilization never happens. They also point out that this trend is consistent with what we know about the incidence of dementia: dementia risk stabilizes for men around age 85, but increases for women from ages 77 to 95.

Because women and men have different life expectancies (women live on average 5-10 years longer), Berchtold et al. were concerned that the differences in aging between men and women might just be reflecting the difference in longevity – i.e., that women might show almost the same sequence of aging events as men, only drawn out over a longer scale. To test this idea, they compared lists of significantly differentially expressed genes from the most critical aging period for men and women. They found that more than 75% of gene expression changes for each sex were unique to that sex – i.e., most gene change differences can’t be ascribed to simple differences in longevity.

Finally, Berchtold et al. used Gene Ontology annotations to determine whether any functional categories of genes were significantly differentially regulated with age between young (20-59yrs) and old (60-99yrs) brains. In males (but not females), they found a general decreasing capacity for energy production with age (e.g., several relevant Gene Ontology categories were downregulated, including electron transport, oxidative phosphorylation, ATP metabolism, mitochondrial transport, etc.). In females (but not males), categories for neuronal morphogenesis and intracellular signalling were significantly downregulated. In both sexes, genes associated with synaptic transmission were downregulated, and genes associated with cell death and angiogenesis were upregulated. Interestingly, for both sexes many genes associated with inflammation and the immune system were upregulated (while a bit of inflammation can be neuroprotective, too much is undesirable, and a general feature of aging in many tissues).

…….So what do all these results mean? Can we immediately conclude that male brains change for the worse at a relatively young age – but then stabilize – and that female brains just keep on getting worse with increasing age? While evolutionary theory predicts that many of the observed gene expression changes are deleterious, others could be adaptive damage-control responses, beneficial, or even just plain neutral. Also, to interpret this data properly, we need to be able to disentangle cause from effect – some gene expression changes matter a lot more than others. Berchtold et al. have given us a wonderful resource to study how aging affects the brain at the gene level, but we still need to do a lot of work before we can connect this vast catalogue of gene expression values to the higher-level biological and cognitive phenomena that we are most interested in.

Mutations in the CLK-1 gene, which is involved in the synthesis of coenzyme Q (ubiquinone), slow down aging in both worms and mice. The gene’s mechanism of action has been murky: Deficiency in the gene leads to a dietary dependence on ubiquinone and accumulation of a precursor molecule, DMQ, but neither the high levels of DMQ nor a shortage of Q is responsible for the physiological changes observed in CLK-1-/- mutants — therefore, it’s possible that the lifespan function of CLK-1 protein is unrelated to its role in co-Q biosynthesis.

Wang et al. have characterized the wide-spectrum anti-neurodegeneration drug cliquinol, and discovered that it downregulates the activity of the CLK-1 enzyme. The data suggests that heavy metal cations are important for the protein’s longevity-regulation function:

The development of neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s disease is strongly age-dependent. Discovering drugs that act on the high rate of aging in older individuals could be a means of combating these diseases. Reduction of the activity of the mitochondrial enzyme CLK-1 (also known as COQ7) slows down aging in C. elegans and in mice. Clioquinol is a metal chelator that has beneficial effects in several cellular and animal models of neurodegenerative diseases as well as on Alzheimer’s disease patients. Here we show that clioquinol inhibits the activity of mammalian CLK-1 in cultured cells, an inhibition that can be blocked by iron or cobalt cations, suggesting that chelation is involved in the mechanism of action of clioquinol on CLK-1. We also show that treatment of nematodes and mice with CQ mimics a variety of phenotypes produced by mutational reduction of CLK-1 activity in these organisms. These results suggest that the surprising action of clioquinol on several age-dependent neurodegenerative diseases with distinct etiologies might result from a slowing down of the aging process through action of the drug on CLK-1. Our findings support the hypothesis that pharmacologically targeting aging-associated proteins could help relieve age-dependent diseases.

Note the underlined section (emphasis mine) — this reminds me of a speculation I offered up a couple of years ago: Could coenzyme Q supplementation, which has a variety of health benefits in mammals, act by end-product inhibition of the ubiquinone synthesis pathway? In other words, high levels of the pathway’s ultimate product could be shutting down the both the enzymatic and lifespan-regulatory function of CLK-1, resulting in a phenocopy of the CLK-1 loss-of-function mutation. Here, the authors argue that direct enzymatic inhibition of the pathway might be preventing neurodegeneration primarily by slowing down the aging process.

Of course, it’s also possible that the effect on CLK-1 is an epiphenomenon and that heavy metal cations cause neurodegeneration directly, so that chelating them is a generally good thing totally unrelated to the drug’s effect on ubiquinone synthesis. (If that were true, then we would predict that clioquinone would further prevent the delayed neurodegeneration that eventually occurs in CLK-1 mutants as well.)

Racing toward its ultimate goal of being involved in every aspect of biology, the mammalian sirtuin SIRT1 has been the subject of a number of recent papers, each dealing with a different aspect of the protein’s role. (Abstracts are excerpted; ellipses, emphases, and interpolated commentary are mine.)

In energy metabolism and liver cirrhosis: Sirt1 is involved in energy metabolism: The role of chronic ethanol feeding and resveratrol, Oliva et al.:

These results support the concept that ethanol induces the Sirt1/PGC1α pathway of gene regulation and both naringin and resveratrol prevent the activation of this pathway by ethanol. However, resveratrol did not reduce the liver pathology caused by chronic ethanol feeding [In other words, it's probably not a good idea to get your resveratrol by drinking 1000 bottles of red wine a day.]

In diseases of protein aggregation: The role of calorie restriction and SIRT1 in prion-mediated neurodegeneration, Chen et al. [a collaboration between the Lindquist and Guarente labs]:

We tested the role of SIRT1 in mediating the effects of CR in a mouse model of prion disease. … We report that the onset of prion disease is delayed by CR and in the SIRT1 KO mice fed ad libitum. CR exerts no further effect on the SIRT1 KO strain, suggesting the effects of CR and SIRT1 deletion are mechanistically coupled. In conjunction, SIRT1 is downregulated in certain brain regions of CR mice. … Surprisingly, CR greatly shortens the duration of clinical symptoms of prion disease and ultimately shortens lifespan of prion-inoculated mice in a manner that is independent of SIRT1. [i.e., CR isn't actually therapeutically beneficial since the mice die young.]

In inflammation, inflammaging, and HIV/AIDS: SIRT1 longevity factor suppresses NFκB -driven immune responses: regulation of aging via NFκB acetylation?, Salminen et al. (review):

HIV-1 Tat protein binds to SIRT1 protein, a well-known longevity factor, and inhibits the SIRT1-mediated deacetylation of the p65 component of the NFκB complex. As a consequence, the transactivation efficiency of the NFκB factor was greatly potentiated, leading to the activation of immune system and later to the decline of adaptive immunity. … Longevity factors, such as SIRT1 and its activators, might regulate the efficiency of the NFκB signaling, the major outcome of which is inflamm-aging via proinflammatory responses.

In Notch regulation of stem cell aging: Sirt1, Notch and stem cell “age asymmetry”, Mantel et al. (review):

The protein-deacetylase, SIRT1, has received much attention because of its roles in oxygen metabolism, cellular stress response, aging, and has been investigated in various species and cell types including embryonic stem cells. However, there is a dearth of information on SIRT1 in adult stem cells, which have a pivotal role in adult aging processes. Here, we discuss the potential relationships between SIRT1 and the surface receptor protein, Notch, with stem cell self-renewal, asymmetric cell division, signaling, and stem cell aging.

Across species, a common symptom of advanced age is loss of brain function. Aging negatively affects a broad range of neural activity, including learning (reflected in long-term potentiation), control of motor function, and memory. Wouldn’t it be nice if we could slow that process down, or halt it altogether?

A group at Kyushu University has managed to do just that. By introducing a transgene encoding a human mitochondrial transcription factor into mice, Hayashi et al. have been able to delay the onset of age-related neurological decline, as measured in a number of different assays:

Reverse of Age-Dependent Memory Impairment and Mitochondrial DNA Damage in Microglia by an Overexpression of Human Mitochondrial Transcription Factor A in Mice

Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-κB (nuclear factor-κB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1β (IL-1β) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. … Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

Note that the title is a little bit misleading — they didn’t “reverse” the age-related decline so much as prevent it (unless I’m misunderstanding something; from what I could tell, the transgene was expressed from birth rather than turned on late in life).

The molecular details are still a mystery. The HeLa data suggest that transgene-expressing cells produce less reactive oxygen species (ROS) in response to electron transport poisons such as rotenone, but this could occur by a number of mechanisms: TFAM overexpression could result in boosted antioxidant defenses, or even simply an increase in the levels of electron transport proteins (with higher levels of these proteins in the mitochondria, it would take higher doses of a given poison to cause the sorts of malfunctions that lead to ROS production).

Mechanism aside, the result still provides strong support for the idea that cellular oxidation — and in particular, mitochondrial damage — are important causative factors in the age-related decline in neurological function. These transgenic animals, which show decreases in particular types of oxidative damage as well as significant delays in the deterioration of a wide variety of important brain functions, could help us identify the specific sorts of oxidative lesions that are the most important targets for intervention.

Welcome to the 52nd installation of Encephalon, a blog carnival devoted to presenting the best recent blog posts in neuroscience and psychology.

Science blogging isn’t merely a means of recording information. The best science bloggers are expert at asking, and then answering, a question that the reader might never have even thought about before. That gives us the organizing theme of today’s carnival: Q&A.

Q: What is the relationship between neurogenesis and depression?
A: Find out about the interplay between depressive disease, the creation of new nerve cells, and circuits in the brain at the new blog Neurospeculation.

Q: For that matter, is there a relationship between depression and diabetes?
A: The correlation between the two diseases is described at BrainBlogger.

Q: What is the molecular basis of bipolar disorder?
A: We’re getting much closer to an answer than I’d anticipated. At Channel N, listen to a talk by a prominent researcher in the field.

Q: Can brain stimulation make you a better driver?
A: At Brain Stimulant, learn about the application of transcranial direct current stimulation to improving decision making and risk assessment in tasks like driving a car.

Q: What is the perceptual defect underlying tone deafness?
A: Guest blogging at Scientific American, the authors of Cognitive Daily sing the praises of a new study describing four possible causes of poor music perception

Q: What determines plasticity in the visual cortex?
A: At least one newly discovered protein factor, which moves through synapses from the eye toward the brain, is now thought to play an important role in experience-dependent synaptic plasticity. Read about it at Neurophilosophy.

Q: Can we do anything to control our own brain’s plasticity?
A: At SharpBrains, a contributor describes what she learned about adult learning and neural plasticity at a “Learning and the Brain” conference held earlier this year.

Q: Are concepts encoded in single neurons?
A: The latest findings and theories regarding “grandmother neurons” are discussed at combining cognits.

Q: Speaking of dear old granny, how are social attachments encoded in the brain?
A: A recent fMRI study compiled data regarding how individual attachment style modulates neural activity in two separate parts of the brain during social appraisals. Neurotic Physiology has the scoop.

Q: Should you smoke pot? (Actually: What are the effects of the various active ingredients in cannabis?)
A: At MindHacks, just say yes to learning about the latest findings regarding THC and cannabidiol.

Q: Does culture determine the neural substrates of cognition?
A: The deep connections between culture and brain activity are investigated in a lengthy post at Neuroanthropology. The piece focuses on “context-dependent differences in attention between Americans and East Asians.”

Q: Why do we sleep?
A: The latest information regarding what flies can teach us about this important evolutionary question is reviewed at Neuroscientifically Challenged.

Q: Is there a correlation between the percent coverage of women’s bodies by clothes, and the hours of coverage they receive on television? If so, is that correlation positive or negative?
A: Learn the completely unsurprising truth at The Neurocritic, who analyzes a data set fresh from the Olympics.

Thanks for reading. Ouroboros will return to its regularly scheduled programming tomorrow. The 53rd installation of Encephalon will be held at Ionian Enchantment on September 1st (or maybe September 2nd, since the 1st is Labor Day). Send your submissions to [][at][gmail][dot][com].

As cells age, detritus inevitably accumulates; one theory of aging holds that rising levels of unwanted molecules will eventually become cytotoxic — the so-called “garbage catastrophe” model — and this, in turn, could cause age-related decline in cell and tissue function.

Cells have a variety of means to eliminate misfolded, damaged and covalently altered proteins, among them the ubiquitin-proteasome pathway and the various flavors of autophagy. These mechanisms of cellular trash collection have come under increasing scrutiny by biogerontologists — and the results, while generally consistent with the idea that protein recycling is important in the aging process, can often be surprising: in some organ systems (like the brain) excessive autophagy can be deleterious. And in prematurely aging mice, the most recent observations are somewhat counter-intuitive:

Activation of autophagy in progeria: Autophagy and aging: New lessons from progeroid mice, Mariño y López-Otín:

We have recently reported the unexpected finding that distinct progeroid murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging. … [T]he observed autophagic increase is associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong lifespan.

Regulation by circadian clocks: Diurnal rhythms of autophagy: Implications for cell biology and human disease, Sachdeva and Thompson:

As a consequence of the induction of autophagy during short periods of fasting, animals experience diurnal rhythms of autophagy in concert with their circadian cycle. … Whether the circadian clock directly regulates autophagy in mammalian cells, or whether autophagy may play a role in the cycling of mammalian cell clocks is not yet clear. Nevertheless, the relationship between circadian cycles and autophagy is an intriguing area for future study and has implications for multiple human diseases, including aging, neurodegeneration, and cancer.

Life extension therapeutics?: Proteasome activation as a novel antiaging strategy, Chondrogianni and Gonos:

As proteasome has an impaired function during aging, emphasis has been given recently in identifying ways of its activation. A number of studies have shown that the proteasome can be activated by genetic manipulations as well as by factors that affect its conformation and stability. Importantly the developed proteasome activated cell lines exhibit an extended lifespan. … Finally as few natural compounds have been identified having proteasome activation properties, we discuss the advantages of this novel antiaging strategy.

Protein misfolding in neuropathological states: Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging, Rick Morimoto:

Adaptation and survival requires the ability to sense damaged proteins and to coordinate the activities of protective stress response pathways and chaperone networks. Yet, despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress when conformationally challenged aggregation-prone proteins are expressed in cancer, metabolic disease, and neurodegenerative disease. The decline in biosynthetic and repair activities that compromises the integrity of the proteome is influenced strongly by genes that control aging, thus linking stress and protein homeostasis with the health and life span of the organism.

Looks like tomorrow will be a big one on mitochondria and oxidative damage.

Welcome to the first installation of Hourglass, a blog carnival devoted to the biology of aging. This first issue corresponds with the second blogiversary of Ouroboros, but mostly I consider it a celebration of the excellent (and growing) community of bloggers who are writing about biogerontology, lifespan extension technologies, and aging in general.

Without further ado, then, let’s get started:

Reason at Fight Aging! reports on AnAge, a curated database of longevity, aging, and life history in a wide range of animals. The database contains information about average and maximum longevity within species, and also cool features like lists of the “world-record” holders for the longest-lived organisms on the planet. AnAge will be a great tool for anyone interested in studying evolution of negligible senescence or exploiting lifespan diversity across related species to learn about mechanisms of aging. For those who are interested in databases of this kind, AnAge is a component of a larger project, the Human Ageing Genomic Resources.

The most widely studied technique for extending the lifespan of diverse animals is calorie restriction (CR), whose benefits in humans are still under careful study. One of the disadvantages of studying humans, of course, is that you can’t keep them in completely controlled environments, free from temptation to cheat on their defined diets — but this may be more than adequately compensated by the main advantage of human subjects, namely, that they can tell you how they’re feeling about the study while it’s underway. Over at Weekly Adventures of a Girl on a Diet, Elizabeth Ewen describes her experiences as a subject in the CALERIE study, a large-scale test of the effects of CR on humans (we’ve discussed CALERIE here before). In her post, Elizabeth describes the CALERIE study in detail, and also critically assesses some of its specific features — something that no mouse, however talented, could ever do.

While methods like CR may delay aging, or at least aspects thereof, they can’t stop it dead in its tracks — and they certainly can’t reverse large-scale age-related decline in tissue function. For those applications, we will have to look to more dramatic interventions, such as tissue engineering. In this exciting new field, biomedical engineers are seeking, essentially, to grow new organs for people whose originals have worn out due to injury, disease, or aging itself. One of the major challenges of tissue engineering is morphology: Even assuming that the appropriate sorts of stem cells are available, and that one can induce them to differentiate appropriately, how would one guarantee that they grow into the appropriate spatial architecture for efficient function? According to Attila Csordás at Partial Immortalization, one solution would be to use the “decellularized matrix hack“: to chemically or enzymatically remove the cells from cadaver organs, and then regrow new cells over the extracellular matrix left behind. (Since ECM is much more highly conserved than cell-surface markers, I suspect that such an approach could also be used to overcome immune rejection issues.) Attila’s post includes a video of the application of this concept to the heart.

Moving from the heart to the brain, we’re going to finish up with two huge posts about aging, mental fitness, and age-related changes in neurological function.

Ward Plunet at BrainHealthHacks writes about recent evidence that smarter people live longer. This is true whether your metric of intelligence is education (which could be problematic, as education levels are often correlated with lifelong affluence and access to medical care) or whether you’re looking at individual genetic variations correlated with both longevity and intelligence. It’s a giant post that quotes several articles from the primary literature as well as studies by international organizations. Nature, nurture, Ward has it all.

Assuming for the moment that long life and intelligence are associated — in which direction does the causal arrow point? We’re still unsure about that at the level of the whole organism, but in the case of brain health we know a bit more. At SharpBrains, Alvaro Fernandez interviews U. of Illinois’ Prof. Art Kramer, who describes ways that everyone can extend their mental healthspans and even delay the onset of age-related neurological dysfunction such as Alzheimer’s disease. That’s just the beginning of the lengthy interview, which goes on to talk about people’s desire for magical solutions to age-related declines in mental function, the results of prior studies, and the synergy between physical and cognitive exercise — among many other subjects.

Thanks for reading. I’m going to try to make Hourglass a monthly carnival on the second Tuesday of every month, so the next one will be held on August 12th. If you’re interested in hosting, please email me.

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 ( 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.

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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