In their own words:

Aims: Pathobiology of Aging & Age-related Diseases (PBA) is a new peer reviewed journal serving as a forum for researchers to communicate pathology data as a primary scientific focus of aging; data that might be of less interest in other journals more focused on generic aging or specific scientific disciplines. We are especially interested in developing a focus for advancing the pathological basis of aging in mammalian systems, in particular the mouse and humans.

Scope: Pathobiology of Aging & Age-related Diseases is interdisciplinary in nature and covers all aspects of pathology of aging related to disease phenotypes including cancer, cardiovascular disease, neurological disorders, metabolic dysfunction, renal and gastrointestinal disorders, endocrine dysfunction, musculoskeletal conditions and skin disorders. The underlying theme is based on the sound scientific principles of the pathogenesis of aging and age-related diseases as well as intervention data with resolution of pathological endpoints. The emphasis will be on preclinical studies as well as clinical studies related to strategies developed in animal models and will be image intensive. Papers on the basic biology of aging in invertebrates will not be considered unless comparative mammalian data is also included.

We welcome Research papers, Review articles, Brief reports, Case reports, New animal models, Technical reports, Images, PhD thesis Summaries, and Commentaries.

Target groups: Anatomical and molecular pathologists, gerontologists, geriatricians, transgenic mouse geneticists, toxicologists, and scientists, veterinarians and physicians focused on basic and clinical research in cardiovascular disease, cancer, gastrointestinal disease, endocrine disorders, metabolic dysfunction, renal disease, neurological disorders including Alzheimer’s disease, skin disorders, and musculoskeletal disease.

PBA is open-access; the publisher, Co-Action Press, is a relatively new entity whose small but growing stable consists entirely of open-access journals spanning a wide range of fields.

My personal feeling is that there are probably already too many journals, mostly because I don’t think I or my colleagues actually interact with journals as entities. Mostly we just do literature searches, and choose papers to read based on titles and abstracts. The exception is when we’re submitting papers, but then the diversity of formats and author requirements creates obstacles to rapid submission (and re-submission, if necessary).

I wouldn’t mind seeing individual journals be replaced by a robust tagging system on a relatively laissez-faire neo-journal such as PLoS ONE (to allow scholars to create communities and filters on the firehose of new papers), and a little time spent teaching everyone how to set up PubMed RSS feeds. That said, if we’re going to start new enterprises, this is probably the right way to go, so good luck to PBA.

You are kindly invited to the Baltic Sea, for the

*RoSyBA: Rostock Symposium on Systems Biology and Bioinformatics in Ageing Research*
15th-17th September 2011 (Rostock, Germany)

Confirmed speakers: Stuart Kim (Stanford), Ann Brunet (Stanford), Jan Hoeijmakers (Rotterdam), Günter Lepperdinger (Innsbruck), Aubrey de Grey (Cambridge), Joao Pedro de Magalhaes (Liverpool), Thomas von Zglinicki (Newcastle), ….

URL: http://goethe.informatik.uni-rostock.de/ibima/rosyba2011/

Early Registration: until June 15, 2011 – Save up to 100%
Call for Contributions: deadline June 1, 2011

I am writing to inform you that June 15th is the deadline for
discounted registration and abstract submission for the fifth
Strategies for Engineered Negligible Senescence (SENS) conference, to
be held at Queens’ College, Cambridge, England on August
31st-September 4th 2011. After the deadline, all registration fees
rise by £150.00. Also, after that date, we cannot guarantee that
submitted abstracts will be considered for oral presentation or that
they will be included in the conference abstract book.

All details of the conference, including forms for abstract submission
and online registration, are at the conference website:

http://www.sens.org/sens5

The conference program features 33 confirmed speakers so far, all of
them world leaders in their field. As with previous SENS conferences,
the emphasis of this meeting is on “applied gerontology” – the design
and implementation of biomedical interventions that may, jointly,
constitute a comprehensive panel of rejuvenation therapies, sufficient
to restore middle-aged or older laboratory animals (and, in due
course, humans) to the physical and mental robustness of young adults.
The list of sessions and confirmed speakers is as follows:

SENS Lecture:
Caleb Finch, ARCO/Keischnick Professor of Gerontology and Biological
Science and Director, Gerontology Research Institute, U. Southern
California
Decellularised organs for tissue engineering
Shay Soker, Laura Niklason
New advances in stem cells
Xiao-Dong Chen, Mariusz Ratajczak
Gut rejuvenation
James Wells, Graca Almeida-Porada
Brain aging
David Rubinsztein, Einar Sigurdsson, Charles Greer, Rodolfo Goya
Combating mitochondrial mutations
Matthew O’Connor, Michael Teitell
Genetic dysregulation in aging
Silvia Gravina, James Kirkland
Cancer
Minoru Ko, Bill Andrews, Dan Kaufman, Michael Lisanti
Novel treatments for atherosclerosis
Pedro Alvarez, Alexandr Kharlamov
Crosslink accumulation in the extracellular matrix
Daniel Nyhan, Paul Thornalley, David Spiegel
Novel antibody technology
Kenneth Shea, Michael Sierks
Immunorejuvenation
Janko Nikolich-Zugich, Doren Melamed
Bioinformatics in aging
Alex Zhavoronkov, Pat Langley, Maria Konovalenko
The long-term context of truly effective medicine aginst aging
Max More, Dana Goldman

In addition, there will be at least twenty short talks selected from
submitted abstracts, as well as poster sessions each evening. Authors
of short talks and posters will, like the invited speakers, be invited
to submit a paper summarising their presentation for the proceedings
volume, which will be published in the high-impact journal
Rejuvenation Research early in 2012.

Please note that registration fees are fully inclusive of
accommodation and all meals. Those not requiring accommodation,
journalists wishing to obtain free press passes (not including
accommodation), and those who are unable to register using a credit
card are asked to contact me by email (aubrey@sens.org).

I hope to welcome you to Cambridge in August!

Cheers, Aubrey

Aubrey de Grey
Organiser, SENS5
Chief Science Officer, SENS Foundation
Editor-in-Chief, Rejuvenation Research

Talks in this session:

1. Sagi: Engineering a long-lived worm
2. Suchanek: The germline and somatic reproductive tissues influence C. elegans
3. Stanfel: Ribosome Function and Aging

Dror Sagi (Stanford; Kim lab) — Engineering a long-lived worm

If aging is an engineering problem, then we should be able to solve the engineering challenges more easily in simple systems.

By introducing genes from a long-lived organism into the genome of a short-lived organism, it should be possible to add pro-longevity functions – in effect “upgrading” the short-lived animal so that it lives longer. Sagi has set out to do just that, by transferring genes from the long-lived zebrafish (4-year lifespan) to the short-lived work (4-week lifespan).

The first gene he described was the UCP2 gene, the subject of an earlier talk. Expressing fish UCP2 in the worm lowers overall ATP, and extends worm lifespan. As an important control, expressing an additional copy of the worm UCP2 under the same promoter control does not extend life.

Likewise, fish lysozyme results in lower daf-16 activity, and also extends lifespan. The fish enzyme appears to act by decreasing the pathogenesis from E. coli, an unnatural food source for the worm that causes health problems in late life.

Overall, Sagi characterized 5 well-characterized longevity pathways, testing 16 genes and getting 7 hits.

The next obvious question: Can “upgrade” genes be combined to further increase lifespan? Indeed they can: several pairwise combinations of genes combined to extend lifespan longer than either single gene alone. At some point it worked a little to well: the lifespan of the worms started getting long enough that the survival curves became unwieldy.

• Staying with the worm…

Monika Suchanek (UCSF; Kenyon lab) — The germline and somatic reproductive tissues influence C. elegans

Classically, it had been assumed that there is a tradeoff between lifespan and the number of progeny produced over the lifespan. We now know that this isn’t necessarily true; there are several examples of long-lived mutants that have a normal number of progeny (though the kinetics may be slower, which poses an issue with respect to fitness: if I live twice as long as you and have the same number of progeny but half as quickly, I will probably lose the evolutionary race).

Suchanek began by reviewing old data (like, from when I was a rotation student in the Kenyon lab: old) demonstrating that removal of the germ cells results in lifespan extension, but that this longevity enhancement requires the presence of the somatic gonad. This loss of the germline causes nuclear accumulation of the DAF-16/FOXO protein in the intestine. It is clear from several diverse pieces of data that the somatic gonad and germ line exert their effects on longevity somewhat independently.

Two other genes, daf-9 and daf-12 are required for the extended longevity of germline-deficient worms. DAF-9 is an enzyme that makes dafachronic acid, the ligand of a receptor encoded by DAF-12. Addition of dafachronic acid has no effect on lifespan of germ-cell-deficient, somatic-cell-competent cells, but it does extend the lifespan of animals that lack both germ cells and the somatic gonad.

How does the intestine know that the germ line is gone? To answer this question, Suchanek screened a “signaling sublibrary” of 1304 genes, and got 115 unique hits including several components of the Wnt pathway. Two components, mom-2 and wrm-1 (ß-catenin), are required for nuclear accumulation of DAF-16/FOXO and for the extended lifespan of germline-deficient worms. Suchanek favors a model in which germ line cells emit Wnt inhibitors.

• Finishing on a strong note…

Monique Stanfel (Buck Institute; Kennedy lab) — Ribosome Function and Aging

The Kennedy lab is interested in identifying longevity/aging genes that are conserved in yeast and worm, and then testing these in the mouse.

In both yeast and worm, deletion/knockdown of many ribosomal proteins (RPs) can extend lifespan. In yeast, most if not all of the RPs with a role in lifespan are components of the large subunit (60S). In worm, knockdowns of both small and large subunit components can increase lifespan. Three of the genes conserved between worm and yeast can be knocked down in mice.

In order to characterize translation in mouse mutants, Stanfel ran polysome gradients on liver tissue. She analyzed the fractions in two ways, looking at both ribosome-associated RNAs and at the ribosome-associated proteins.

Surprisingly, the Rpl22 gene can be knocked out and has very little effect on global translation in the mouse liver. This may be because a homologous gene, Rpl22L (“-like”) is compensating for the loss of the major species.

Knockout of another gene, Rpl29, has a larger effect on global translation, decreasing the levels of 80S ribosomes. When fed a high-fat diet, Rpl29 knockouts were protected against weight gain, and their blood glucose also remained low; furthermore, the animals were leaner than wildtype. They also resist developing cardiac hypertrophy in another assay – thus, they meet all the preliminary criteria for the time and resource investment of a lifespan study.

Talks in this session:

1. Choy: Intracellular trafficking and processing of amyloid precursor protein
2. Kown: Age-associated decline in immune function; new role of SIRT1 in regulatory T cells
3. Pan: Regulation of p53 and ageing by SnoN
4. Grueter: Disruption of the lipid synthesis gene, DGAT1, extends longevity

Regina Choy (Berkeley; Shekman lab) — Intracellular trafficking and processing of amyloid precursor protein

The talk began with a review of the proteolytic processing of amyloid precursor protein (APP) into Aß peptides. Choy emphasized that it is important to have a balance between the amyloidogenic and non-amyloidogenic pathways – a bias toward amyloidogenesis places one at risk for Alzheimer’s disease (AD).

The big question: Where is Aß being produced inside the cells? (What are the possible intracellular sites of Aß peptide production? Where is it actually happening). The approach: study of APP trafficking. The goal: Insights into regulation of Aß production and its relationship to AD.

Building on evidence that the primary site of Aß is the endosome, Choy performed RNAi knockdowns of the endosomal sorting machinery (ESCRT complexes as well as the ATPase VPS4). Knockdown of early components in endosomal sorting result in decreased Aß production, but knocking down the later components or VPS4 results in an increase in Aß production. Together with immunofluorescence results, these findings suggest that Aß production happens after APP leaves the early endosome. Surprisingly, however, APP does not colocalize with early endosome markers in the VPS4 knockdown – in fact, it ends up getting rerouted to the TGN. This raises the possibility that Aß production may happen after APP recycles through the TGN.

More beautiful immunofluorescence data followed, bolstering the recycling hypothesis and leading Choy to conclude in favor of a model in which the primary site of Aß production is in the TGN.

• Yet another role for SIRT1, coming right up…

Hye-Sook Kown (Gladstone; Ott lab) — Age-associated decline in immune function; new role of SIRT1 in regulatory T cells

Regulatory T cells (Treg) maintain immune tolerance, i.e., they stop the rest of the immune system from attacking the body. They accomplish this by suppressing differentiation of naive cells and the activation of effector cells. This, in turn, helps to prevent autoimmune disease and graft rejection. However, Treg cells increase their activity during aging, which might make elderly people more susceptible to infection.

Treg activity is regulated by FoxP3, which is in turn modified by acetylation that is regulated by SIRT1. Kown used mass spec to identify the specific acetylation sites on FoxP3; she found three, and raising specific antibodies against the acetylated peptides.

Inhibition of SIRT1, a deacetylase, enhances acetylation of FoxP3 at a specific site in both Jurkat T cells and mouse inducible Treg (iTreg) cells. The acetylated protein is stabilized and active, promoting Treg differentiation and survival in a variety of cell culture and in vivo assays.

Thus, by downregulating the activity of Treg cells, SIRT1 promotes a more active immune system: lower iTreg activity promotes increased differentiation of naive T cells and activation of Th1, Th2 and Th17 effector cells. In older people where SIRT1 levels are lower, higher Treg activity may result in a less responsive immune system and higher susceptibility to infection.

In questions, I asked whether SIRT1 inhibition could therefore be used to prevent autoimmune disease – the short answer is “yes”; this has advantages over expanding Treg populations ex vivo, which sometimes results in loss of FoxP3 expression.

• More mammalian regulatory biology…

Deng Pan (Berkeley; Luo lab) — Regulation of p53 and ageing by SnoN

Starts off with a review of the cancer-aging hypothesis, i.e., the idea that the anticancer activity of tumor suppressors like p53 have a cost: apoptosis and senescence of damaged cells ultimately reduces the regenerative capacity of tissues, contributing to age-related decline in tissue function.

Pan has focused on SnoN, an inhibitor of TGFß/Smad signaling, using a knock-in mouse in which SnoN can no longer bind the Smad promoter. Using this system, he demonstrated that SnoN can function as a tumor suppressor by activating p53-dependent senescence.

SnoN can interact with the PML-p53 pathway; the SnoN protein is a component of PML-nuclear bodies, which in turn activate p53. There are several ways to activate p53: stabilization (i.e., preventing ubiquitination); antiprepression, and promoter-specific activation. How specifically is SnoN activating p53?

Using pulldown assays, Pan showed that SnoN can directly bind to p53, in a manner that does not depend on PML. This binding stabilizes p53, probably because SnoN competes with Mdm2 (which ubiquitinates p53, targeting it for destruction). The working model is that SnoN is a stress transducer that communicates information about cellular stress to the p53 pathway.

The knock-in mice showed premature aging-related phenotypes, including kyphosis and hair loss, as well as higher levels of senescent and apoptotic cells.

• The final speaker of the session is clearly working on a novel organism…:-)

Carrie Grueter (Gladstone; Farese lab) — Disruption of the lipid synthesis gene, DGAT1, extends longevity

Given how much we know about fat and lifespan, it is perhaps surprising that very few longevity studies have focused on mice with modified lipid metabolism. To remedy this omission, Carrie Grueter has been studying the effect of the DGAT1 (diacylglycerol O-acyltransferase) knockout on phenotypes including lifespan. (DGAT is involved in triglyceride synthesis.)

Hypothesis: Leanness, with a concomitant improvement in metabolism, will extend longevity.

DGAT-deficient mice use more oxygen than wildtype siblings, but do not consume proportionally more food. The knockout mice are protected from the age-related increase in fat mass, as well as age-related increases in inflammation. (Not surprising since abdominal fat is associated with chronic inflammation.) The knockouts exhibit decreased serum IGF-I levels.

The payoff: DGAT knockouts live 25% longer than wildtype. There’s a cost: according to Grueter’s data, DGAT-KO have trouble lactating and therefore have decreased fecundity. Furthermore, the knockouts are bad at surviving short-term calorie restriction: half the mice fail to survive a 48-hour fast, probably because their core body temperatures plummet in the absence of stored fat to burn – the lethality can be rescued by group-housing the mice with wildtype animals or by raising the temperature to 30°C.

So in sum, the hypothesis enumerated above seems to hold, at least when calories are abundant – but when times are tough, it’s nice to have a little bit of extra padding.

(Next session –>)

Talks in this session:

1. McGee: Loss of intestinal nuclei with age in C.elegans
2. Mookerjee: UCP proteostasis and implications toward lifespan
3. Furman: Human immune system aging, vaccination and longevity

Matt McGee (Buck Institute; Melov lab) — Loss of intestinal nuclei with age in C.elegans

Despite the importance of C. elegans in the biology of aging, there is currently no comprehensive source of information about the changes in anatomical structure that occur over the worm lifespan. Or at least, until recently, there wasn’t.

McGee set out to assemble a 3D digital atlas of aging, comparing the anatomy of tissues in 4-day-old (“young”) and 20-day-old (“old”) worms. Essentially he has taken thin latitudinal sections along the entire length of young and old worms, stained them, aligned them, and used the slices to reconstruct a full 3D model of all tissues.

The images themselves are stunningly detailed – each worm is a whole universe. The age-related tissue degeneration McGee observes is striking; the slices barely look like members of the same species. Young worms are very similar to one another, but old worms exhibit highly varied morphologies.

One of the most significant changes occurs in the intestinal lumen, which degrades and collapses with age. The lumen diameter becomes irregular; microvilli diminish and disappear. Cell nuclei, as visualized with DAPI, are also lost in old worms – from a tight average of 30 on day 4 to a wide range at day 20; in the interim, the nuclei shrink before they start to disappear. This nuclear loss appears not to be due to apoptosis or germ line swelling (it still happens in ced-3 and glp-4 mutants).

The 3D Worm Atlas of Aging is coming along very nicely: Multiple old and young worms have been sectioned and imaged, with 3D segmentation of tissues. McGee and his collaborators have also imaged multiple individuals with confocal microscopy, respectively allowing greater detail and the use of fluorescent markers.

• From microscopy, we move on to mitochondria…

Shona Mookerjee (Buck Institute; Brand lab) — UCP proteostasis and implications toward lifespan

This work focuses on the mitochondrial UCP (uncoupling) proteins. Mitochondrial uncoupling modulates both the protonmotive force and ROS production; small changes in PMF can result in large changes in ROS production. (Conversely, a small amount of uncoupling can make a big difference in the amount of ROS production).

There are multiple UCP proteins: UCP1 is the canonical thermogenic protein found in brown fat, whereas UCP2 and UCP3 are expressed in other tissues – UCP2 in organs (pancreas, lung, CNS, spleen) and UCP3 in muscle, i.e., in “supply”-type cells and “demand”-type cells. These proteins are important in different contexts, as a function of glucose availability and other factors.

The non-canonical UCPs are known to modulate the “healthspan”: UCP2 plays a role in both diabetes and cancer. In the latter disease, UCP2 is upregulated in tumors, and has been associated with resistance to chemotherapy. During “normal” aging, UCP2 levels increase, resulting in a rise in proton leakage across the mitochondrial membrane.

UCP2 and UCP3 are rapidly degraded in a proteasome-dependent manner, which poses a challenge: the proteasome is in the cytosol, whereas the UCPs are in the mitochondrial inner membrane. Mookerjee proposes a model in which a ubiquitin tag is attached to the UCP, and subsequently “stitched” back across the outer membrane to the cytosol. To test the hypotheses, she has reconstituted UCP degradation in vitro, allowing determination of the biochemical requirements.

What is the purpose of rapid UCP2/3 turnover? Possibilities include regulation of activity or the management of a threshold response. It is clear, Mookerjee argues, that the proteostatic regulation of UCP2/3 are important for sustained mitochondrial function throughout the lifespan.

• What does a healthy immune system look like?

David Furman (Stanford; Davis lab) — Human immune system aging, vaccination and longevity

Not all people respond equally to to the same pathogens, and one of the principal sources of inter-personal variation is chronological age. Older people are exponentially more likely to die of SARS than young people; likewise, the seroprotection rate of vaccination drops significantly in old age.

It’s difficult to quantify the efficacy/competence of a given person’s immune system. How can we address this challenge?

Furman looked at the response of 85 individual human subjects to vaccination, making a wide range of measurements (antibody titer, cytokine levels, gene expression), with the goal of creating a classifier system that can be used to predict the efficacy of the immune response.

Young people tend to respond to antigen very similarly to one another (i.e., efficiently), whereas elderly subjects were split into two categories: cytokine responders and non-responders. These categories correlated with expression of genes associated with longevity, suggesting that immunosenescence and longevity represent two sides of the same coin.

(Next session –>)

Talks in this session:

1. Rafalski: Sirt1 in adult neural stem cells
2. Charville: Non-random chromosome segregation in skeletal muscle precursor cells
3. Xie: Connecting molecular markers and morphological changes to the lifespan of individual yeast cells

Victoria Rafalski (Stanford; Brunet lab) — Sirt1 in adult neural stem cells

Cognitive decline occurs with age: speed of processing, working memory, and long-term memory all decline. Presumably cell loss is partially to blame – not only loss of neurons, but also other types of cells (e.g., oligodendrocytes). Neural stem cells (NSC) can regenerate lost cells to some extent, but their ability to do so diminishes with age.

The Brunet lab is looking at the idea that pathways that control lifespan in “lower” organisms (worms; yeast) may be involved in regenerative capacity in “higher” organisms (us; mice). Rafalski’s work is focusing on the now-famous SIRT1. SIRT1 is downregulated over the course of differentiation, so there’s a smoking gun – but is there a causative relationship between SIRT1 downregulation and loss of regenerative capacity in NSCs?

Rafalski has constructed a mouse with a brain-specific deletion of SIRT1. Her metabolic labeling experiments show that loss of SIRT1 results in increased NSC proliferation in part of the brain called dentate gyrus – leading to the hypothesis that SIRT1 prevents the premature proliferative exhaustion of the NSC pool – in other words, SIRT1 prevents early cell division in order to preserve replicative capacity for late life. She also asked whether SIRT1 plays a role in differentiation. Loss of SIRT1 increases the number of oligodendrocytes, probably because in the absence of SIRT1 there are more oligodendrocyte precursors in the brain.

Overall, the findings point toward a role for SIRT1 in maintaining regenerative capacity in the brain. Hopefully, future experiments will explore the functional role of this pathway in maintenance of cognitive function throughout the aging – e.g., do mice that lack neuronal SIRT1 undergo more rapid cognitive decline than wildtype? (From previously published work on whole-organism knockdowns, it appears that the mice do indeed have memory deficits.)

• Moving from neural stem cells to muscle stem cells…

Greg Charville (Stanford; Rando lab) — Non-random chromosome segregation in skeletal muscle precursor cells

Satellite cells are committed adult muscle stem cells. Under normal conditions they are senescent, but upon injury they rapidly proliferate into myoblasts, which in turn beget muscle.

Proliferating muscle precursor cells divide asymmetrically, to regenerate the satellite cell and produce a new myoblast. During this division, chromosomes are also segregated asymmetrically. Charville used a clever and subtle metabolic labeling approach to demonstrate that newly synthesized chromosomes are preferentially segregated to one of the two sister nuclei generated in this asymmetric division.

Why does this happen? Charville explored the hypothesis that the nonrandom segregation was a function of persistent DNA damage. Activated muscle precursor cells exhibit replication-associated DNA damage, and the markers of DNA damage localize asymmetrically in the sister nuclei. The Numb protein, a pro-differentiation factor that also is an inhibitor of the Notch pathway, cosegregates with markers of DNA damage. Numb stabilizes p53, so this protein could be orchestrating the more robust DNA damage response required in the more damaged sister nucleus. It is not yet known how these asymmetries influence the cells’ ultimate fate (in the sense of differentiation).

Overall, Charville hypothesizes that this phenomenon serves to maintain the genomic integrity of the stem cell population.

• And now on to a (somewhat) simpler system…

Zhengwei Xie (UCSF; Li lab) — Connecting molecular markers and morphological changes to the lifespan of individual yeast cells

Yeast have proven an important model system in the study of aging; budding yeast undergo asymmetric divisions in which the mother (old) and daughter (new) can be distinguished, allowing a study of replicative aging in a genetically tractable system.

Xie has developed a microfluidic system for studying yeast aging. Mother cells are immobilized with streptavidin, while daughter cells are washed away; this allows the direct observation of an aging population of mother cells – how many daughters does each mother produce? What is the division timing? The system also allows Xie to measure lifespan in an automated manner, and simultaneously follow fluorescently labeled proteins, cell morphology, and staining for a variety of other phenotypes (ROS, mitochondria).

Using this system, Xie has shown that lifespan is negatively correlated with the activity of the HSP104 promoter, in particular with the levels of a specific transcriptional factor that acts on that promoter. He has also observed progressive mitochondrial abnormalities arising in old mother cells: Old mothers contain “blobs” that contain mitochondrial protein markers but not mitochondrial DNA.

The microfluidics system is very powerful, allowing temporal sequencing of molecular events in single cells. Exploiting this power, Xie demonstrated that the HSP104 promoter is induced after the appearance of the mitochondrial blobs, suggesting that the high HSP104 activity may be a marker of a stressed or moribund cell. Indeed, cells with damaged mitochondria appear to have elevated levels of reactive oxygen species (ROS).

(Next session –>)

Each session will have its own article; this entry will serve as a central hub for all related entries – the links below will go live as soon as the sessions start.

The organizers have encouraged me to blog the talks, as I did last year. More importantly, we’re hoping that the conference attendees (and others following along elsewhere in the world) will chime in via the internet.

There are two main ways to play along: in the comments below each session entry, and via Twitter.

If you’re tweeting during the talks, mark your tweets with the hashtag #baam10. (Even if you’re not tweeting, you can use the hashtag to follow the tweetstream here.) If you have no idea what I’m talking about, don’t worry about it. Follow along as the blog entries emerge, or just sit back and enjoy the conference.

• Session I
• Session II
• Session III
• Session IV

Earlier this year, the biogerontologists of the San Francisco Bay Area held the first of a series of biannual research meetings, the Bay Area Aging Club. More or less right on schedule, the next meeting is in a couple of weeks on Saturday, December 4th.

It’s now the slightly more official-sounding Bay Area Aging Meeting, but the format is the same: A full day of talks from labs from all around the Bay Area, with lunch, and an opportunity to network with the large and growing local community of researchers in biogerontology and allied subjects. Last time the meeting was at UCSF; this time it’s at Stanford.

Here’s the initial event announcement from Stuart Kim. Note the registration link, which contains more detailed information about time and location. Registration is free.

Eric Verdin (Gladstone), Danica Chen (Berkeley) and I are organizing the next Bay Area Aging Meeting. This is a one day meeting to hear talks from students and post-docs from the Bay Area on aging. The meeting is on Saturday Dec. 4, 2010 at Stanford University, from 900 am to 5 pm. The last meeting in April at Gladstone was very successful with about 150 attendees.

There will be talks from students/post-docs in Bay Area Aging labs, as well as a poster session. The labs and topics are:

lab/topic
Brian Kennedy (Buck) Yeast aging
Simon Melov (Buck) worm aging
Martin Brand (Buck) mitochondrial biochemistry
Melanie Ott (Gladstone)SirT1 in T cells
Bob Farese (Gladstone) mouse metabolism
Cynthia Kenyon (UCSF) worm aging
Hao Li (UCSF) systems biology of yeast aging
Kunxin Luo (Berkeley) P53 and aging
Randy Schekman (Berkeley) intracellular traficking of APP
Anne Brunet (Stanford) mouse, worm or fish aging
Tom Rando (Stanford) stem cells and aging
Mark Davis (Stanford) human immune aging

Please reserve the day for the meeting. We will send out more information including the schedule soon. To receive more information about the meeting, register for the meeting, and sign up to give a poster, please go to:

https://www.onlineregistrationcenter.com/register.asp?m=288&c=2

Sincerely,
Eric, Danica and Stuart

The April meeting was a lot of fun. I live-blogged the event, which definitely kept my fingers flying. This year I’ll be doing that again, with some degree of official blessing/support. We’ll make some kind of an announcement at the beginning of the talks directing people to Ouroboros and encouraging them to participate in comments on the posts for each session or talk. I’ll also be spreading the word Twitter and/or FriendFeed, using hashtag #baam10, and hoping that others join in that as well.

Please come! The organizers want to reach “hard core aging people,” so if your research falls under that umbrella, register now. For a sense of how the meeting went last time, here are my posts:

• Session I: Model organisms & model systems
• Session II: Sirtuins; telomeres
• Session III: Calorie restriction; protein aggregation
• Panel discussion: Free radical theory of aging

P.S.: There’s no official website for BAAM yet. I’m thinking of whipping something up for them – basically for announcements and abstracts – but if anyone with experience would like to pitch in, drop me a line in the comments.

Now, another (possible) black eye: GlaxoSmithKline (the company that purchased Sirtris, a pharmaceutical company co-founded by sirtuin/resveratrol pioneer David Sinclair) has suspended a trial of a resveratrol formulation, SRT501 in multiple myeloma patients, because several of the study’s subjects developed kidney failure.

GSK emphasizes that the trial has not been cancelled, but they are observing a moratorium on recruiting new patients until they determine whether the resveratrol was responsible for the subjects’ kidney problems. Nephropathy is a frequent complication in myeloma; one hypothesis being entertained is that the very high doses of resveratrol used in the trial caused vomiting, which in turn resulted in dehydration and tipped the balance in kidneys already close to failure due to the underlying cancer.

More elsewhere:

• Is the bloom off the resveratrol rose?
• Buzzkill for Red-Wine Drug: GlaxoSmithKline Suspends Trial

At the end of the meeting, Martin Brand and Stuart Kim led a group discussion about the free radical theory of aging. Martin began the discussion by pointing out that “after 50 years, you would expect a theory to accumulate enough evidence to convince us that it’s true or false – but the fact that we’re still discussing it today means that hasn’t happened.” I’m paraphrasing slightly, but that’s the general idea.

Martin Brand (who doesn’t, by the way, adhere to this theory) started by summarizing the evidence in favor of FRTA:

• “50 million Frenchmen can’t be wrong” (i.e., there are lots of correlative experiments)
• SOD2 knockout is bad
• catalase overexpression is good

Stuart rejoined with some contradicting evidence:

• Superoxide dismutase protects against oxidative stress but has little effect on lifespan in mice
• Deletion of mitochondrial SOD extends lifespan in C. elegans
• High oxidative damage levels in the longest-living rodent, the naked mole-rat.

To the last of which, others answered:

• The naked mole rat isn’t suffering from a global increase in oxidative damage – rather, there are a small number of proteins with increased damage, which may represent antioxidant proteins protecting the rest of the cell
• There’s no evidence that naked mole rats increase damage with age, which is a more relevant metric

The first two pieces of Stuart’s contradicting evidence were more difficult to challenge. Some ideas:

• Overexpressing an antioxidant enzyme in the wrong subcellular compartment wouldn’t be predicted to have any effect on lifespan

Martin also asked questions about whether FRTA is even falsifiable, and lamented the absence of an alternative clear, single-sentence “singular” theory of aging.

No final resolution but on the balance it seems like the theory is on the ropes, as we’ve discussed here before.

Craig Skinner (Lin Lab, UC Davis): Identification of potential calorie restriction mimics in yeast using a nitric oxide-based screen. Yeast are an important model system in biogerontology, useful not only for genetic studies of longevity control but also for discovery of bioactive compounds. Calorie restriction (CR) in yeast causes increased levels of nitric oxide (NO) — somewhat surprising in that yeast cells lack a homolog of nitric oxide synthase — and elevated NO is sufficient to extend yeast lifespan. These observations led Skinner to screen a yeast deletion library for elevated NO levels, yielding several genes that extend lifespan.

Mark Lucanic (Lithgow Lab, Buck): Endocannabinoid signaling mediates the effect of diet on lifespan in C. elegans. Mutants in the dauer pathway in C. elegans often influence longevity; the daf-2 mutation, which causes constitutive dauer formation at elevated temperatures, extends lifespan by several fold. Lucanic discovered that endocannabinoids are involved in the regulation of the dauer pathway — and therefore, of longevity — either independently of or far downstream of daf-2 and daf-16. Endocannabinoids are upregulated under well-fed conditions, and shorten lifespan.

Delia David (Kenyon Lab, UCSF): Widespread protein aggregation is an inherent part of aging in C. elegans. Protein aggregates are a hallmark of many age-related neurodegenerative diseases, leading to the hypotheses that the cellular mileu changes with age in a manner that causes native, aggregation-prone proteins to form aggregates. David used mass spectrometry to identify a subset of normal worm proteins aggregate as a function of age. As with the proteins associated with neurodegeneration, specific proteins aggregate in specific cell types. Mutations that extend lifespan (such as daf-2) decrease aggregation, and tend to downregulate the expression of genes encoding aggregation-prone proteins. Curiously, regulators of protein homeostasis tend to aggregate themselves, leading to a destructive positive feedback loop in which the very factors that protect the cell from proteotoxicity disappear into aggregates, leading to further aggregation.

Cherry Tang (Zhong Lab, Berkeley): The Clearance of Ubiquitinated Protein Aggregates Via Autophagy. Autophagic protein degradation has been implicated in control of lifespan: autophagy slows cell and tissue aging. Tang has identified a protein that participates in degradation of ubiquitinated proteins and co-localizes with autophagosomes; when the protein is knocked down, protein aggregates become more toxic.

(next session)

Matt Hirschey (Verdin Lab, UCSF-Gladstone): Lack of SIRT3 results in the metabolic syndrome. SIRT3 is a mitochondrial sirtuin (NAD+-dependent deacetylase) that is upregulated in liver upon fasting; knockout mice (SIRT3KO) are grossly normal but have trouble with lipid metabolism (specifically, beta-oxidation). Hershey identified several mitochondrial proteins involved in lipid oxidation that are deacetylated in response to fasting, in wildtype but not SIRT3KO. The knockouts are prone to developing obesity and metabolic syndrome with age.

Kate Brown (Chen lab, UC-Berkeley): Calorie restriction reduces oxidative stress by inducing SIRT3. Beginning with an invocation of the free radical theory of aging, and the observation that calorie restriction (CR) reduces oxidative stress, Brown asked whether the mitochondrial sirtuin SIRT3 could be involved in resistance to reactive oxygen species. She showed that CR induces SIRT3 expression, and that the SIRT3 protein deacetylates the mitochondrial antioxidant enzyme SOD2. Furthermore, consistent with Subhash Katewa’s talk in the first session, she demonstrated that CR reduces oxidative stress by switching from glucose to fatty acid oxidation, and that this switch requires SIRT3 activity.

(We’ve discussed SIRT3 before, most recently regarding its role as a tumor suppressor and also with respect to its relationship with exercise).

Ruth Tennen (Chua lab, Stanford): Insight into SIRT6 function at telomeres and beyond. Another member of the sirtuin family, SIRT6, is not localized to mitochondria but rather to telomeres, where it maintains telomeric chromatin in a healthy state and regulates the activity of the senescence-associated transcription factor NF-κB – for more background, see this previous post.) Tennen has shown that SIRT6 is involved in regulating the telomere position effect (TPE) – the silencing of gene expression caused by proximity to a telomere. The TPE has been implicated in age-related changes in gene expression: as telomeres shorten over time, telomere-proximal genes are aberrantly expressed — meanwhile, silencing factors are liberated to wander throughout the genome, repressing genes that should be turned on; similar logic has been applied to the relationship between DNA damage and transcriptional dysregulation.

Jue Lin (Blackburn Lab, UCSF): Telomere length maintenance and aging-related diseases. This talk described work that builds on significant progress, from this lab and others, demonstrating relationships between telomere length and stress, psychological outlook, and lifespan. Lin reviewed evidence that perceived stress is correlated with telomere length in white blood cells (consistent with previous results showing a relationship with intrusive thoughts). New-to-me data included a demonstration that people who increased omega-3 levels or made favorable lifestyle changes exhibited a slower rate of telomere shortening.

(next session)

Adam Freund (Campisi lab, Buck Institute) spoke about the sources of age-related inflammation, focusing on the senescence-associated secretory phenotype (SASP). Freund has elucidated mechanisms of SASP control that intermediate between the most upstream events in senescence (DNA damage) and its downstream effects (secretion of inflammatory factors). I have it on good authority that he has a completed manuscript on the subject, hopefully to be publshed soon, so I won’t say more about his story here. (Mr. Freund happens to be my baymate.)

Dario Valenzano (Brunet lab, Stanford University) is studying the genetic architecture of longevity in a short-lived fish Nothobranchius furzeri, the shortest-living vertebrate that can be reared in captivity. As a graduate student, Valenzano developed a system of biomarkers for tracking the progress of aging in skin, brain and other tissues – not only physical markers like the senescence-associated beta-galactosidase but also behavioral markers that change over the lifespan. He is now proceeding to map the longevity-associated genes in N. furzeri and testing the sufficiency of the genes he finds. Early results indicate that short-lived and long-lived fish are dying from different causes, as evidenced by a bimodal distribution of death rate vs. age.

Adolfo Sánchez-Blanco (Kim lab, Stanford University Medical School) described the “molecular odometer” for aging in the worm C. elegans. He began with the observation that lifespan is variable, even among clonally identical individuals kept under identical conditions. With genetics and environment taken out of the picture, what makes some individuals live longer than others? In order to address this question, SB had to develop a molecular marker (e.g., promoter activity of some gene) that measures physiological age (as opposed to chronological age), and then determine whether the expression level of that marker in individual worms is predictive of lifespan. SB has identified several such genes whose expression at middle age strongly predicts remaining lifespan. He is now actively looking for interventions that abolish the correlation between marker expression and longevity: if the marker gene’s activity is serving to overcome the life-shortening effect of some stress, then removing that stress will not necessarily abolish the variability in the marker, but will eliminate the correlation between marker levels and lifespan. (This is a subtle but important logical issue; I would have thought that one should look for interventions that drove the population distribution of marker levels toward the favorable side of the distribution. It was clear from questions that a lot of audience members had trouble with this logic, and I’m still not sure I understand it myself.)

(next session)

The conference is drawing from a fairly big population – everyone at the Buck Institute, comprising the members of 15 or so labs, and at least as many from Berkeley, Stanford, UCSF; I’d estimate more than 300 scientists. Turnout is pretty good: as of the morning session there are about 75 people in the auditorium, and more are trickling in.

The format is one that I like: All the talks are from postdocs and graduate students, and the talks themselves are short (15 minutes + questions). This allows us to cover a lot of different subjects over the course of the day, and gives the junior scientists who are actively doing the experiments to discuss their own work.

I’ll blog each session separately.

• Session I: Model organisms & model systems
• Session II: Sirtuins; telomeres
• Session III: Calorie restriction; protein aggregation
• Panel discussion: Free radical theory of aging

On the off chance that you’re around and see this guy, come up and say hi.

Gillis et al. developed a new framework for identifying pairs of genes differentially coexpressed with age that is based on Haar wavelets, and tested it on a large set of human expression data mined from the handy GEMMA database. Unlike other methods that can interpret data coming from only two groups (e.g. young mice vs. old), the new wavelet method is designed to handle multiple ordered groups – such as animals of many different ages. The authors don’t discuss the biological implications of their results in any detail, instead promising these will be explored in a later paper.

Southworth et al. showed that coexpression patterns of groups of related genes become less coherent as animals age. Using several different methods for grouping genes together (e.g. assigning genes to the same group if they share a function, or if they are targets of the same transcription factor), they calculated intra-group correlation in 16- and 24-month-old mice using data from the AGEMAP study. They identified a surprisingly large number of groups with lower correlation in old mice. One of these is the targets of NF-κB – a transcription factor that, when knocked down, can reverse skin aging. Only a few groups (including one enriched for DNA damage genes) showed higher correlation in old mice. Also, the authors found that genes showing decreases in correlation aren’t randomly located on the chromosome – instead, they form several clusters.

What are the causes and consequences of these changes in gene group correlation? Previous single-cell studies have shown that transcriptional noise, or cell-to-cell variation in the expression levels of individual genes, increases with age. Clearly transcriptional noise is going to affect coexpression to some degree: any increase in a gene’s noise level will automatically reduce its calculated coexpression with other genes. But changes in coexpression can also occur without any corresponding change in noise. These changes may reflect cellular processes that are active or suppressed at different times of life, and many or all such changes (such as a ramped-up DNA damage response in old age) may be adaptive. Further analyses are needed to tease out which age-related coexpression differences result from noise, and which ones are telling us something new.

Gillis, J., & Pavlidis, P. (2009). A methodology for the analysis of differential coexpression across the human lifespan BMC Bioinformatics, 10 (1) DOI: 10.1186/1471-2105-10-306

Southworth, L., Owen, A., & Kim, S. (2009). Aging Mice Show a Decreasing Correlation of Gene Expression within Genetic Modules PLoS Genetics, 5 (12) DOI: 10.1371/journal.pgen.1000776

If only because of the size of the heap, I nonetheless still suspect that there’s a pony in there somewhere; I’ve often wished I had the time to do a comprehensive literature review of my own, so that I could identify the compounds whose associated claims are supported by the best evidence. Now it looks like I can start wishing for something else, because someone did it for me.

At the (amazing) blog Information is Beautiful, David McCandless and Andy Perkins have assembled a “generative data-visualisation of all the scientific evidence for popular health supplements“. In David’s words:

I’m a bit of a health nut. Keeping fit. Streamlining my diet. I plan to live to the age of 150 in fact. But I get frustrated by constant, conflicting reports and studies about health supplements.

Is Vitamin C worth taking or not? Does Echinacea kill colds? Am I missing out not drinking litres of Goji juice, wheatgrass extract and flaxseed oil every day?

In an effort to give myself a quick reference guide, I dove into the scientific evidence and created a visualization for my book. And then worked with the awesome Andy Perkins on a further interactive, generative “living image”.

The image itself is dynamic with respect to both user input about what information is desired, and introduction of new data – it is based on the information in a spreadsheet, which can be updated (new compounds, or information about compounds already mentioned), altering the visual rendering the dynamic image. You can play with the image here; I’ve attached a still snapshot below.

The rendering is imperfect (as also discussed elsewhere): More reliable claims are near the top, and more dubious claims are near the bottom, but this positioning is the result of a single variable, “evidence,” which may the based largely on a citation count. This is a problem because not all citations that mention a compound should be weighted equally; furthermore, it’s not clear how conflicting claims end up getting counted. The abstraction of a complex body of data into a single number unquestionably involves some judgment calls that could be made differently – that’s not necessarily a lethal criticism, but the process should be as transparent as possible.

On a visual level, the image is attractive, but color is mostly a wasted variable: position along the color spectrum is synonymous with height — except in the case of orange, which indicates a compound with “low evidence, promising results”. The orange compounds are still assigned an evidentiary weight, according to an algorithm I can’t fathom; this is particularly confusing at both ends: beta-glucan is in the “high evidence” position, which seems to contradict the label’s definition (“low evidence”); whereas noni and astragalus are in the “no evidence” position, raising questions about how there could be “promising results”.

The strength of the project, however, is that it can evolve; the creators are already enthusiastically updating it. So far the changes (as detailed in this log) are content-oriented; one hopes that the methodology of generative data visualization will also enjoy improvements as time goes by.

(For another example of user-driven visualization, see the Timeline of Discoveries in the Science of aging, which we discussed here previously (1 2). That piece hasn’t been updated in a while – perhaps it could use some new contributors.)

Ageing, the accumulation of damage to molecules, cells and tissues over a lifetime, often leads to frailty and malfunction. Old age is the biggest risk factor for many diseases, including cancer and cardiovascular and neurodegenerative diseases. … Ageing research is clearly gaining momentum, as the reviews in this Insight testify, bringing hope that at some time in the future we will be able to keep age-related diseases at bay by suppressing ageing itself.

The five reviews are all by prominent scholars — many of whose work we’ve discussed here — and cover a wide range of subjects within gerontology and biogerontology:

• The genetics of ageing, Cynthia J. Kenyon
• Lessons on longevity from budding yeast, Matt Kaeberlein
• Linking functional decline of telomeres, mitochondria and stem cells during ageing, Ergün Sahin & Ronald A. DePinho
• Neural mechanisms of ageing and cognitive decline,
  Nicholas A. Bishop, Tao Lu & Bruce A. Yankner
• Biodemography of human ageing, James W. Vaupel

As always, Nature Insight supplements are free-access, so even if you don’t have access to a university subscription, you can still read these articles.

(For a previous aging-related Nature Insight on DNA repair, see here.)

Abstract deadline is March 25th (still time!), and the early registration deadline is April 19th.

There are a couple of UK-based people on the roster whom I know from conferences (João Pedro de Magalhães, curator of senescence.info and developer of the Human Aging Genomic Resource; Aubrey de Grey of the SENS Foundation), and a larger number of German scientists whom I haven’t had the pleasure of meeting, but who sound like they’re doing interesting work.

More information at the workshop web page. It’s a short conference and the registration fees are extremely reasonable, so it’s totally something I would go to if I were going to be in northern Germany at that time.

This might be good news if it turns out that the longevity-enhancing qualities of rapamycin end up generalizing to humans: If you need to maintain constant levels of a chronically administered drug, t’s way easier to use timed-release oral capsules than injections. Also, as millions of diabetics will tell you, it’s just nice not to have to shoot up.

But the drug itself might be bad news, especially if it is taken over long periods of time: mTOR, the target of rapamycin, appears to be necessary for reconsolidation of long-term memory in mammals; inhibition of mTOR is efficacious enough at blocking fear memories that it’s discussed as a strategy for treating PTSD. The role of mTOR in memory appears to be general, i.e., in memories other than fearful ones, and it is evolutionarily ancient: TOR is important for long-term potentiation in the sea slug Aplysia, beloved model of scholars of learning and memory.

So, as I’ve commented before, I have this fear that rapamycin (or a derivative) will turn out to be a bona fide longevity enhancement drug, but one whose chronic use erodes long-term memory, which does defeat the purpose to some extent.

Then again, blood-brain barrier is an issue here: even though Everolimus can survive the stomach and pass through the gut into the blood, that doesn’t mean it will make it into the brain efficiently. Then again again, if the drug has a long half-life once it’s inside the brain, it might still accumulate there if one had to take it every day for the rest of one’s life.

On the happy side, if you find this possibility traumatic, the rapamycin will take care of that for you.