There’s a Keystone Symposium on this subject Jan 31-Feb 5 2010:

Aging can be defined as the gradual loss of the ability of the organism to maintain homeostasis. Our aim will be to focus on the molecular and cellular mechanisms by which tissue and organ function deteriorate and homeostasis fails rather than on longevity itself, which has been the theme of previous Keystone Symposia meetings on aging. Work from a variety of models is recognizing that organisms, especially humans, are complicated systems in which interventions that extend lifespan might not necessarily block the aging and loss of function in specific organs or tissues and vice versa. Continuing this approach will help us gain an understanding and appreciation of the complexity that underlies aging in humans. The aim of this meeting is to reveal the integration and communication between pathways and systems during functional aging and their relationship with longevity. This meeting will highlight important questions to address in future research. Most importantly, what are the common and disparate causes underlying the cellular and physiological mechanisms responsible for human senescent phenotypes?

It’s at Granlibakken, an adorable Tahoe resort where my old department used to go on retreat every autumn. I’ve never been in the winter, but I hear it’s nice.

Registration information is can be found here. Early registration deadline is November 30, but you can continue to register for full price up until January 31 (or until the conference fills up).

Just to follow up on that last post asking you to help the SENS Foundation win $5000 — it worked! SENS came in first, and won the grand prize. The margins were pretty narrow — well below the number of people who visited the contest page from Ouroboros alone — so it can truly be said that every vote counted.

Thanks to the readers of Ouroboros and everyone else who helped SENS over the top.

The amount of money raised is, in the grand scheme, rather small, but it’s possible that the victory for SENS in what amounts to a popularity contest will help increase awareness of the life extension cause.

“I’m immensely grateful to 3banana for involving us in this great opportunity, and to all the SENSF supporters who took the time to leave comments at the site,” said SENS Foundation CSO, Dr Aubrey de Grey. “These supporters have recognised that a public and eloquent expression of broad-based support for our mission has the potential to raise the profile and perceived legitimacy of our work and thereby greatly amplify the impact of the competition itself.”

The SENS Foundation (which organizes the Strategies for Engineered Negligible Senescence conferences) is in the running for the $5000 grand prize in 3banana’s Share to Win event. The contest seeks to raise money “for causes serving unmet needs in health, education and environment.”

And you can help. It’s pretty simple: All you have to do is leave a comment on this page. (The award goes to the cause with the most comments.) You can sign on using a Google account if you already have one of those, or register for a free one-off account. It’s painless and takes about thirty seconds.

Your comment/vote makes a difference! Right now, SENS is neck-and-neck with the competition — as of this post, they’re 17 votes behind first place. (Well, sixteen, since I just commented.) So don’t just sit there — this is your opportunity to help send real money to a very important cause, at no cost to yourself.

Post your comment now.

There are only four days left in the contest, so time is of the essence.

(For all you social media users, feel free to spread the word via blogs and Twitter. If you’re interested in regular updates from the SENS Foundation, there’s a Facebook page as well.)

UPDATE: The push yesterday put SENS into the lead — thanks to all Ouroboros readers who took the time to comment! But the current lead is tenuous, and it could still be lost. If you haven’t commented yet: it doesn’t take much time, and with margins like these your vote really makes a difference. Would you really want to find out that SENS had lost by a single vote? Please consider taking a minute or so and leaving a comment on the contest page.

A prominent scholar of the CLK-1 story has called the coroner on the mitochondrial free radical theory of aging (MFRTA). From Lapointe & Hekimi:

When a theory of aging ages badly

According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is the cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1 +/− mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.

MFRTA recently turned 50, and consequently has received a lot of attention lately; q.v. this review and this retrospective by Denham Harman, the originator of the theory. The thesis of most pieces seems to be that the theory hasn’t been demonstrated to explain the bulk of age-related decline, but that there’s still life in the idea. In contrast, the authors of this review argue that the relevant experiments have been performed and that the theory has been falsified — in other words, we’ve done our scientific duty and it’s now time to move on.

I doubt very much that this article will put a permanent end to the controversy. Data reported fairly recently have breathed new life into oxidative theories in general and the MFRTA in particular. While these authors contend that the CLK-1 mouse mutant contradicts the underlying mechanisms of the MFRTA, other recently reported work on this pathway supports the claim that inhibiting mitochondrial respiration delays aging, a key prediction of MFRTA.

Furthermore, if mitochondrially generated oxidative radicals are truly not playing a causative role in aging, it becomes much harder to explain how mitochondrially targeted antioxidants can extend lifespan in mammals.

Lapointe, J., & Hekimi, S. (2009). When a theory of aging ages badly Cellular and Molecular Life Sciences DOI: 10.1007/s00018-009-0138-8

(From the Perry Bible Fellowship. For the previous installment of Sunday Funnies, see here.)

I attended the inaugural Singularity Summit back in 2006 — it was full of ideas, certainly, but I came away mostly skeptical and disillusioned about the quality of thinking on display there.

The event itself seems to be here to stay, however, and it’s growing: It now lasts two days (up from 1), with 26 speakers (up from 13). The scale of the event seems to be doubling every three years. According to the extrapolative logic so familiar to singularity believers, within 30 years the event will last more than a year, causing each Summit to flow into its successor (the “Calendarity”); within 100 years, everyone in the world will be a speaker (the “Popularity”). Except, of course, that by then we’ll all be hyperintelligent machines, and the event will be a historical re-enactment rather than an exercise in projecting the future.

I mention the summit here because of its small but growing anti-aging and longevity components. Of interests to biologists, biogerontologists and advocates of extending (biological) lifespan:

• DNA: Not merely the secret of life, Ned Seeman
• Artificial biological selection for longevity, Gregory Benford
• The Singularity and the Methuselarity: Similarities & Differences, Aubrey de Grey

There will also be a totally unbiased talk on “Critics of the singularity” by Ray Kurzweil, who doesn’t have a dog in that fight and will be sure to give equal play to both sides.

The cost has more than doubled: It’s up to $498, from $0 – frustrating any attempt to apply logarithmic extrapolation – though there are a number of opportunities to earn discounts.

The 2009 Summit will be held in New York City. You can find out more at the website.

Gabor Forgacs gave a very interesting talk about using bioprinting to build entire organs from scratch. He argued that while traditional scaffold-based methods of tissue engineering work for thin tissues, they are not appropriate for thick, complex tissues. They have designed a computer-aided printing system that can put down layers of single cells according to a blueprint, and are applying it to produce vascular and nerve grafts.

Sally Dickinson spoke about the first transplant of a tissue-engineered airway, which took place in June 2008. She played a cool video explaining the whole procedure, which is up on youtube. Using a donor trachea, they first treated it to remove all the donor’s cells; they then took some stem cells from the patient’s bone marrow, turned them into chondrocytes, grew them up and seeded them onto the scaffold; finally, they transplanted the engineered trachea into the patient.

(For an index of coverage of all sessions, see here.)

Daniel Kraft spoke about stem cell transplantation in bone marrow. They developed an alternative method of ‘making room’ in bone marrow for new stem cells that uses antibodies (which is much less toxic than chemotherapy, the usual approach). Also, they developed MarrowMiner, a faster and less painful way to extract bone marrow from a donor using only a single entry site – previous methods require making hundreds of individual needle jabs.

(For an index of coverage of all sessions, see here.)

Carlos Barbas talked about altering the activity of individual genes using zinc finger recombinases. They have developed an automated approach for producing enzymes that can accurately target any region of DNA, and made it publicly available – just input your target sequence to ZFTools.

(For an index of coverage of all sessions, see here.)

Justin Rebo spoke about some initial experiments that show it’s feasible to selectively remove anergic T cells from old mice. The basic idea: remove some blood from a mouse; mix it with some selective superparamagnetic antibodies; clean the blood by applying a magnet to separate out tagged cells; put it back into the animal.

(For an index of coverage of all sessions, see here.)

Paul Hallenbeck of Neotropix spoke about a promising new treatment for neuroendocrine cancers. Initial trials of the “Seneca Valley Virus” were conducted on patients with carcinoid cancer or small cell lung cancer (SCLC) that had failed to respond to standard therapies. Results were very good; they plan to start a phase 2b trial in a couple of months.

Adela Ben-Yakar talked about using lasers for the precise surgical removal of tumours. They are developing a femtosecond laser system that can both image and target individual cancer cells – a nice overview of this work has been published in Technology Review.

Cassian Yee spoke about treating cancer with adoptive T cell therapy. Briefly, it’s a personalized approach to cancer research that attacks tumours using the patient’s own T cells. T cells are extracted, modified in a number of different ways to improve their function, grown into a much larger population, and then finally re-infused back into the patient.

(For an index of coverage of all sessions, see here.)

A couple of interesting talks from Sessions 9 and 10:

Mark Pepys talked about treating amyloidosis by targeting serum amyloid P component (SAP), which is present in all amyloid deposits and plays a role in stabilizing them. Several years ago, Pepys discovered a compound (CPHPC) that quickly removes SAP from the bloodstream and from most amyloid plaques; however, clinical trials showed that CPHPC alone does not help people with advanced disease. Today, Pepys reported on some very promising results from combining CPHPC with an antibody, effectively targeting the antibody to amyloid: in mouse studies, plaques completely disappear. Clinical testing of this combination approach will begin in 2011.

Kendall Houk gave a very interesting talk on computationally designing enzymes from scratch. They plan to apply their recently published protocol to develop enzymes that can reverse the formation of Advanced Glycation End-products (AGEs) – sugar-modified proteins that accumulate with age and are implicated in several age-related diseases.

(For an index of coverage of all sessions, see here.)

Claude Wischik spoke about preventing aggregation of tau protein, which is implicated in Alzheimer’s disease. Clinical trials of their aggregation-inhibiting drug Rember are promising: it seems to slow the down the rate of cognitive decline in patients with mild to moderate Alzheimer’s disease. 

Andrei Seluanov talked about naked mole rats, those odd-looking miracle rodents that live for 30 years and don’t seem to ever get cancer (this talk was unrelated to the session topic). Their work provides some clues to this extraordinary cancer-resistance: naked mole rat fibroblasts are hypersensitive to contact inhibition (an anti-cancer mechanism that keeps cell density from getting too high) – much more so than mouse fibroblasts. They found that this contact inhibition was controlled by p53 and pRB, both known tumour suppressors.

Alex Whitworth spoke about the relationship between mitochondrial degradation and Parkinson’s disease genes. Mitochondria are highly dynamic – fusion and fission events are going on all the time – and fission promotes the degradation of damaged mitochondria. Whitworth showed that PINK1 and Parkin, genes linked to Parkinson’s disease, promote mitochondrial fission; furthermore, Parkin and PINK1 may work together to regulate mitochondrial turnover.

(For an index of coverage of all sessions, see here.)

Jeffrey Grubb spoke about new methods for delivering missing enzymes to the lysozomes of patients suffering from lysosomal storage diseases. Several of these should be able to deliver any protein to the lysozome, including novel ones capable of degrading undesirable intracellular molecules that accumulate with age and that normal lysosomes can’t handle – a central goal of the LysoSENS project.

Ana Maria Cuervo spoke about the relationship between autophagy and aging. Rates of autophagy decline with age, and they recently showed that artificially maintaining autophagy at youthful levels in old mouse livers improves their function (which we previously discussed here).

John Schloendorn discussed ongoing work at the SENS Foundation Research Center to develop new enzymes that can degrade harmful intracellular junk that accumulates with age. So far, they have discovered enzymes that can degrade A2E and 7-ketocholesterol, which are implicated in macular degeneration and atherosclerosis, respectively. Their next step will be to construct a drug delivery system to get these enzymes to lysozomes, possibly using methods similar to those of Jeffrey Grub. On the lighter side, Schloendorn also described some of the Center’s methods for building functional lab equipment on the cheap, all good examples for aspiring DIY biologists.

(For an index of coverage of all sessions, see here.)

Brandon Reines presented a counterintuitive result on regeneration: sometimes old animals have a higher regenerative capacity than young animals. In particular, if you punch a hole in the ear of a young mouse, then it won’t heal; but in a middle-aged mouse it will heal completely. He argued that this happens because mouse ear connective tissues never fully differentiate, and suggested that other neural-crest-derived connective tissues might show similar properties.

Kaisa Selesniemi talked about possible methods for sustaining fertility in older women. They found that an infusion of bone marrow from younger females keeps older mice fertile longer; they are also conducting a high-throughput screen of chemical libraries to find compounds that might stimulate stem cells to produce new oocytes. They hope that these treatments might not only prolong fertility, but also female health: mice with longer “ovarian lifespan” show reduced disease incidence.

Alexandra Stolzing presented a new method for generating induced pluripotent stem cells (i.e., for reprogramming adult somatic cells to become pluripotent) that doesn’t use viral compounds or plasmids. Viruses can cause abnormalities in the reprogrammed cells, so much recent work has focused on developing alternate methods for deriving iPS cells.

(For an index of coverage of all sessions, see here.)

Stephen Spindler described his (ongoing) project to screen a large number of potential lifespan-affecting compounds in mice – so far, several candidates look promising. Interestingly, he also argued that the majority of previous studies measuring the effects of various compounds on rodent life expectancy suffer from serious flaws. In particular, he argued that many of them were confounded by a possible calorie restriction effect: mice are picky eaters, and if you change their diet by adding some compound to it, they will often eat less of it. Since most studies did not report the weight of mice or how much they ate, it is impossible to be sure that the lifespan increase reported is actually attributable to the compound tested, rather than to simple calorie restriction. In all, Spindler thought that only 2 of 82 previous studies showed reliable evidence of a novel compound increasing mouse lifespan.

Manuel Serrano talked about his recent experiments with sirtuins in mice. Overexpression of sirtuins in yeast, worms, and flies delays aging, but their role in mammalian aging is still highly controversial. He found that mice overexpressing Sirt1 had improved health, according to several metrics – but no difference in lifespan. 

David Melzer talked about his analyses of human genetic association studies. A large number of single nucleotide polymorphisms (SNPs) have been associated with age-related diseases in humans; Melzer showed that many of these are near genes that play a role in pathways relevant to aging, and also identified three genes associated with two or more age-related diseases: p16/p15, MYC, and TERT.

(For an index of coverage of all sessions, see here.)

This opening session focused on interventions that could help to prevent the damage caused by reactive oxygen species (ROS). ROS are produced as a byproduct of normal mitochondrial function, and can damage mitochondrial DNA and other cellular components – for this reason, they play a central role in some theories of aging.

The talks:

Vladimir Skulachev spoke about his extensive work with SkQ1, an antioxidant targeted to mitochondria. He reported that SkQ1 supplementation extends median lifespan in several species (including mammals), and slows the development of multiple age-related diseases and conditions. His results to date are summarized in this paper; we have also recently discussed his work here.

Holly Brown-Borg talked about the connections between stress resistance and longevity in Ames dwarf mice, which live around 50% longer than normal mice and show elevated levels of some antioxidants. They are working on detangling the complex changes in pathways that contribute to these differences, focusing on the methionine and glutathione metabolic pathways.

James Joseph talked about his investigations into dietary interventions that could help to protect our brains from oxidative damage. The take-home message: eating berries and walnuts can protect against cognitive decline. He also provided some new insights into their possible mechanisms of action.

Cathy Clarke tested an original and interesting approach to avoiding free radical damage to poly-unsaturated fatty acids, or PUFAs: isotope reinforcement. Yeast mutants deficient in Coenzyme Q, an antioxidant that can terminate destructive radical chain reactions, are highly sensitive to PUFAs: they die shortly after being exposed to them and taking them up. However, if the PUFAs are modified in an unusual way – by replacing some hydrogen atoms with the heavier isotope deuterium – then the antioxidant-deficient yeast take up the modified PUFAs and show normal survival. The basic idea here, explained in an earlier paper,  is very simple: heavier isotopes make stronger bonds, so isotope-reinforced PUFAs will be more resistant to free radical attack. Will these results transfer to higher organisms? Is there any chance that the deuterium could get incorporated into other molecules, stabilizing proteins that we want to degrade? The authors plan to follow up this study in worms and mice.

(For an index of coverage of all sessions, see here.)

Our contributor Kristen Fortney is at the fourth Strategies for Engineered Negligible Senescence (SENS4) meeting in Cambridge, England. Over the next few days, she’ll be providing coverage of the talks and other items of interest.

Watch this space for further developments!

UPDATE: We’ll link to each session as Kristen blogs it.

• Session 1: Combating oxidation
• Session 3: Optimising metabolism against aging
• Session 4: Adult regenerative capacity
• Session 5: Eliminating recalcitrant intracellular molecules: the lysosome
• Session 6: Eliminating recalcitrant intracellular molecules: other
• Sessions 9 & 10: Rejuvenating extracellular material
• Session 12: Novel anti-cancer approaches
• Session 15: Rejuvenating the immune system
• Session 16: Delivering genes, proteins and larger structures in vivo
• Session 18: Recent advances in cell therapies
• Session 21: Tissue engineering

UPDATE: You can get updated about new posts by following me on Twitter: @DoNotGoGently There are also a few others microblogging the conference via Twitter, and I will add them as I become aware of them: @retxim @dw2

Ouroboros has been slumbering for the past couple of months — this was for a variety of reasons, mostly to do with the editor’s other professional obligations. Apologies for the absence.

We’re back, starting with on-site coverage of an exciting conference. Posts about the biogerontology literature will resume next week.

We’ll also be looking for more scientist-writers to help us cover the literature. If you’re interested, see here.

I’m sitting in the Drexler Auditorium of the Buck Institute, where I’ve been working over the last six months. Today we’re being treated to an off-schedule “Special Institute Lecture” by Harvard’s Gregory Verdine. These are my notes about the talk; below, I’m paraphrasing Verdine’s words, not writing my own.

To fix it you have to find it: Repairing oxidative damage to DNA.

Mitochondrial metabolism generates oxygen radicals, which damage DNA and increase the risk of mutation. The primary oxidative adduct of guanine, 8-oxoG, differs by only two atoms from the original guanine, but this small difference is still enough to change the residue’s base-pairing characteristics (i.e., from G=C to 8-oxoG=A). 8-oxoG is repaired by the enzyme Ogg1, which displaces the damaged residue by covalently bonding to the DNA backbone.

Ogg1 has a tough job: oxoG-C base pairs are perfectly stable, and from the outside they look just like G-C pairs, so the detection of rare lesions within the genome poses a tremendous challenge. In crystallographic studies that exploited a catalytically dead Ogg1 enzyme (which can recognize but not cleave DNA), Verdine’s lab has shown that the binding of Ogg1 at a G-C base pair results in the extrusion of G or oxoG to the exterior of the double helix, setting the stage for repair — but how does Ogg1 find the lesion site in the first place? To answer this question, Verdine’s group visualized single molecules of Ogg1 diffusing in one dimension along a double helix. They observed that Ogg1 moves so quickly that it can’t be checking every G-C base pair along its path. Instead, Ogg1 (and other lesion-repair proteins) may exploit subtle rearrangements in the DNA backbones near lesion sites. The enzyme amplifies these local structural changes into substantial conformational changes, leading to base extrusion and starting the process of repair.

We want a new drug: Synthetic biologicals as novel pharmaceuticals

Small-molecule drugs have “good geography,” in the sense that they can cross cell membranes. However, they’re limited, in that they can only target proteins that engulf them (e.g., in hydrophobic pockets or active sites). Proteins, on the other hand, have much more diverse function, but terrible geography — they simply can’t get into cells, and they’re therefore useless for intracellular targets. Both classes of drug can attack (generously) only ~10% of prospective targets. Therefore, we need an entirely new class of drug: synthetic biologics like stapled peptides and RIPtides, which combine the bioavailability of small molecules with the functional diversity of proteins.

Stapled peptides are essentially the interaction domains of proteins, conformationally restrained in such a way that they still retain the active structure. (Think of a protein as a delivery system for an interaction domain, in which the non-interacting portions serve primarily to hold the ID in place.) An interaction domain alone would be too floppy to have a biological effect; conversely, the intact protein has the desired function but can’t cross the membrane. Solution: replace the main body of the protein with a hydrocarbon “staple” that keeps the interactive domain in the active conformation, without substantially increasing its size. Surprisingly, stapled peptides are taken up by cells via an energy-dependent active transport process, one upshot of which is that they don’t need to be uncharged and hydrophobic in order to cross the membrane. Drugs of this kind have already been used in animal studies to suppress leukemia by activating apoptotic factors in tumor cells.

Declaring open season on transcription factors

A brief concluding note: Transcription factors are among the most well-validated prospective targets, but they have historically been outside the scope of drug developers. TFs function primarily by protein-protein interactions that aren’t amenable to interference by small-molecule drugs. Recently, however, Verdine and others have been able to use synthetic biologicals to interfere with a specific oncogenic transcription factors.

My own comments

OK, so, not a lot of specific about either aging or cancer, but the idea of a novel class of pharmaceuticals that could be used to attack the “missing 80%” of validated prospective drug targets is still very exciting.