Time flies - it really doesn't seem like it's been two and a half years since the SENS Foundation was launched to steer the SENS research program independently of the Methuselah Foundation umbrella. Come to think of it, it really doesn't seem like eight years since the Methuselah Foundation was just a tiny thing, a couple of advocates and the first few $5,000 checks in the bank. If you look back in the Fight Aging! archives, some of the first blog posts relate to the early days of the Methuselah Foundation.

People come and go across any organization's life span - and here is news of the departure of one of the SENS Foundation co-founders for a new venture:

On 19 September, 2011, Sarah Marr will be stepping down as our Executive Vice President at SENS Foundation. She has been a committed co-founder, and she will of course continue to be a trusted advisor and closely involved with the organization. But we couldn't have her term of full-time service with us pass without noting the significant contribution she has made to the professionalism of the organization and to the quality of our overall message. She helped make us, in a very real way.

From Sarah Marr's blog:

I think it's important to understand that the Foundation is a lifetime commitment for me. I'm a co-founder, after all, and I can't imagine a world in which I'm not extolling the virtues of the organization, its mission, and the wider concept of rejuvenation biotechnology; whatever else I'm doing, or whatever environment surrounds me.

Why am I stepping down? Because I have a personal project which I wish to pursue. And given the criticality of rejuvation biotechnology, you should get a feeling for just how important I consider this next project, but also how hard it has been to reach this decision. Why can I step down now? Because the team which we've built at the Foundation over the past two-and-a-half years is so very, very talented and capable.

Non profits set up for the long term must be able to thrive independently of the turnover of their staff and leaders - to have a continuation of capabilities and culture that are too robust to much miss the loss of any one individual's time and skills. Indeed, this is one of the implicit goals for the early stages of any venture, and a very good way of measuring success in advance of more obvious results in research, fundraising, licensing, and so forth.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A short open access paper: "Hormesis (a neologism coined from the ancient Greek term hormáein, which literally means 'to set in motion, impel, urge on') describes a favorable biological response to harmless doses of toxins and other stressors. Hormesis-stimulating compounds initiate an adaptive stress response that renders cells/organisms resistant against high (and normally harmful) doses of the same agent. On the theoretical level, hormesis may constitute (one of) the mechanisms that allows stressed cells to avoid senescence and death, and hence might have some impact on the (patho)physiology of aging. Thus, measures that reportedly prolong the healthy lifespan of multiple species, such as caloric restriction and the administration of resveratrol, may do so by inducing a hormetic response ... [Hormesis] is best represented by ischemic preconditioning, the situation in which short ischemic episodes protect the brain and the heart against prolonged shortage of oxygen and nutrients. Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction."

Link: http://impactaging.com/papers/v3/n9/full/100380.html

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

I am not unsympathetic to this viewpoint: recent research shows that "women should raise their glasses to a healthier old age, but we've heard it all before - and just the opposite. ... This is the conclusion of a study of 14,000 female nurses that started in 1976. The brainchild of the Harvard School of Public Health, Boston is the latest result from numerous studies of this nature that have produced all manner of contradictory results. ... In 1976, the [Framington study] is supposed to have shown a connection between menopause and the increased risk of heart disease, which is a bit like saying it found a connection between age and life expectancy - exactly what is one supposed to do with a datum like that? ... At the end of the day, one must ask what is the point of such studies, and specifically what is the point of a study that attempts to link the consumption of wine by women with longevity, especially when Marie Lloyd was telling us a little of what you fancy does you good way back in 1915? Rather than mounting expensive years' or decades' long studies as make-work schemes for medical scientists and their chums in Whitehall, Washington and elsewhere, the governments of the world might be better advised setting them to work to discover the actual causes of disease, and maybe to develop vaccines and other methods of combatting them, or better still, maybe they should follow in the footsteps of gerontologist Aubrey de Grey and his SENS organisation?"

Link: http://www.digitaljournal.com/article/311235

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

I am not unsympathetic to this viewpoint: recent research shows that "women should raise their glasses to a healthier old age, but we've heard it all before - and just the opposite. ... This is the conclusion of a study of 14,000 female nurses that started in 1976. The brainchild of the Harvard School of Public Health, Boston is the latest result from numerous studies of this nature that have produced all manner of contradictory results. ... In 1976, the [Framington study] is supposed to have shown a connection between menopause and the increased risk of heart disease, which is a bit like saying it found a connection between age and life expectancy - exactly what is one supposed to do with a datum like that? ... At the end of the day, one must ask what is the point of such studies, and specifically what is the point of a study that attempts to link the consumption of wine by women with longevity, especially when Marie Lloyd was telling us a little of what you fancy does you good way back in 1915? Rather than mounting expensive years' or decades' long studies as make-work schemes for medical scientists and their chums in Whitehall, Washington and elsewhere, the governments of the world might be better advised setting them to work to discover the actual causes of disease, and maybe to develop vaccines and other methods of combatting them, or better still, maybe they should follow in the footsteps of gerontologist Aubrey de Grey and his SENS organisation?"

Link: http://www.digitaljournal.com/article/311235

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There are several rare conditions that present the appearance of accelerated aging, the changes they cause extending far enough down into the fundamentals of human biochemistry that there yet remains much to learn about their operation and some debate over whether they are in fact forms of greatly accelerated aging. The best known of these conditions are Hutchinson-Gilford Progeria (HGPS, or just progeria) and Werner syndrome; significant progress has been made in identifying their root causes over the past decade, but that is still a way removed from knowing whether there is any great relevance there insofar as concerns research into ordinary aging.

A recent open access paper takes a look at the question, though the bottom line at this time is that more time and greater understanding is needed:

Hutchinson-Gilford Progeria (HGPS) and Werner syndromes are diseases that clinically resemble some aspects of accelerated aging. HGPS is caused by mutations in the LMNA gene resulting in post-translational processing defects that trigger Progeria in children. Werner syndrome, arising from mutations in the WRN helicase gene, causes premature aging in young adults. What are the molecular mechanism(s) underlying these disorders and what aspects of the diseases resemble physiological human aging?

...

In both diseases recent evidence indicates that mutations in the genes responsible for these premature aging diseases result in increased DNA damage, particularly at telomeres. Although shortening and/or damage to telomeres is associated with proliferative arrest of cells in vitro, it remains unclear how accurately these diseases recapitulate the processes of tissue aging in humans. Here we discuss recent advances, using in vitro cell culture and mouse models of progeroid syndromes to highlight important questions that remain: A) what is the molecular mechanism of how such seemingly unrelated proteins cause similar degenerative diseases? B) are these mechanisms representative of normal aging?

Like a fair amount of nonetheless interesting research, work aimed at understanding accelerated aging conditions - and mining that knowledge for material that may prove useful in the development of ways to intervene in ordinary aging - is something of a sideshow. The trouble with science in general is that you have to spend time on the sideshows in order to confirm that they are in fact sideshows; every presently major field of endeavor in the life sciences started off small, unpromising, and prospective. I don't think the odds are good that something spectacular will result from investigations of progeria: you can't completely rule it out at this stage, but there are other places to concentrate resources that have a much higher expectation of value.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Some enthusiasm from the research community: "induced pluripotent stem (IPS) cells [are] where I'm putting almost all of my chips these days, because it combines many of my interests - genomics, sequencing, epigenetics, synthetic biology, stem cells. I don't think people have fully appreciated how quickly adult stem cells and sequencing and synthetic biology have progressed. They have progressed by orders of magnitude since we got IPS. Before that, they basically weren't working. ... There is much to be worked out. But here's the leap. If you want to accelerate this, you have to pick an intermediate target that doesn't sound so scary. So you'll start out with bone marrow patients. And you're going to basically make a synthetic version of that patient's bone marrow using IPS, which is going to work much better than the diseased bone marrow. And once this works that's going to catch on like wildfire. And then you'll do skin, and then you'll do every other stem cell you can get. ... Will people who are, say, aging but not yet sick ever be able to use this technology? I don't consider this medicine, it's preventive. I expect somebody who is truly brave, who has nothing wrong with them other than maybe the usual aging, saying: 'I want a bone marrow transplant', or intestinal, or whatever. And it will gain momentum from there. ... Initially it will be wealthy people who will try this. Ironically, wealthy people are often willing to be the guinea pigs that are really in a sense the front line of new technologies. They're the foot soldiers. They're willing to put themselves at risk, and to spend money on it."

Link: http://www.technologyreview.com/blog/experimentalman/27164/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The New York Times is running a piece on a recent small trial of immune therapy for leukemia: "A year ago, when chemotherapy stopped working against his leukemia, William Ludwig signed up to be the first patient treated in a bold experiment at the University of Pennsylvania. Mr. Ludwig, then 65, a retired corrections officer from Bridgeton, N.J., felt his life draining away and thought he had nothing to lose. Doctors removed a billion of his T-cells - a type of white blood cell that fights viruses and tumors - and gave them new genes that would program the cells to attack his cancer. Then the altered cells were dripped back into Mr. Ludwig's veins. At first, nothing happened. But after 10 days, hell broke loose in his hospital room. He began shaking with chills. His temperature shot up. His blood pressure shot down. He became so ill that doctors moved him into intensive care and warned that he might die. His family gathered at the hospital, fearing the worst. A few weeks later, the fevers were gone. And so was the leukemia. There was no trace of it anywhere - no leukemic cells in his blood or bone marrow, no more bulging lymph nodes on his CT scan. His doctors calculated that the treatment had killed off two pounds of cancer cells. A year later, Mr. Ludwig is still in complete remission. Before, there were days when he could barely get out of bed; now, he plays golf and does yard work."

Link: http://www.nytimes.com/2011/09/13/health/13gene.html?pagewanted=all

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

We age in part because a small number of important genes in our mitochondria are broken over time by the polluting effects of their day to day operation: broken genes mean the protein machines produced from their blueprints are also broken, or cannot be produced at all. Mitochondria are bacteria adapted to act as the power plants for our cells, swarms of them circulating inside every cell - and perversely the broken ones tend to win out in the ongoing, dynamic process of replication, damage control, and recycling of cellular machinery that takes place inside all of our cells. Cells can become overtaken by broken mitochondria, each herd of malfunctioning power plants spawned from one original chance breakage, and enough of these unfortunate cells produce a chain of unpleasant consequences throughout the body. Aging is damage, after all. This is a long story, and a better introduction than this can be found back in the archives, however.

SENS stands for the Strategies for Engineered Negligible Senescence, a detailed proposal for what must be done at the cellular and molecular level to reverse the damage of aging and thereby rejuvenate the old. SENS-related research is to vary degrees conducted in labs around the world, and where the research community isn't already large and hard at work - such as in the field of regenerative medicine - the SENS Foundation organizes and encourages research programs. One of the earliest SENS programs to move from concept to actual research, starting back when the initiative was conducted by the Methuselah Foundation, is MitoSENS: a way to use biotechnology to prevent mitochondrial damage from contributing to degenerative aging.

Mitochondrial genes are distinct from those in the nucleus of a cell, and as such are vulnerable. The available repair mechanisms are not as good as those in the nucleus, and the genes in each mitochondrion are right next door to power plant machinery that sustains the cell but also kicks out damaging reactive molecules. The MitoSENS strategy is twofold: (a) gene therapy to copy the few important mitochondrial genes into the cell nucleus, known as allotopic expression, and (b) one of a range of clever biotechnological strategies to get the protein machinery produced from those gene blueprints from the nucleus back out to the mitochondria where it is needed. You might look at the work of Corral-Debrinsky's group to see this in action in a real research program: when you have nuclear copies of mitochondrial genes, it doesn't matter if the more vulnerable mitochondrial versions suffer mishaps, everything continues as before.

A further good introduction to this topic and the work of the SENS Foundation is spurring this research can be found in video recorded at the recent SENS5 conference. Conference videos are being posted to the SENS Foundation YouTube channel as they are processed, and here is an educational presentation on the state of allotopic expression of mitochondrial genes:

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Sir2 in yeast is one of the earliest discovered sirtuins, an important set of genes in the study of calorie restriction. Unfortunately that research has yet to generate a useful calorie restriction mimetic drug, and is looking less promising than it did initially. But here is an interesting result: "Activation of Sir2-orthologs is proposed to increase lifespan downstream of dietary restriction (DR). Here we describe an examination of the effect of 32 different lifespan-extending mutations and four methods of dietary restriction on replicative lifespan (RLS) in the short-lived sir2? yeast strain. In every case, deletion of SIR2 prevented RLS extension; however, RLS extension was restored when both SIR2 and FOB1 were deleted in several cases, demonstrating that SIR2 is not directly required for RLS extension. These findings indicate that suppression of the sir2? lifespan defect is a rare phenotype among longevity interventions and suggest that sir2? cells senesce rapidly by a mechanism distinct from that of wild-type cells. They also demonstrate that failure to observe life span extension in a short-lived background, such as cells or animals lacking sirtuins, should be interpreted with caution." Things are, as ever, more complex than we'd like in other words. One of the reasons that sirtuins haven't led directly to calorie restriction mimetics is that they are only one small part in a larger mechanism, and possibly not even a critical part - just the one that was easiest to notice.

Link: http://www.ncbi.nlm.nih.gov/pubmed/21902802

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via ScienceDaily: researchers "are applying new techniques and materials to come up with artificial blood vessels [that] will be able to supply necessary nutrients to artificial tissue and maybe even complex organs in the future. ... It seemed practically impossible to build structures such as capillary vessels that are so small and complex, especially the branches and spaces in between. But production engineering came to the rescue because rapid prototyping makes it possible to build workpieces specifically according to any complex 3-D model. Now, scientists [are] working on transferring this technology to the generation of tiny biomaterial structures by combining two different techniques: the 3-D printing technology established in rapid prototyping and multiphoton polymerization developed in polymer science ... A 3-D inkjet printer can generate 3-dimensional solids from a wide variety of materials very quickly. It applies the material in layers of defined shape and these layers are chemically bonded by UV radiation. This already creates microstructures, but 3-D printing technology is still too imprecise for the fine structures of capillary vessels. This is why these researchers combine this technology with two-photon polymerization. Brief but intensive laser impulses impact the material and stimulate the molecules in a very small focus point so that crosslinking of the molecules occurs. The material becomes an elastic solid, due to the properties of the precursor molecules that have been adjusted by the chemists in the project team. In this way highly precise, elastic structures are built according to a 3-dimensional building plan."

Link: http://www.sciencedaily.com/releases/2011/09/110913122056.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

It is possible that important future biotechnologies to enhance human longevity might be built on top of a better understanding of the mechanisms that cause similarly sized species to have quite radically different life spans. It seems just as plausible as the idea of generating a family of age-slowing biotechnologies from a better understanding of human metabolism, though who is to say at this early stage in the game just how effective any final result might be. Still, research groups are successfully raising funds, sequencing genomes, and delving much deeper into the comparative biology of aging than has been the case in the past. For example:

The Long Life of Birds: The Rat-Pigeon Comparison Revisited

As a group, birds are long-living with their maximum lifespan potential (MLSP) being on average twice that of similar-sized mammals, and it can be much greater for some individual comparisons. The most common mammal-bird comparison in the scientific literature is the rat-pigeon comparison. The rat has a MLSP of 5 y, compared to 35 y for the similar-sized pigeon (both from the AnAge database: genomics.senescence.info). This seven-fold MLSP difference has the potential to give considerable insight into the processes that determine longevity. Importantly, this is many times the longevity difference generally achieved either by genetic manipulation or environmental manipulation (such as dietary restriction).

...

We have revisited the rat-pigeon comparison in the most comprehensive manner to date. We have measured superoxide production (by heart, skeletal muscle and liver mitochondria), five different antioxidants in plasma, three tissues and mitochondria, membrane fatty acid composition (in seven tissues and three mitochondria), and biomarkers of oxidative damage. The only substantial and consistent difference that we have observed between rats and pigeons is their membrane fatty acid composition, with rats having membranes that are more susceptible to damage.

That's a pretty good piece of supporting evidence for the membrane pacemaker hypothesis of aging: longer lived species are longer lived because their cellular membranes are more resistant to damage. This ties in nicely to the role of mitochondria and mitochondrial damage in aging: swarming mitochondria in cells churn out damaging free radicals as a consequence of their day to day operations, and as a consequence damage themselves in ways that spiral out to cause all sorts of harm in the long term. If a species is more resistant to that damage in the places where it matters the most, then it lives longer.

As I have said before, I tend to view this as support for the importance of mitochondrial repair research. If resistant mitochondria give pigeons even a fair chunk of that multiplier of seven over rat life spans, then how much further could the research community take things if armed with a way to completely fix the self-inflicted mitochondrial damage rather than just resist it?

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm