Alzheimer Research Forum on the web

Kinoshita and Clark announce Alzforum, an online community for Alzheimer’s disease (AD) researchers:

Alzforum: E-Science for Alzheimer Disease

The Alzheimer Research Forum Web site (http://www.alzforum.org) is an independent research project to develop an online community resource to manage scientific knowledge, information, and data about Alzheimer disease (AD). Its goals are to promote rapid communication, research efficiency, and collaborative, multidisciplinary interactions. Introducing new knowledge management approaches to AD research has a potentially large societal value. … In addition to imposing a heavy burden on family caregivers and society at large, AD and related neurodegenerative disorders are among the most complex and challenging in biomedicine. Researchers have produced an abundance of data implicating diverse biological mechanisms. Important factors include genes, environmental risks, changes in cell functions, DNA damage, accumulation of misfolded proteins, cell death, immune responses, changes related to aging, and reduced regenerative capacity. Yet there is no agreement on the fundamental causes of AD. The situations regarding Parkinson, Huntington, and amyotrophic lateral sclerosis (ALS) are similar. The challenge of integrating so much data into testable hypotheses and unified concepts is formidable. What is more, basic understanding of these diseases needs to intersect with an equally complex universe of pharmacology, medicinal chemistry, animal studies, and clinical trials. In this chapter, we will describe the approaches developed by Alzforum to achieve knowledge integration through information technology and virtual community-building. We will also propose some future directions in the application of Web-based knowledge management systems in neuromedicine.

It’s an ambitious mission and could use the support of the community, beginning with your participation.

 

Mitochondrial dysfunction in Alzheimer’s

The brains of Alzheimer’s disease (AD) patients are riddled with plaques of amyloid-beta (Aß) protein — but what causes the accumulation of the plaques?

One candidate is mitochondrial dysfunction, which can result in high levels of reactive oxygen species (ROS) and also rob the cell of energy it needs for maintenance of homeostasis. Hauptmann et al. report that in an AD mouse model, mitochondrial dysfunction can be observed very early in the progression of the disease: Indeed, mitochondria begin to exhibit respiratory-chain defects well before extracellular plaques can be observed:

Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice

Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer’s disease integrating genetic factors related to enhanced amyloid-beta (Aß) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Aß pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Aß deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Aß. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Aß dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Aß and progression accelerates substantially with aging.

To the extent that mitochondrial dysfunction contributes to pathology, it could partially explain why AD is a disease of old age, since mitochondria deteriorate over the course of aging.

Granted, these mice are APP mutants and already primed to develop AD. In a wildtype animal, could mitochondrial dysfunction somehow interfere with protein folding, secretion or clearance machinery and thereby jump-start the process of Aß aggregation?

 

The big picture: Alzheimer’s transcriptome, insulin phosphoproteome

For all you genomics and systems-level junkies out there, here are two very juicy genome-scale (in one case, proteome-scale) studies of two very different aging-related phenomena: From Miller et al., we have a systems-level analysis of gene expression in both Alzheimer’s disease (AD) and normal aging. The authors use the transcriptional data in conjunction with genome annotation to identify pathways that are coherently regulated, either by neurodegenerative changes or age-related decline. Since the authors focus on brain tissue rather than the more easily accessible (or biopsy-able) parts of the body, these findings will be more relevant to understanding the pathology of AD than to its diagnosis. Hence, this approach is complementary to recent studies aimed at identifying proteins that are differentially expressed in the blood of AD patients and can therefore be used as diagnostic biomarkers for the disease.

Meanwhile, Krüger et al. have used mass spectrometry to characterize the tyrosine phosphoproteome of the insulin signaling pathway — in other words, they looked for proteins that are differentially tyrosine-phosphorylated as a result of insulin action. In addition to rounding up proteins already known to be involved, they also report the identification of several novel effectors of insulin signaling. The technique appears quite robust, and I look forward to seeing this methodology extended to other aging-related signaling networks (such as the closely related IGF-1 pathway).

 

A statin that prevents inflammation

The anticholesterol drugs known as statins act primarily by inhibiting the rate-limiting step in cholesterol biosynthesis. However, these compounds also have effects mediated by other mechanisms: for example, we recently learned that the antioxidant activity of one such drug, rosuvastatin, helps limit age-related increases in reactive oxygen species.

Now, Andras et al. report that another statin, simvastatin, can protect against the inflammatory effects of expression the Alzheimer’s-related protein Aß:

SIMVASTATIN PROTECTS AGAINST AMYLOID BETA AND HIV-1 TAT-INDUCED PROMOTER ACTIVITIES OF INFLAMMATORY GENES IN BRAIN ENDOTHELIAL CELLS

Increased deposition of amyloid beta (Aß) is characteristic for normal aging and HIV-1-associated alterations of the central nervous system. In addition, both Aß and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that Aß and HIV-1 protein Tat can potentiate their proinflammatory effects at the brain endothelium level. To address this hypothesis, we studied promoter activity of three proinflammatory genes in an in vitro BBB model of human brain microvascular endothelial cells (HBMEC) co-cultured with a human astrocyte cell line producing Tat (SVGA-Tat cells) and exposed to Aß. Treatment of HBMEC with Aß(1-40) in the presence of SVGA-Tat cells resulted in a significant upregulation of E-selectin, CCL-2, and IL-6 promoter activities and protein levels as compared to the individual effects of Aß or Tat. In addition, A markedly amplified E-selectin promoter activity in HBMEC co-cultured with HIV-1-infected Jurkat T cells. Simvastatin, the HMG-CoA reductase inhibitor, effectively blocked proinflammatory reactions induced by Aß in co-cultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to A and Tat or HIV-1 can synergistically potentiate expression of inflammatory genes in brain endothelial cells. In addition, simvastatin may provide a beneficial influence by reducing these effects at the BBB level.

The compound also prevents inflammation resulting from HIV infection, suggesting that the mechanism of simvastatin action is not peculiar to the effects of one specific protein. It remains to be seen whether the compound is directly altering transcription of inflammatory genes, or whether the effect on inflammation is somehow mediated by the drug’s effect on cholesterol.

Reports like this always make me marvel: Is there anything statins can’t do? (I remember attending a conference where one speaker half-jokingly suggested we put statins in the drinking water; my only objection at the time was that I don’t think they’re particularly soluble.) When I have thoughts like that, I always take care to remind myself that we have yet to invent a drug with no side effects. In the case of statins, the problem is myalgia (muscle weakness), and it can be severe enough to be debilitating. Definitely not for recreational use.

 

Stress, APP, and Alzheimer’s disease

File under “Stress is bad for you, Reason #6508.” Chronic stress increases the expression of the amyloid precursor protein (APP); the abnormal processing of this protein is a key event in the development of Alzheimer’s disease (AD).

Of course that’s not the whole story: Numerous factors contribute to the pathologenesis of AD, including inflammatory factors secreted by glial cells; this is likely exacerbated by glial senescence, which accumulates with age.

 

2007 Hillblom meeting: Afternoon session

(continued from Morning session 2)

After a delicious lunch in the courtyard of the behemoth Frances Arrillaga Alumni Center, we’re back for the afternoon session of the meeting.

First up: Charlie Glabe, whose excellent talk I highlighted in my review of last year’s conference. He began with a discussion of continuing progress in the use of anti-amyloid antibodies in both basic disease research and the clinic. Many of these antibodies are conformation-specific but not sequence-specific, i.e., they can identify amyloid oligomers or fibrils regardless of the protein composition of the amyloid structure; one such antibody has been used to detect heretofore uncharacterized amyloid deposits in macular degeneration. Other antibodies can identify both conformational and sequence characteristics of protein aggregates. The Glabe lab and their collaborators have been using the various specificities of a large panel of antibodies to probe disease-related amyloids and identify subtypes that have greater or lesser roles in pathogenesis.

In other news, Glabe’s group is also performing chemical screens to identify small molecules that can inhibit the formation of amyloid oligomers. So far, they have discovered several compounds that block amyloid formation even at very low drug concentrations (indeed, substoichiometric levels, as though the drugs are targeting rare “seed” conformers of the amyloid proteins). Several of the active compounds both inhibit oligomerization and promote assembly of amyloid fibrils, which are thought to be protective (e.g., see this report about AD models in the worm).

Continuing with the theme of small-molecule studies, Gordon Lithgow of the Buck Institute for Age Research described ongoing work on the chemical biology of aging. Lithgow begins from a simple premise: Given that genetic manipulations have revealed significant plasticity in the rate of aging, shouldn’t we be able to discover drugs that phenocopy, simulate or even outstrip the effects of longevity-extending mutations? Thus far, early screens for both stress resistance and lifespan extension per se have generated several lead compounds that delay aging in yeast, worms and flies (and in at least one case, both species). Studies from multiple labs are beginning to converge, with the ultimate goal of testing multi-species hits in mouse models of aging and age-related diseases. In closing, Lithgow acknowledged that understanding of the mechanism of action of these compounds is lagging behind their discovery, in part because some of the most promising molecules have mystifyingly large numbers of candidate targets.

The poster session is next, but I have to run off and catch a plane to Irvine immediately afterward, so I’ll have to comment on that tomorrow. Hope you’ve enjoyed today’s coverage.

 

2007 Hillblom meeting: Morning session 2

(continued from Morning session 1)

Back from bagels and coffee.

Bill Mobley (Stanford) began with the bold claim that all neurodegenerative illnesses are ultimately breakdowns of neural circuitry — if not etiologically, then symptomologically. He went on to summarize and review the body of evidence supporting the view that axonal dysfunction contributes to Alzheimer’s Disease (AD) pathology, focusing especially on the idea that decreases in neurotrophic factor signaling and retrograde transport play a causative role in AD. The talk concluded with breathtaking tomography and fluorescence video microscopy of intact circuits manipulated in culture.

Mobley turned over the microphone to a collaborator (Tony Wyss-Coray) who argued that age- and AD-related changes in autophagy (e.g., decreases in the level of the autophagy protein beclin) could explain how receptors and transport factors might get “stuck” in axons, further contributing to pathology and neurodegeneration. Consistent with this, both Aß plaque deposition and APP accumulation are dramatically increased in beclin^+/- mice. The collaborator was senior author of the recent paper about a serum cytokine profile of AD, and he said some more about the possibility that the factors shown to be associated with AD are actually contributing to disease pathology.

Changing gears from the brain to the pancreas (half the LLHF’s mission is devoted to diabetes), Alberto Hayek and C. C. King from the Whittier Institute for Diabetes described efforts to derive populations of insulin-producing beta cells, suitable for transplant, from stem cells and other sources. Quick version: So far, not so good, but researchers are learning a ton about the basic regulatory biology of pancreatic cells (especially the miRNA, proteomic and epigenetic/methylation profiles of beta cells), and hopes are high that at some point in the not-too-distant future, stem cell-based approaches will indeed fulfill their oft-cited promise in potential treatments for diabetes.

(continued in Afternoon session)

 

Toward a blood test for Alzheimer’s

Via Neurophilosophy and Mind Hacks, news of new progress toward a blood test that may someday be used to diagnose Alzheimer’s disease (AD) and mild cognitive decline. The study is published in the most recent issue of Nature Medicine:

A molecular test for Alzheimer’s disease could lead to better treatment and therapies. We found 18 signaling proteins in blood plasma that can be used to classify blinded samples from Alzheimer’s and control subjects with close to 90% accuracy and to identify patients who had mild cognitive impairment that progressed to Alzheimer’s disease 2–6 years later. Biological analysis of the 18 proteins points to systemic dysregulation of hematopoiesis, immune responses, apoptosis and neuronal support in presymptomatic Alzheimer’s disease.

This test measures levels of proteins in blood plasma, and could certainly be used alongside nucleic-acid based tests such as this assay of white blood cell mRNA expression proposed last year. As I pointed out at that time, it’s likely that such tests could be made even more accurate if every patient had individual baseline measurements taken in earlier life, before any hint of dementia had emerged; this would allow physicians to distinguish between patients who had always been at one end of the population distribution and those who had recently undergone changes in biomarker levels.

 

A role for microglial senescence in Alzheimer’s?

Why do amyloid plaques cause Alzheimer’s disease? While it would seem to be self-evident that neurons would prefer not to be surrounded by tangled forest of malfolded, insoluble protein deposits, the mechanism by which these plaques cause neuronal death remains an active subject of inquiry.

Cell-autonomous mechanisms (i.e., those in which the plaques act directly on the neurons that will ultimately die, which are the same cells that produced the Aß and tau protein that make up the plaques) are likely to be most important, but some scholars have begun to consider the cell-non-autonomous possibilities. What if the primary action of amyloid plaques is on another type of cell entirely — such as the ubiquitous, essential, yet still poorly understood neuronal support cell, the microglia? Flanary et al. argue that the presence of amyloid plaques accelerates the process of microglial senescence:

Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer’s disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.

To summarize: Long-term activation of microglia exposed to amyloid results in telomere shortening (presumably the cells undergo more divisions than when they’re not activated), which ultimately leads to cellular senescence when telomeres become critically short. Consistent with this, senescent cells can be observed in amyloid brains, at higher levels than one would expect as a result of chronological age alone.

The authors do not demonstrate a direct connection to Alzheimer’s pathology, but it’s easy to build a model in which senescent microglia contribute to cell death. Evidence from our lab and others has shown that senescent cells, which accumulate throughout the body as a function of age and genotoxic damage, secrete high levels of dangerous signaling molecules, e.g., inflammatory cytokines, growth factors, and matrix metalloproteases. While the post-mitotic cells in the vicinity of senescent microglia are unlikely to respond to growth factors, the inflammatory factors and protease activity could easily conspire to make life quite unpleasant for the delicate neurons. This would be especially likely if the amyloid plaques are also causing direct damage to these cells.

Several labs are already considering ways to therapeutically eliminate senescent cells, either exploiting the body’s natural methods (immunologically) or using gene therapy. A firm connection between senescence and a scourge like Alzheimer’s (which, unlike aging as such, is already recognized by funding agencies as a pathology) could go a long way toward energizing such efforts.

 

Conference report: SENS3

Okie here, back from the SENS3 conference in Cambridge, and slowly recovering from jet lag.

General thoughts: As a scientist, it is a challenge to present my work to a mixed group of scientists and (particularly well-educated) lay people. Where translational research is concerned, however, I think that lay people do a great job keeping us researchers focused on the prize and not just on (interesting) esoteric points.

As in my previous conference reports (see here and here) I will cover general themes of the meeting, as well as summarizing specific presentations that I found most interesting. Unfortunately I can’t cover them all; what I decide to cover is purely subjective and perhaps even a bit arbitrary. Also, I may skip or gloss over talks/themes that were repeated from the Edmonton conference with little progress.

Themes:

• Biomedical remediation
• Would Healing/Artificial Repair
• Muscle Aging
• Other topics

Biomedical remediation

The fascinating field of biomedical remediation (essentially the brain-child of Aubrey de Grey) is moving along quickly. We heard from two collaborating/competing groups: Pedro Alvarez from Rice and John Schloendorn, a student from Tempe, Arizona being supported directly by the Methuselah Foundation. Pedro is a brilliant environmental chemist/bioremediation guy turning some of his talents on the biological problem of lipofuscin accumulation. The work is progressing rapidly. Both teams have identified strains of bacteria capable of using 7-ketocholesterol (one precursor of the poorly defined lipofuscin) as energy. The next goal is to clone the genes. After that they want to purify the enzyme responsible and feed it to people and see if it will break down our lipofuscin.

My only criticism isn’t with the method, results, or rate of progress (which are all fantastic). My issue is that they are trying to solve a problem that hasn’t been proved to be a problem yet. Lipofuscin accumulation has long been associated with aging in many tissues, but never (as far as I am aware) proved to be responsible for any illness, ailment, or disease. Now, don’t get me wrong, Aubrey makes an excellent argument for this being a serious problem with no traditional biomedical solution in sight, but it’s still just theory. As one of my old mentors used to say, “In this game you’ve got to have data!” Here’s my 2 cents: Now that they’re homing in on the genes, how about cloning the gene and making a transgenic mouse? Might be easier to look at toxicity, long-term affects, and efficacy with a transgenic; though dosage control is problematic with transgenics.

Wound Healing/Artificial Repair

In my opinion, this was the most provocative and promising aspect of the research at SENS 3. Really cool stuff below.

Cato Laurencin is an amazing individual. He is one of those rare clinicians who can aim high-quality research directly at clinical applications. He calls his approach “regenerative engineering.” As I work in a bioengineering department, I sit through a lot of boring biomaterials talks. It was amazing, however, to see someone actually using a few in something practical! In my opinion, this is the reality of regenerative medicine: an innovative surgeon combining technology and knowledge of biology to partially repair injuries such that they will heal as well, or better than they started. Dr. Laurencin showed results from his work on 3D absorbable poly L-lactide (PLLA) scaffolds that seem to promote recovery from surgery much more efficiently than traditional methods. This is a microsphere-based scaffold, which promotes efficient invasion and engraftment of osteoblasts to help repair bone. He is also investigating surfaces with nano-scale grooves, which are more conducive to mesenchymal stem cell proliferation.

Rutledge Ellis-Behnke spoke on his work with SAPNS: Self Assembling Peptide Nanofiber Scaffold. Essentially, he squirts a solution containing these nanofibers into wound sites and reportedly achieves amazing results. He reports dramatic recovery from serious brain injury: both scarless repair of bulk brain tissue removal and reinnervation. In addition, he claims that the nanofibers can dramatically stop bleeding in wounds (he showed video of this). These results are so dramatic that they are almost unbelievable. There are some videos attached to this paper that are pretty darn amazing. The mechanism of action is unknown.

Right along these lines, Robin Franklin gave an interesting talk about myelin repair/regeneration. To summarize the take-home message: the presence of differentiated tissue/cells/debris inhibits efficient re-myelination. If they inhibit clearance of dead myelin by artificial or natural means, re-myelination does not occur. The real trick now is to figure out how to stimulate clearance of damaged myelin (especially in old animals), and the holy grail will be to discover which factor(s) in the damage/differentiated tissue inhibit regeneration.

Muscle aging

Two groups and three speakers addressed the issue of aged muscle, muscle regeneration, and muscle stem cells.

Gillian Buttler-Brown summarized her previous work on human cells, establishing that myoblasts (muscle progenitors) senesce in culture and that cells from old people senesce slightly faster than those from young donors. Interestingly, she showed preliminary work analyzing the “secretome” of myotubes generated from old or young myoblasts. This was inspired by the work of the Campisi lab on the secretome of senescent cells.

Michael Conboy summarized the recent work from the Conboy lab showing how old muscle stem cells can be revitalized after being exposed to a young systemic environment and how embryonic stem cells can have a similar paracrine affect on revitalizing old muscle cells. He then described his recent work on asymmetric cell division in muscle stem cells. Basically, the stem cells tend to divide so that the original copy of the DNA stays with one daughter cell and the newly synthesized DNA segregates with the other daughter cells. This ensures that some stem cells remain behind with original copies of the DNA (which are presumably of higher fidelity).

Another talk from the Conboy lab (by yours truly) was a short study on the telomere regulation of muscle stem cells. Basically, we discovered that truly pure, undifferentiated muscle stem cells (satellite cells) have very high telomerase activity. Furthermore, they continue to fully maintain their telomerase activity and telomeres with age. This supports the idea that muscle stem cells remain intrinsically young, even while their tissue ages around them.

Other topics

If you’re not already familiar with Sangamo, I highly suggest you check out this exciting young company. This isn’t garden-variety gene therapy - it’s gene editing, for lack of a better word. It’s not introducing exogenous DNA into your cells, it’s editing your genomic DNA. Right now (since gene therapy doesn’t work) the best approaches (in my opinion) involve ex vivo manipulation of cells (and the immune system is the most amenable to this approach). As you can imagine, this technology could also be extremely useful for cell culture lab experiments. No more need to create knockout mice just to generate knockout cells. You can do it with many cell types and should work in any species. Right now it is ridiculously expensive to have them generate a cell line for you (I heard $20k a while ago), but they just made a deal with Sigma to start selling the tech to labs, so I figure they are planning on making it large-scale and affordable to researchers. What I would like to hear are ways to apply this tech to make cells better, in addition to curing diseases (like AIDS).

There is an NIA project to test various compounds on the lifespan of mice. No real results are available yet, but if you have a favorite drug, vitamin, or supplement of any kind then you too can recommend that it be tested on mice! Randy Strong of UT-San Antonio gave this presentation.

A great disappointment to me was the cancellation of Rita Effros’ talk. A rather, um, interesting talk was pulled together at the last minute to replace her. A gentleman from a small company collaborating with Geron is selling a “nutraceutical” which is supposedly a potent activator of hTERT expression. For the low, low price of $25k per year, you too can extend your telomeres. They are avoiding FDA regulation by calling it a nutraceutical instead of a drug and by NOT doing any clinical trials. I find it ironic that it’s possible to escape regulation by not doing any testing to ensure its safety. They don’t know what tissues the drug nutraceutical is targeted to. About a dozen clients have been taking the compound for 3-9 months. They report extension of mean telomere length of granulocytes (but not yet other immune cells) and an improvement in vision. There are no placebos or negative controls of any kind (controls would make it an experiment, which would make it a drug). Honestly, I’m really glad that there are people out there willing (desperate enough) to do this sort of self-experimentation and I’m anxious to see the long-term results.

Ruth Itzhaki has made an interesting connection between Alzheimer’s disease and herpes virus infection. According to her results, people with the APOE4 allele and an HSV1 infection (that’s the “kissing disease” with which 90% of people are infected, not genital herpes) were more likely to develop symptoms of Alzheimer’s, and more severe symptoms, than patients with the APOE4 allele alone. She finds that viral load is concentrated in AB plaques and speculates that one HSV1 glycoprotein has a similar structure to the AB protein. Finally, she finds increased phosphorylation of Tau protein after HSV1 infection. Currently, no HSV1 vaccination is approved for use in humans…

Zheng Cui (Winston-Salem, NC) is a man with a mission to cure cancer. You may have heard about his method before: it’s a sort of brute force immunotherapy approach. He isolates white blood cells from a donor and injects them into the “patient” (in most cases a mouse). The granulocytes then attack the tumor and “cure” the cancer. One drawback from this type of therapy is that it requires 10 donors for every recipient. He has done some human work and human granulocytes definitely do the job in vitro.

These are just a sampling a lot of fantastic talks and I wish I had time to write about all of them. The videos of all of the talks will eventually be posted online and I urge you to check them out when they become available at the conference website. There were also a number of talks of questionable scientific quality or virtue. I like to think that the field of aging science is separating from the age-old snake-oil stereotypes, but there was definitely a fair amount of what I would term “pseudo-science.” You can check those talks out too.

On a final note, I would like to make a comment about the state of the art. I would like to see more theoretical and statistical work on which problems of aging are the most pressing/serious ones. I think Aubrey’s “7 deadly things” is a well thought out plan for tackling the problem of universal aging. What I would like to see is some data on which problem(s) are rate limiting. For example, what if solving the problem of “too few cells” (cell death and senescence in aging) would double human lifespan all by itself while all the others put together would barely accomplish the same? The keynote talk (by Ryan Phoenix) included some modeling of how soon SENS treatments could be available, how soon we would need to solve the 7 things in order to treat people alive today, and how often treatments would need to be repeated. This all relied, however, on the assumption than all 7 deadly things were created equally. Everyone agrees that we should take steps to provide the most immediate benefits to humankind, but no one agrees on what these are.

In closing: The humorous poster of my friend and fellow conference attendee George Hinkal, who helped with this piece by encouraging me to add a couple things and helping to clarify a couple others.