The scientific consensus these days is that ingesting antioxidants in the hope of improving your metabolism isn't going to work.

Since the early 1990s scientists have been putting these compounds through their paces, using double-blind randomised controlled trials - the gold standard for medical intervention studies. Time and again, however, the supplements failed to pass the test. True, they knock the wind out of free radicals in a test tube. But once inside the human body, they seem strangely powerless. Not only are they bad at preventing oxidative damage, they can even make things worse. Many scientists are now concluding that, at best, they are a waste of time and money. At worst they could be harmful.

It is, however, quite true that the antioxidants generated by your own biochemistry are important in health and longevity. Some of the difference in longevity between species is ascribed to the degree to which they manufacture their own antioxidants:

It's reasonable to theorize that if you happen to be a member of a species that naturally generates a lot of antioxidants around the mitochondria, you're going to live longer than members of another, similar species with worse luck in the antioxidant stakes.

The key here appears to be where the antioxidants end up performing their work. Mouse studies have shown that carefully directing antioxidants to the cellular mitochondria extends healthy life span on the order of 20-30% - a fairly complex feat of biochemical engineering that no presently available pill can match. Those studies further showed that no benefit emerges from the same antioxidants sent elsewhere in mouse biochemistry. If you'd like to learn more about why antioxidants in the mitochondria make such a large different, head back into the archives for an outline of the Mitochondrial Free Radical Theory of Aging: mitochondria create free radicals that cause all sorts of damage, but targeted antioxidants can soak up some portion of the free radicals before that damage occurs.

Our biology is complex - why would we expect that successfully modifying it with chemicals would be as simple as eating those chemicals? Ingesting antioxidants in the hope of benefit because they happen to do certain things in certain portions of your biochemistry is magical thinking given the evidence on the table to date. It certainly doesn't have the best record in experimental studies. Here's one of the latest:

New study on antioxidants shows mixed results for life extension:

First the good news: a study by scientists at the Buck Institute for Age Research shows four common antioxidants extended lifespan in the nematode worm C. elegans. And the not such good news: those four were among 40 antioxidants tested, the majority of which did nothing or caused harm to the microscopic worms.


“We’ve taken a careful look at the way antioxidants affect aging in simple animals and what we find is that it’s a hodge-podge of effects,” said Buck Faculty member Gordon Lithgow, PhD, lead author of the study. “We see antioxidants that appear to make simple invertebrates live healthier, longer lives and we also find antioxidants that have precisely the opposite effect, that compromise the animal’s survival,” he said.


"I’m an optimist, I think we can make positive statements about the potential for intervening in aging with compounds that manage oxidative stress,” said Lithgow. “I’m also saying that we’re not there yet, and if only four of the 40 compounds are having the desired effect, that’s not good when we think about applying these results to humans today.”

Life is the Road to Utopia, If You Can Stay On It

From JET, a Nick Bostrom fiction in the spirit of the Fable of the Dragon Tyrant: "Your body is a deathtrap. This vital machine and mortal vehicle, unless it jams first or crashes, is sure to rust anon. You are lucky to get seven decades of mobility; eight if you be fortune's darling. That is not sufficient to get started in a serious way, much less to complete the journey. Maturity of the soul takes longer. Why, even a tree-life takes longer. Death is not one but a multitude of assassins. Do you not see them? They are coming at you from every angle. Take aim at the causes of early death - infection, violence, malnutrition, heart attack, cancer. Turn your biggest gun on aging, and fire. You must seize the biochemical processes in your body in order to vanquish, by and by, illness and senescence. In time, you will discover ways to move your mind to more durable media. Then continue to improve the system, so that the risk of death and disease continues to decline. Any death prior to the heat death of the universe is premature if your life is good. ... One day you or your children should have a secure home. Research, build, redouble your effort!" The road to Utopia is to continue to live well - which, as Bostrom notes, will require great labor devoted to new medical technologies of engineered longevity.


Aubrey de Grey in JET

Here's an essay from Aubrey de Grey in one of the recent issues of the Journal of Evolution and Technology: "A pervasive reaction to the idea of extreme or indefinite postponement of human aging - one heard from many professional bioethicists and also from a high proportion of the general public - is that aging differs morally from other causes of debilitation and death in a manner that exempts us from the duty to combat it that we perceive as so self-evident in respect of those other causes. Precisely what characteristic of aging underpins this alleged distinction? I argue here that it is in fact a false distinction, perpetuated only by unwarranted psychological forces posing as philosophical arguments. ... There are many conspicuous issues regarding which contemporary Western society generally takes a different moral view than it did a century or two ago. Slavery, universal suffrage and homosexuality constitute a representative selection. In all these cases, the view that originally prevailed was overturned because the arguments for the status quo were eventually seen to come down to no more than a fear of the unknown, a faith in the 'natural order' and other similarly unrooted emotions."


Cancer in the Context of Immune System Aging

Our immune systems slowly become ineffective with age, a consequence of their evolved design and exposure to persistent viruses like CMV across a lifetime.

Your immune system is capped in its use of resources; it can only have a set number of T cells in operation at one time. A reserve of naive T cells is needed to effectively respond to new threats. These are untrained cells that will be educated and drafted to combat new intrusions. A small reserve of memory cells is needed to respond effectively to previously encountered threats - one reserve per threat. The more threats you have encountered, the more cells become devoted to memory; eventually you don't have enough naive T cells left to mount any sort of effective defense.

This contributes to a range of problems, starting with a lack of resistance to disease, one of the roots of age-related frailty, and most likely including buildup of damage-inducing senescent cells and increased risk of cancer with age. The immune system is responsible for destroying errant cells of all sorts, and so it is reasonable to speculate on the degree to which cancer risks can be blamed on immune system dysfunction:

Compromised immunity contributes to the decreased ability of the elderly to control infectious disease and to their generally poor response to vaccination. It is controversial as to how far this phenomenon contributes to the well-known age-associated increase in the occurrence of many cancers in the elderly. However, should the immune system be important in controlling cancer, for which there is a great deal of evidence, it is logical to propose that dysfunctional immunity in the elderly would contribute to compromised immunosurveillance and increased cancer occurrence.

The chronological age at which immunosenescence becomes clinically important is known to be influenced by many factors, including the pathogen load to which individuals are exposed throughout life. It is proposed here that the cancer antigen load may have a similar effect on "immune exhaustion" and that pathogen load and tumor load may act additively to accelerate immunosenescence. Understanding how and why immune responsiveness changes in humans as they age is essential for developing strategies to prevent or restore dysregulated immunity and assure healthy longevity, clearly possible only if cancer is avoided.

Here, we provide an overview of the impact of age on human immune competence, emphasizing T-cell-dependent adaptive immunity, which is the most sensitive to ageing. This knowledge will pave the way for rational interventions to maintain or restore appropriate immune function not only in the elderly but also in the cancer patient.

That's an open access paper, so don't miss the PDF link underneath the abstract. It is pleasing to see researchers outside the normal pro-longevity groups thinking in terms of restoring youthful function - that's very necessary to the future of medicine I'd like to see.

Axolotl Biochemistry as a Goal to Aim For

It is plausible that mechanisms of unlimited tissue regeneration will be learned from lesser species and then ported to humans: "Urodele amphibians such as the axolotl are the champions of tissue regeneration amongst vertebrates. These animals have mastered the ability to repair and replace most of their tissues following damage or amputation even well into adulthood. In fact it seems that the ability of these organisms to regenerate perfectly is not affected by their age. In addition to being able to regenerate, these animals display a remarkable resistance to cancer. They therefore represent a unique model organism to study regeneration and cancer resistance in vertebrates. The need for this research is even more pressing at the dawn of the 21st century as we are faced with an ever aging world population which has to deal with an increase in organ failure and cancer incidence. ... studying tissue regeneration in salamanders could yield significant knowledge to help regenerative medicine achieve the desired goal of allowing humans to repair and regenerate some of their own tissues as they age."


Mechanisms of Osteoarthritis

Researchers continue to learn more about the underlying biochemistry of common age-related conditions: "Until relatively recently, osteoarthritis was believed to be due solely to wear and tear, and an inevitable part of aging. Recent studies have revealed, however, that specific biochemical changes contribute to the disease, changes that might be reversed by precision-designed drugs. Our study provides the first solid proof that some of those changes are related to pain processing, and suggests the mechanisms behind the effect ... the study revealed that pain signals originating in arthritic joints, and the biochemical processing of those signals as they reach the spinal cord, worsen and expand arthritis. In addition, researchers found that nerve pathways carrying pain signals transfer inflammation from arthritic joints to the spine and back again, causing disease at both ends. ... We believe this to be a vitally important process contributing to orthopaedic and neurological diseases in which inflammation is a factor."


My Project 10100 Submission: Mitochondrial Repair

Here is an example of what I think is a passable submission to Google's Project 10100, with a focus on mitochondrial science. I could probably run one up for LysoSENS-like work as well, but one thing at a time.

Your idea's name (50 characters maximum):

Bring Mitochondrial Repair to Phase 1 Trials

What one sentence best describes your idea? (maximum 150 characters):

Our mitochondria degrade over the years, contributing greatly to age-related disease and frailty - but medical technology can fix this problem.

Describe your idea in more depth. (maximum 300 words):

I propose that the most promising of nascent mitochondrial repair technologies be funded from their present early-stage standing to readiness for Phase I clinical trials in humans. As a condition of funding, methodologies will be published free of restriction for any group to further develop and bring to market. This will be accomplished with the aid of a non-profit research organization like the Methuselah Foundation, with a history of raising matching funds for large donations, so as to maximize the impact of the funding program.

Mitochondria are tiny power plants inside our cells, churning away to turn food into energy. They were once free-roaming bacteria and have retained their own mitochondrial DNA, distinct from our own nuclear DNA. As our mitochondria fail, however, so do we. The Mitochondrial Free Radical Theory of Aging points to progressive damage to our mitochondrial DNA as an important - and arguably the most important - root cause of age-related degeneration, disease, and frailty.

At present, a range of plausible technologies exist to repair mitochondrial DNA, replace mitochondrial DNA, or make damage to this DNA irrelevant. These technologies stand at varying points between ideation and animal trials: whole-body replacement of mitochondrial DNA was demonstrated in mice as early as 2005, for example, as has the process of allotopic expression: moving a single important mitochondrial gene into the cellular nucleus, such that the necessary proteins are still made, and a damaged mitochondrion continues to function.

These technologies are progressing very slowly and with a paucity of funding, partly because this is the nature of early research, partly because of perverse regulatory incentives. This is unacceptable when considered against a) the comparatively low cost of basic research in this age of biotechnology, and b) the vast potential benefits to humanity. Philanthropic funding can overcome these hurdles.

What problem or issue does your idea address? (maximum 150 words):

Consequences of damaged mitochondrial DNA include failing organs, clogged arteries, neurodegeneration, and much more. This is the Mitochondrial Free Radical Theory of Aging, well supported by decades of evidence. A working repair technology pushed into the clinical system has the potential to entirely remove this large contribution to disease and frailty. But first it must be finalized from the promising beginnings presently in the laboratory.

Regulatory bodies like the FDA restrict all application of medical science to specific, named diseases; this makes early stage research to produce a general repair technology for mitochondria unprofitable. It would be hard to license, as a developer would struggle to make money on that license. Yet it costs little to move established research to Phase I trial readiness - $1 million is a fortune for a single laboratory - and developers leap at license-free medical technology. This is where careful philanthropy can unjam the gridlocked system.

If your idea were to become a reality, who would benefit the most and how? (maximum 150 words):

A mitochondrial repair technology demonstrated to be ready for human trials, free of licensing cost, free from intellectual property restrictions, and unjammed from the system of perverse incentives in early-stage research stands to benefit everyone. It will be as universally beneficial a medicine as aspirin; the elderly will benefit immediately upon availability, we will benefit from it in decades to come, and our children will benefit when their bodies too start to run down.

Everyone has mitochondria, and mitochondrial degeneration is a universal condition, bringing myriad forms of suffering and pain. We got rid of tuberculosis and smallpox as soon as we could, so why not this? Repair of mitochondrial DNA damage is a very plausible near-future win for everyone, given where the science is today. We can make it happen.

What are the initial steps required to get this idea off the ground? (maximum 150 words):

I envisage the opening labor as follows: 1) Identify the existing non-profit research group and volunteer cadre to run this project - my vote is for the Methuselah Foundation, given their record and contacts within the research community, and the way their mission aligns with that of this project; 2) Identify the best groups and laboratories presently engaged in mitochondrial repair and related research; 3) Develop prospective work, milestone, and funding plans with researchers; 4) Start raising matching funds through existing channels; 5) Select the initial funding opportunities from the best of those produced, and get the researchers to work.

From there, I would like to see established a low-overhead but effective volunteer group of researchers and advocates to manage the cycle of grants, matching fundraising, and evaluation of progress and new research opportunities going forward.

Describe the optimal outcome should your idea be selected and successfully implemented. How would you measure it? (maximum 150 words):

The optimal outcome, after the completion of the project, is: a) for one or more different repair technologies to be successfully readied for Phase 1 human trials; b) protocols and methods to be fully detailed and published, free of restriction; c) multiple medical development concerns to be working on bringing applications to market in diverse regulatory regions; d) independently funded follow-on research taking place with the aim of improving upon the initial technology; e) matching fundraising to effectively continue even after the Google grant is complete.

Sample metrics for success include: a) the breadth and effectiveness of the technologies developed; b) the quality of the published material; c) range of developers working on applications; d) the range of independently funded lines of work spawned by this philanthropic funding; and, most crucially, e) the amount of matching funding and independent research and development funding drawn by this philanthropic project.

If you'd like to recommend a specific organization, or the ideal type of organization, to execute your plan, please do so here. (maximum 50 words):

The ideal organization is a research non-profit with existing connections to scientists already involved in mitochondrial repair research, a very low cost of operation for delivered funding, and a history of raising matching funds for large donations. The ideal example is the Methuselah Foundation, as you might have gathered.

Revisiting the Boredom Objection

A common objection to engineered longevity is that long lives will mean boredom. People leap directly in their minds from "longer life" to "immortality" and postulate all sorts of unrealistic outcomes. From Depressed Metabolism: "The argument that immortality leads to boredom can take two forms; empirical and logical. In the first case we would observe immortal people and conclude they will become (increasingly) bored. Clearly, this approach is not possible. A milder form of this approach would be to observe very old people and to extrapolate from this to immortality. But this does not seem to be very promising. Many old people are still very curious and involved with the world, even when struggling with aging-induced medical complications. Perhaps there is a tipping point after which old people will get bored. Perhaps not. ... The assumption in [logical] arguments is that an immortal person will exhaust all there is to live for. There are at least two problems with such a line of reasoning. The first problem is whether such a state of affairs (a fixed person with finite possibilities and experiences) logically follows from immortality. Why not assume there will be infinite possibilities and experiences (even if the person stays 'the same') instead? The other problem is that such a line of reasoning reflects an impoverished view of life, emphasizing just quantity and progress."


Writing Off Telomolecular

I was on the way to writing off research company Telomolecular earlier this year. It looks like that was the right sentiment; I am disappointed, as the science they were claiming looked very promising. From the Sacramento Bee: Telomolecular "was accused of bilking investors nationwide out of $6.5 million by lying about the progress it was making in finding cures for cancer. ... Telomolecular's lawyer, Gerald Nieser, said the company has already cleaned up its act. 'The company has got all new management. Virtually no one is there now who was involved in the activities that the charges are based on.' ... the Securities and Exchange Commission said Telomolecular Corp. boasted to potential investors that was 'on the verge of success as a biotechnology firm.' That claim was untrue, the SEC said. The company instead was selling a cosmetic skin cream over the Internet and had done less than $100,000 in business in two years." There's no telling what's actually going on under the covers here, but any future science emerging from this direction should meet with skepticism.


Update on Calorie Restriction and Bone Loss

The pendulum of evidence is swinging back to suggest that the practice of calorie restriction doesn't lead to bone loss. Via ScienceDaily: "Calorie restriction is the only intervention known to decrease the rate of biological aging and increase longevity ... Young adults who follow a diet that is low in calories but nutritionally sound for six months appear to lose weight and fat without significant bone loss ... After six months, average body weight was reduced by 1 percent in the control group, 10.4 percent in the calorie restriction group, 10 percent in the calorie restriction plus exercise group and 13.9 percent in the low-calorie diet group ... Bone mineral density and blood markers of bone resorption and formation (processes by which bone is broken down and regenerated on a regular basis) were measured at the beginning of the study and again after six months. ... Compared with the control group, none of the groups showed any change in bone mineral density for total body or hip."


Calorie Restriction: Animals Versus People

The present scientific consensus on calorie restriction in humans is that it will do wonderful things for your health and resistance to age-related disease, but won't extend the maximum human life span to the same degree that is seen in lower animals: "In the majority of the animal models of longevity, extended lifespan involves pathways related to a growth factor called IGF-1 (insulin-like growth factor-1) ... In calorie-restricted animals, levels of circulating IGF-1 decline between 30 percent and 40 percent. ... We looked at IGF-1 in humans doing calorie restriction [and] found no difference in IGF-1 levels between people on calorie restriction and those who are not. ... we know there are two major influences on IGF-1 levels: calorie intake and protein intake. So we decided to look at the influence of protein ... six [human testers] agreed to lower their protein intake and after three weeks their circulating IGF-1 declined dramatically ... It's much easier to restrict protein than to restrict calories. If our research is on the right track, maybe humans don't need to be so calorie restricted. Limiting protein intake to .7 or .8 grams per kilogram per day might be more effective. That's just a hypothesis. We have to confirm it in future studies."


Google's Project 10100 Initiative

Google is running an initiative called Project 10100, similar to the Amex Members Project that the Methuselah Foundation volunteers and healthy life extension community recently took a swing at winning. People are invited to submit ideas for charitable projects that will benefit humanity; Google employees winnow down the (no doubt thousands of) entries to the 100 they like the most; the public at large vote on the 100; and an advisory board picks five to split $10 million in funding. From the FAQ:

Q: How will you decide which ideas to fund?
A: A selection of Google employees will review all the ideas submitted and select 100 for public consideration. The 100 top ideas will be announced on January 27, 2009, at which point we will invite the public to select twenty semi-finalists. An advisory board will then choose up to five final ideas for funding and implementation. We plan to announce these winners in early February.

Q: Who is on the advisory board?
A: The advisory board will be composed of five to seven individuals known for their expertise in the submission categories.

Q: What criteria will be used to select the winning ideas?
A: The following five criteria will be considered by the advisory panel in evaluating and selecting the winning ideas:

Reach: How many people would this idea affect?
Depth: How deeply are people impacted? How urgent is the need?
Attainability: Can this idea be implemented within a year or two?
Efficiency: How simple and cost-effective is your idea?
Longevity: How long will the idea's impact last?


Q. How will Google implement these ideas?
Once we've selected up to five ideas for funding, we will begin an RFP process to identify the organization(s) and proposals that are in the best position to help implement the selected ideas.

Q: I know an organization that I believe can implement my idea if it is selected. What should I do?
The submission form includes a field where you can recommend an organization to implement your idea. If your idea is selected for funding, we will contact this organization when we begin the selection process for the implementation phase. Please note that this does not guarantee that they will be chosen to implement the idea.

As for the Amex Members Project there is a disconnect between voting and the advisory board choice: there is no guarantee that strong support for a longevity science proposal that made it into the top 100 would see it funded. But it costs little for us to try - if you don't swing at the balls that come out of the blue, you certainly won't hit any of them into the outfield.

The submission deadline for ideas is October 20th. I encourage you all to think carefully about a good longevity science project to submit for consideration to Project 10100:

  • Is the project scope appropriate for a $1-2 million award?
  • Are you referencing the organizations you think best able to carry it out - such as the Methuselah Foundation?
  • Carefully consider Google's requirements - especially the time requirement for implementation, given the way in which medical research works.

Other than that - have at it! This is a competition of merit in the early stages: if you think your plan has merit, then submit it. It doesn't matter if someone else has submitted a similar plan, and in fact I suspect that volume of similar (not the same, but similar) project submissions is a metric all of its own by which Google staff will judge merits. The more varied project submissions there are relating to engineered longevity, the more likely it is that Google employees sympathetic to the cause will see them and move one or more of them ahead into the top 100.

Ouroboros at the Cold Spring Harbor Labs Conference

Chris Patil of Ouroboros is blogging this year's Cold Spring Harbor Labs conference on the molecular genetics of aging. You might recall his coverage of the 2006 meeting as well. This time round:

I’m going to try to blog the sessions a bit more than I did last time, though I’m not sure how that will work out. Actually taking notes at the same time as I make blog entries sounds pretty hard. Still, though, I’ll try.

The first conference post is up:

This first session focused on the smaller model organisms that led the first wave of modern biogerontology: yeast, worm, and fly. The talks covered a wide range of systems and techniques, but they held together nicely because they (mostly) converged on common themes: control of calorie-restriction-mediated lifespan extension, and the genetics of the insulin-like growth factor pathway that governs lifespan in many organisms.

A lot of interesting detail follows, so take a look.

UPDATE: The rest of the session posts:

Stephen Spindler (current Mprize record holder for mouse rejuvenation) started off with the refreshing title "Searching for longevity therapeutics." He discussed a variety of strategies to identifying lifespan extension drugs, as well as some of their shortcomings, and then proceeded to describe aging-intervention studies currently ongoing in his lab. The project is testing a variety of CR mimetics as well as orally bioavailable rapamycin, green tea flavonoids (which inhibit fatty acid synthase), a histone deacetylase inhibitor, and microencapsulated curcumin. Also on the list are statins, AGE breakers, omega 3 fatty acids, and old standbys of the life-extension movement like DHA, Juvenon (cartinine/lipoate), and resveratrol. No results yet, but we’ll be eagerly awaiting the outcome of these studies.

Nitric Oxide and Aging Blood Vessels

Nitric oxide is important in the operation of the endothelium - the lining of blood vessels - but diminishes with age: "The normal endothelium exerts a major vascular protecting role by secreting substances, above all nitric oxide (NO). In disease conditions (such as the presence of cardiovascular risk factors) the activation of endothelial cells can lead to the production and release of contracting factors, which counteract the beneficial effects of NO, and reactive oxygen species (ROS), which in turn cause NO breakdown. ... ageing has been demonstrated to be associated to a progressive impairment in endothelial function both in conduit arteries and resistance vessels, mainly because of an increased production of ROS. Therefore, it is conceivable that endothelial dysfunction plays a major role in favoring age-related increased cardiovascular risk in the elderly." This is an example of the way in which age-damaged cells cause problems in the normal operation of surrounding tissue: cells taken over by damaged mitochondria are exporting reactive oxygen species that breakdown NO, and senescent cells are pushing out their own cocktail of unhelpful chemical instructions as well.


Rust in Your Mitochondria

From ScienceDaily: "A restricted-calorie diet, when started in early adulthood, seems to stymie a mitochondrial mishap that may contribute to muscle loss in aging adults ... scientists found pockets of excess iron in muscle cell mitochondria, the tiny power plants found in every cell. The excess iron affects the chemistry inside the mitochondria, sparking the formation of harmful free radicals that can lead a mitochondrion straight to the emergency exit ... Researchers don't know exactly what causes iron to accumulate in mitochondria in aging animals, but a breakdown in how iron is transported through cells could be one reason why. ... If the mitochondria become unhappy or are ready to kick the bucket, they have proteins in the inner and outer membranes that they can open up and commit suicide. ... suicidal mitochondria can damage the rest of the muscle cell, leading to cell death and perhaps to muscle wasting."


An Overview of Longevity Genes

Today I thought I'd share a readable overview of presently discovered longevity genes: how they fit into a small number of broad categories, and are surprisingly similar across a range of different organisms. It's an open access paper, so don't miss the PDF link underneath the abstract.

Longevity Genes: Insights from Calorie Restriction and Genetic Longevity Models

In this review, we discuss the genes and the related signal pathways that regulate aging and longevity by reviewing recent findings of genetic longevity models in rodents in reference to findings with lower organisms. We also paid special attention to the genes and signals mediating the effects of calorie restriction, a powerful intervention that slows the aging process and extends the lifespan in a range of organisms.

An evolutionary view emphasizes the roles of nutrient-sensing and neuroendocrine adaptation to food shortage as the mechanisms underlying the effects of CR. Genetic and non-genetic interventions without CR suggest a role for single or combined hormonal signals that partly mediate the effect of CR.

Longevity genes fall into two categories, genes relevant to nutrient-sensing systems and those associated with mitochondrial function or Redox regulation. In mammals, disrupted or reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling robustly favors longevity. CR also suppresses the GH-IGF-1 axis, indicating the importance of this signal pathway.

Surprisingly, there are very few longevity models to evaluate the enhanced anti-oxidative mechanism, while there is substantial evidence supporting the oxidative stress and damage theory of aging. Either increased or reduced mitochondrial function may extend the lifespan. The role of Redox regulation and mitochondrial function in CR remains to be elucidated.

It is my impression from watching this all develop for some few years that mitochondrial research is where the big payoff is in the mainstream of aging research - those researchers who are not yet thinking along the lines of damage repair strategies, but are instead moving ahead with a slower approach. Half the field is working on a range of interconnected metabolic control mechanisms, which I can't see producing anywhere near as dramatic results as quickly as a full-court press towards repairing mitochondrial damage. Even somewhat slowing oxidative damage to mitochondria produces gains in life span in mice that are on the same order as that of calorie restriction - imagine what we could do with one of the more comprehensive mitochondrial repair technologies presently under development.

Out of Context, Many Old Cells Work Just Fine

It is a recurring theme in stem cell and immune system research that cells removed from the context of the aging cellular environment can do their jobs just as well as cells in a young environment: "Understanding how aging impacts the function of memory CD4 T cells is critical for designing effective vaccines. Our studies show that immunological memory generated during youth functions well into old age, whereas that generated later in life functions poorly. This is the result of declines in the function of naive CD4 T cells from aged individuals and contributes to reduced efficacy of vaccines in the elderly. To begin to identify the cause of this defect, we examined the function of memory T cells generated from bone marrow precursor cells (BMPC) from young or aged mice in young hosts. In two different models, memory cells derived from young and aged BMPC exhibit good ex vivo and in vivo function. Importantly, memory CD4 T cells generated from aged BMPC exhibit potent cognate helper function for humoral responses, which are critical for effective immunization. These results indicate that there are no apparent age-related intrinsic defects in BMPC with regards to generation of functional memory T cells." As for many aspects of aging, the problem is one of failing systems and signal controls, not failing components.


A Recellurization Update

Via Popular Science: "Some people say they can grow a heart from scratch in 10 years, which is ridiculous. But Dr. Taylor's approach is more realistic because it's so simple and elegant. By using an existing heart, she's taken away all of the structural issues. ...
Taylor's system involves flushing animal hearts of cells using a cleanser, at which point only the extracellular matrix remains and 'the hearts look almost clear' ... The next step is to infuse the hearts with a mix of mature and progenitor cardiac cells, which can come from a patient's own body to ensure compatibility. Incredibly, for reasons the team still doesn't understand, the cells seem to know how to divide and proliferate into cardiac tissue inside the empty-shell hearts. This year, Taylor has continued to forge ahead toward her goal of creating transplantable, made-to-order human organs. Soon after she published her rat-heart results, she started working on making recellularized pig hearts - closer in size and shape to the human equivalent - that could pump blood and generate electrical impulses. ... Our hope is that someday we'll be able to take a cadaver or pig organ, decellularize it, and transplant your own cells into the matrix to make an organ that matches your body."


The Integrative Genomics of Aging Group

Researcher João Pedro de Magalhães - author of the excellent website - is now set up with his own lab at Liverpool University across the pond. He'll be forming up the The Integrative Genomics of Aging Group and getting to work on what is clearly his passion. From the research introduction:

Ageing has a profound impact on human society and modern medicine, yet it remains a major puzzle of biology. Our group aims to help understand the genetic, cellular, and molecular mechanisms of ageing. Although our research integrates different strategies, its focal point is developing and applying computational and experimental methods that help bridge the gap between genotype and phenotype, a major challenge of the post-genome era, and help decipher the human genome and how it regulates complex processes like ageing.

In the long term, we would like our work to help ameliorate age-related diseases and preserve health. No other biomedical field has so much potential to improve human health as research on the basic mechanisms of ageing.


Because longevity evolved in the human lineage, we are particularly interested in employing modern computational methods in primates to study the evolution, structure, and function of genes associated with ageing, which may shed light on the genetic changes that contributed to the evolution of human longevity. Ultimately, our goal is to understand why we are different from each other and from other species and what is the role of each DNA base in the genome in determining these differences, in particular in the context of ageing and age-related diseases.

This is all fresh from the presses, and there are possibilities for undergraduates and postgraduates to help with this work. Take a look if you're at that stage in a life science career, and haven't already been spirited away by the Methuselah Foundation's Undergraduate Research Initiative.

For my part, I'm pleased to see that the goal of intervening in aging is ceasing to be the dreaded third rail of grantsmanship that must not be mentioned. As more labs around the world are founded with the explicitly stated agenda of treating aging to improve the human condition, the tide of public support and understanding will continue to turn. It's that tide, the broad sentiment of support for longevity science, that will sustain much needed growth in the research community over the long haul.

A Potential Downside to Exercise Mimetics

From Ouroboros: "AMP-activated kinase (AMPK) agonists mimic the effects of exercise, raising the possibility of a 'workout pill' that could simulate the effects of vigorous activity. The applications to human health are, to mildly understate the case, significant; it sounds almost too good to be true, and it leaves one looking for the catch. ... it turns out that AMPK is activated by certain types of genotoxic stress, and contributes to UV-induced apoptosis in the skin ... activation of AMPK could exacerbate the pro-aging effects that UV light exerts on the skin. Judging from the peroxide results, this also applies to endogenously generated reactive oxygen species (ROS) - which one can't avoid by simply staying out of the sun. Before we panic and throw the exercise mimetic baby out with its carcinogenic bathwater, I'd want to see whether AMPK agonists like AICAR do in fact synergize with stresses like UV and peroxide to increase apoptotic cell death in the skin. If they do ... well, I think we found that catch."


More Multipotent Stem Cells Discovered

From EurekAlert!: "The scientists [identified] cells known as pericytes that are multipotent, meaning they have broad developmental potential. Pericytes are found on the walls of small blood vessels such as capillaries and microvessels throughout the body and have the potential to be extracted and grown into many types of tissues ... We believe pericytes represent one of the most promising sources of multipotent stem cells that scientists have been searching for in the quest to make regenerative medicine possible. ... These cells can be extracted easily and painlessly from convenient sources such as fat tissue, dental pulp, umbilical cord and placental tissue, then grown in culture to large numbers and, possibly, re-injected into the patient to heal a broken bone, a failing joint or an injured muscle. ... researchers were able to identify pericytes in all human tissues they analyzed, including muscle, fat, pancreas, placenta and many other samples. Through purification in the lab, these pericytes could then be coaxed into becoming whatever type of tissue the scientists desired. For instance, the researchers took pericytes from the pancreas and then reinjected them into an injured muscle. The cells immediately began regenerating muscle tissue."


Also, Try Not To Stab Yourself Repeatedly

Words of wisdom from the scientific community:

On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related diseases was held in Palermo, Italy. Here, the lecture of V. Nicita-Mauro on Smoking, health and ageing is summarized. Smoking represents an important ageing accelerator, both directly by triggering inflammatory responses, and indirectly by favouring the occurrence of several diseases where smoking is a recognized risk factor. Hence, non-smokers can delay the appearance of diseases and of ageing process, so attaining longevity.

Forms of slow self-destruction are many and varied amongst we humans: smoking, not practicing calorie restriction, failing to keep up a good relationship with a physician, piling on the visceral fat, failing to exercise, and so forth. The vast majority of people are quite comfortable engaging in habits that cause great harm to the old person they will one day be - cutting off years or even decades of health.

This is all a good example of time preference at work: we are hardwired to deeply discount the value of the future, even when it's our own future. What we don't value, we squander - you can see that maxim in action everywhere.

Many of the strategies for success in life revolve around doing what needs to be done rather than what you'd like to be doing - ignoring the inner time preference voice in favor of working towards long-term goals. Saving for retirement, for example. In just the same way, living in good health for long enough to benefit from a future of longevity therapies requires us to act as though future years of health are valuable. They are in fact very valuable: if you lose them, you also lose the chance at decades or even centuries more healthy life made possible by future advances in medical science.

Ouroboros on Telomere Length

Ouroboros discusses complications inherent in measuring telomere length: "regarded as a potential biomarker of aging, there is a growing body of evidence indicating that shorter telomeres are associated with various diseases, including cancer, infectious disease, psychological stress, and cardiovascular disease. In cardiovascular disease in particular this had led to the hypothesis that premature, or accelerated, aging of the vasculature is a major contributing factor. While a handful of papers have estimated telomere length in specific vascular tissues, the numbers and sizes of samples in these studies are usually small, due to the limitations in obtaining the tissues and cells of interest. Thus, telomere length in genomic DNA obtained from circulating leucocytes is routinely used as a proxy for telomere length in other tissues. However, the inflammatory processes involved in disorders such as cardiovascular disease can result in increased white cell turnover, raising the possibility that the shorter telomeres measured simply reflect recent replicative activity." Nothing in biochemistry is ever as simple as we'd like it to be.


Lurking Behind the TOR Gene

Researchers have known for a few years that the TOR gene is important in calorie restriction and other related ways of extending healthy life. Recent research follows the chain of biochemical cause and effect beyond TOR: "In C. elegans, the tiny roundworm that our lab studies, as well as some other animals, a loss of TOR has been shown to slow aging. Our work with C. elegans reveals that TOR depends on a second gene called pha4/FoxA to control the aging process ... When there's lots of food, TOR gets active, which decreases the action of pha4/FoxA down the line, and that in turn shortens the lifespan of C. elegans. When there's little food, there's little TOR and more pha4/FoxA, and that results in a longer lifespan. ... Many organisms have a TOR gene and a gene similar to pha4/FoxA, such as single-cell yeasts, roundworms, and mammals including humans. In mammals, FoxA controls cell metabolism and there is a lot of it in breast and prostate cancers. The findings of this research establish that animals use both genes to sense the amount of food that is available and control the length of lifespan. Further research will be required to establish whether a similar relationship between these factors can control metabolism, longevity or disease in humans."


Glycation Versus Your Mitochondria

Regular readers should by now know that accumulating damage to the mitochondria, the power plants of your cells, contributes to degenerative aging. That damage is a side-effect of being alive - it's something like corrosion in power plant internals, an by-product of operation. When I've talked about this in the past, it's usually in the context of the chain of consequences that occurs when free radicals (or reactive oxygen species) produced by the mitochondria damage mitochondrial DNA. Damage to the mitochondrial DNA eventually means that important proteins, part of the mitochondrial power-generating machinery, are no longer produced. It goes downhill from there.

Regular readers should also recall the evidence for glycation as a bad thing for your long term health. Sugars have a way of running rampant through your biochemistry, gumming together important molecules for a while in glycation reactions, and creating new biochemicals called advanced glycation endproducts (AGEs). The AGEs then trigger abnormal behavior in your cells via the receptor for AGE, or RAGE. The more gylcation that takes place, the more damage your metabolism suffers - and aging is all about rising levels of damage.

Last year, I mentioned a demonstration of life extension in nematode worms achieved by reducing the level of glycation. Researchers increased the levels of a natural enzyme called glyoxalase that reduces the levels of glycated chemicals: this is somewhat analogous to using antioxidants to reduce oxidative stress and levels of free radicals. Today, I noticed the following paper, which theorizes that glycation also causes damage to mitochondria, possibly by preventing vital mitochondrial proteins from doing their jobs, and that lower levels of glycation also reduce the problems that are characteristic of mitochondrial damage.

Dicarbonyls linked to damage in the powerhouse: glycation of mitochondrial proteins and oxidative stress

Protection of mitochondrial proteins from glycation by endogenous dicarbonyl compounds, methylglyoxal and glyoxal, was found recently to prevent increased formation of reactive oxygen species and oxidative and nitrosative damage to the proteome during aging and produce life extension in the nematode Caenorhabditis elegans.

This suggests that dicarbonyl glycation damage to the mitochondrial proteome may be a preceding event to mitochondrial dysfunction leading to oxidative stress. Future research will address the functional changes in mitochondrial proteins that are the targets for dicarbonyl glycation.

More direct evidence is needed to bolster this theory offered to explain the observed results - but isn't it interesting to see how everything links back to the mitochondria in one way or another?

Protecting Donations for Longevity Science

From the Methuselah Foundation blog: "These are uncertain times in the financial markets. We here at the Methuselah Foundation strive to ensure that your donations will retain their value through equity market volatility, allowing them to be put to good use in the MPrize fund or for SENS research. ... The Methuselah Foundation's funds have been and are fully invested in FDIC insured bank bonds and accounts diversified across many major well capitalized banks. No one bank holds more than $100,000, thus ensuring 100% FDIC coverage of the entire corpus.
No CD has a maturity of longer than 12 months, and the bonds are laddered to mature (and roll over) across the calendar on a periodically smooth basis. We have recently modified the size of new CD purchases down from $100,000 to $95,000 so that it will not exceed the $100k FDIC insurance threshold as interest accrues. In the unlikely case of a bank default, the Methuselah Foundation will lose neither principal NOR accrued interest. When we have received donations of marketable securities (stocks) we have usually sold them quickly rather than holding them. At this point, September 2008, the Methuselah Foundation's funds are entirely in FDIC insured accounts diversified over more than 25 different banks. We hold no stocks, uninsured bonds, or any other 'at risk' instruments."


Early Experiments in Cryonics

Depressed Metabolism takes another look at the early days of cryonics: "The question of whether cryonics 'works' or not is too general and hides the point that progressive breakthroughs can make the concept more plausible. ... During its existence as a research program, cryonics researchers have shown great interest in recovering animals from ultra-profound hypothermic temperatures (lower than 5 degrees Celsius). The ability to routinely lower the temperature of mammals to temperatures close to zero degrees Celsius and recover them without adverse effects to the brain does make the initial stages of cryonics reversible. ... Less known than those record setting experiments are earlier explorations in cryonics into whole body asanguineous hypothermia. The following document by cryonics researcher and Alcor patient Jerry Leaf documents a Trans Time experiment during the early days of total body washout experiments in cryonics. This account was published in the November/December 1977 issue of Long Life Magazine."


Iron in the Lysosome

Lipofuscin is the name given to a gunk formed of many varied chemical byproducts of metabolism. It accumulates in your cells with age - and cause a great many problems in doing so. In particular, it accumulates in lysosomes, the recycling units of your cells that are tasked with breaking down unwanted chemical and components (the latter in the process called autophagy). Lysosomes in the old are bloated and inefficient, packed to the gills with lipofuscin that cannot be broken down by the enzymes available to your cells. If your lysosomes aren't working well, then the process of autophagy isn't working well, and you can look back into the Fight Aging! archives to see why that is an issue:

You might think of autophagy as a form of self-maintenance for your cells: it is the destruction of damaged and older cellular components such that newly built components can take their place. It is an attractive, intuitive idea that an increased level of autophagy leads to consistantly better function in cells, which in turn leads to longer-lived animals.

I noticed some coverage today on research into the mechanisms by which lipofuscin is formed, which turns out to tie into iron build up and neurodegeneration:

A glitch in the ability to move iron around in cells may underlie a disease known as Type IV mucolipidosis ( ML4 ) and the suite of symptoms - mental retardation, poor vision and diminished motor abilities - that accompany it ... The same deficit also may be involved in aging and neurodegenerative diseases such as Alzheimer's and Parkinson's


To explore the possible role of iron transport in the disease, Xu's group focused on a protein called TRPML1 [that is responsible for ferrying iron out of the lysosome]. A mutation in the gene that produces TRPML1 is known to cause ML4


Further experiments confirmed that when TRPML1 is defective, iron becomes trapped in the lysosome. One result of the buildup is formation of a brownish waste material, lipofuscin, known as the "aging pigment." In skin cells, lipofuscin is the culprit responsible for the dreaded liver spots that appear with increasing age, but in nerve, muscle and other cells, its accumulation has more serious consequences.

"How lipofuscin causes problems in neurons and muscles is not clear, but it's believed that this is garbage that, in time, compromises the normal function of the lysosome," Xu said. "And we know the lysosome is important for all kinds of cell biology, particularly the recycling of intracellular components, so if it's damaged, the cell is going to suffer." Indeed, abnormal accumulation of lipofuscin is associated with a range of disorders including Alzheimer's disease, Parkinson's disease, and macular degeneration (a degenerative disease of the eye) and also contributes to the aging process.

"In a sense we can think of ML4 as really early onset of aging," Xu said.


"If we can somehow manipulate the lysosome iron level, we probably can provide a treatment for the patient," Xu said. "We're not far enough along for those kinds of experiments yet, but now we know enough to work toward that goal."

This is an interesting avenue of research, but it isn't clear whether it could lead to a way to reverse the problem or merely slow it down. Compare that with the bioremediation approach started by Methuselah Foundation-funded researchers. In that line of work, the aim is isolate bacterial enzymes that break down lipofuscin and that can be safely introduced into the body. Using such enzymes would remove the lipofuscin and thereafter keep it at very low levels, too low to cause issues or contribute to age-related disease.

Struggling to Break Out of the Old Paradigm

From RedOrbit, an example of someone caught halfway between paradigms: learning about the potential of longevity science, but having trouble envisaging the changes it will herald for institutions of insurance, development, and regulation. "Currently our drug development and approval systems aim at disease-specific treatments. Indeed, the Food and Drug Administration approves medications only for specific indications, and 'mortality,' a universal condition, would seem unlikely to qualify under the current system. Further, if senescence begins in one's 30s but the outcome (that is, death) can be measured only in one's 70s or 80s, how will researchers be able to perform timely clinical trials in humans? ... Health insurance is based on the principle of risk pooling. Because nobody can be certain that they will remain healthy, the disease-free are willing to share the cost burden with the sick ... But if resveratrol-like drugs are recommended for everybody over 30 at risk for mortality (a universal condition), there would be no risk pooling." When you catch yourself asking "how will this ever fit?" then the answer is usually "it won't fit, and will never fit in the present structure, because things will change in the future so as to accommodate it."


Learning From AIDS

There are similarities between the progression of AIDS and what happens (more slowly) to our immune systems with aging. Forced overactivation and exhaustion of resources are the focus here. AIDS researchers are making steps towards understanding mechanisms that would allow the immune system to be tuned down for specific threats, to prevent it grinding itself into oblivion. "During both HIV infection in humans and SIV infection in macaques, the host immune system becomes highly activated, experiences increased destruction and decreased production of key immune effector cells and progressively fails as a result. In contrast, natural hosts for SIV infection, like sooty mangabeys, do not exhibit aberrant immune activation and do not develop AIDS despite high levels of ongoing SIV replication. ... sooty mangabeys, dendritic cells produce much less interferon alpha - an alarm signal to the rest of the immune system - in response to SIV. As a result, the dendritic cells are not activated during the initial or chronic stages of SIV infection, and mangabeys fail to mount a significant immune response to the virus." It seems reasonable to expect this knowledge to be applicable to the long-term response to CMV in humans, an important contributer to age-related immune system failure.


Calorie Restriction Changes Your Biochemistry For the Better

Here is the outline of an interesting experiment:

  • take a group of ordinary people and start them on the practice of calorie restriction (CR)
  • extract serum from the participants' blood plasma before starting and after some months of CR
  • culture cells on both sets of serum and examine the differences in biochemistry

You'll find that the CALERIE study research teams have done just this. The abstract is at PubMed:

Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals.

Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period).

Cells cultured in serum from ADF participants showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1alpha mRNA levels.

This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity.

As of late 2008, I'd guesstimate that something in the order of one to two billion dollars have been invested into developing drugs that will produce some fraction of the effects of calorie restriction on mammalian biochemistry - such as increasing the expression of Sirt1. Most people can get these benefits for free, however, by simply eating a less calorie-packed diet. You should look into it - calorie restriction isn't anywhere near as hard as those who have never tried it make it out to be.

A Better Lifestyle Means More Telomerase?

The San Francisco Chronicle reports on an intriguing, if small, study: researchers "studied the levels of an enzyme called telomerase in the prostate tissue of the 30 cancer patients who had volunteered to follow a low-fat diet, exercise moderately and reduce their stress. After only three months, 24 patients showed a highly significant increase in their telomerase levels - an indication that the cell-protecting telomeres in their cells were being restored. ... The long telomere proteins protect the ends of chromosomes in the body, but they shorten naturally and ultimately die unless the telomerase enzyme acts to repair them and increase their length. ... even with only 30 patients [the] association between their extremely healthy habits and the increased amount of telomerase proved highly [statistically] significant." Telomerase is apparently also involved in reducing age-related damage to mitochondria, which in turn slows the rate at which failing mitochondria cause telomeres to shorten.


Mitochondrial Function and Aging

Those of you familiar with the mitochondrial free radical theory of aging - damage to mitochondrial DNA leads to loss of function and a spreading chain of biochemical dysfunctions - will notice a subtle disconnect between this research and the popular science view of mitochondrial function and aging, as outlined in this Boston Globe article. The popular view is very much concerned with contribution to particular diseases, and in finding drugs that improve mitochondrial function as a way of slowing that contribution - without necessarily understanding why those drugs work. We know enough to do much better than that - repairing mitochondrial damage completely, for example, and thus totally removing its contribution to aging. But until the public at large realizes this, funding will continue to move towards the established old-school drug discovery programs. These programs focus on treating specific diseases of aging by patching over or slowing down root causes - as opposed than aiming to repair them fully.


The New New Advertising Policy

I notice that it has been quite some time since I last updated the Fight Aging! advertising policy. The old policy - with its focus on gathering donations in the early days of the Methuselah Foundation - certainly doesn't reflect the present state of affairs. It's been some months since I dropped all for-pay advertising for my websites, and that makes the new policy short and to the point. Here it is:

Fight Aging! does not sell advertising space. Banners and advertisements that appear on this website are there because I think the cause is good. I typically draw attention to nonprofits that fund aging science, specific research initiatives aimed at enhancing longevity, longevity research journals, and patient advocacy groups working to speed research into the repair of aging.

How much easier some things become in the absence of money changing hands.

More on FOXO3A

A little more depth on the recent association of FOXO3A with human longevity from Ouroboros: "Mutations in genes involved in the insulin/IGF-1 signaling pathway (IIS) improve longevity in animal models ... The authors hypothesized that single nucleotide polymorphisms (SNPs) in FOXO related genes could be responsible for the differing longevity phenotypes between the long-lived and average-lived [human] cohorts. Five genes, ADIPOQ, FOXO1A, FOXO3A, SIRT1, and COQ7 were selected as candidates, and three SNPs were analyzed per gene. Despite the small number of genes and SNPs analyzed, the researchers identified FOXO3A as being significantly associated with the long-lived phenotype. Genotype analysis revealed that long-lived study participants had one or more copies of the 'G' allele in the FOXO3A gene. The authors state that this finding is especially exciting because the FOXO family of proteins are closely related to the C. elegans protein, DAF-16, which has been shown to protect cells from oxidative stress, which could be a 'plausible mechanism of action for modification of human aging.'"


A Future of Biogerontechnology

Via Emerging Tech: "The US Census Bureau estimates that life expectancy will increase by another six years by 2050. Biogerontechnology, which offers the means to accomplish control over and improvement in the human condition, promises even greater longevity gains. The advancement of the science and technology underlying the biological aging process has the potential to not only extend the average natural lifespan forecasts but also to simultaneously postpone many if not all of the costly and disabling conditions that humans experience in later life, thereby creating a longevity dividend that will be economic, social and medical in nature. The disruptive potential will also come in the form of new treatment modalities, and shifts in the cost, allocation and use of health care resources. Nations will be challenged as a result of the changing demographic structures and new psychologies, behaviors and activity patterns of aging yet healthy citizens and the concomitant need to formulate new national economic and social policies." Less death and less suffering - if only we could all be so "challenged." Hand-wringing over medical progress is ridiculous nonsense at best, and used as the justification for suppression of research at worse.


Ferociously Complex, Is Metabolism

Metabolic processes are no more than the changing operation of our biochemistry, day to day, and across our lives. It is a hugely complex and dynamic metasystem built of many interacting complex systems. Decades of work remain, even taking into account accelerating progress in biotechnology, to understand metabolism to the point of being able to radically change it. This, as I am given to point out, is why many aging researchers are pessimistic about progress: they believe that the only way to extend healthy life is to re-engineer our metabolism. They think, rightly, that this is a huge undertaking as seen from our present vantage point.

In that vein, I thought I'd point out an open access paper on bee metabolism today. It's not so jargon-heavy that it's impossible for the layman to read, but it gives a very good impression of the sheer complexity of biochemistry - even in a small, comparatively simple insect - and the breadth of what is left to discover. The ocean of metabolism is deep, and we're still fishing around the edges; the research community may have a big list of what's in there, but that's not the same as understanding all the important details of its operation. A moving engine is more than the sum of its parts and materials.

Bees are an attractive point of study because different individuals within the species - queens, workers, drones - have widely divergent rates of aging. This is a strategy for making inroads into the unknown: find a selection of items that are similar yet exhibit different very behavior, find the small differences that exist between the items, and then seek to understand how those small differences lead to such disparate results. In bees, the antioxidant chemical vitellogenin appears to be a good candidate:

Whether this is the actual mechanism by which queens achieve both fertility and long life remains to be seen, Robinson said. In any event, this study suggests that vitellogenin plays a vital role in queen bee longevity, he said, particularly since the honey bee lacks many antioxidants commonly found in other species.

But take a look at the paper mentioned above: vitellogenin is just one item in a long, long laundry list.

Back to engineering longevity: the Strategies for Engineered Negligible Senescence, or indeed any repair-based approach to aging, employs a similar comparison strategy to sidestep our comparative ignorance of metabolism. Take a young metabolism and an old metabolism, and list all the differences between the two. Establish which differences are secondary to others, and in doing so winnow down the list into a set of primary root causes for all the change and degeneration that happens to our biochemistry across the years. Those root causes become the targets for repair strategies.

I should note that all this work has been accomplished already, over the past half century. The list of root causes for aging already existed, complete as of the 1980s - not that anyone then knew that no more would be found in the following two decades. These root causes are all forms of accumulated damage caused by the normal operation of our metabolism: specific forms of wear and tear that lead to a wide variety of age-related conditions and ultimately death.

It doesn't matter that we fall far short of a full understanding of how all these primary and secondary changes fall into place - how exactly damage A leads to damage B that leads to degeneration - the process of comparison and elimination between old metabolisms and young metabolisms shows us the narrow window through which we can focus our efforts to move forward. All additional understanding beyond this window can only help, but it isn't strictly necessary.

This paradigm is how we can move beyond the awe-inspiring complexity of metabolism, and move beyond the limitations of the vast project necessary to understand and manipulate our metabolisms. By focusing very narrowly on the identified changes that occur in our biochemistry with age, and setting forth to repair those changes, we have the chance to make significant progress towards engineered longevity in our lifetimes.

Moscow News on Kriorus

The Moscow News looks at cryonics provider Kriorus, a Russian group that aims to become the Alcor of their country: "established in 2005 with the help of the Russian Transhumanist Movement, the devotees of which believe in the process of humans becoming 'posthumans' - beings capable of waiving aging and death, and forever forgetting of such problems as disabilities and disease. Such a goal is at present obviously unattainable, but one will find that not just transhumanists or immortalists are striving to complete the research on cryonics - the issue of death and prolonging of life is close to all, and the work on cryonics has been in progress for decades. ... The technology of freezing the body available today is considered to be sufficiently developed, and more or less safe; most of the problems associated with freezing living matter - such as ice crystals appearing in cells and thus causing damage - have been solved. However, it is currently impossible to successfully thaw the body or brain without causing some degree of irreparable damage - and even if it were possible, all you'd have would be a corpse ... To make the lifeless body come to life, far more advanced know-how is required. Cryonicists hope not only to reanimate the body [using technologies yet to be developed], but to remove the initial cause of death or any other problems present at the time of death."


Small Steps Towards Medical Nanorobots

As engineered nanoparticles increase in complexity, they will at some point be sophisticated enough to be considered true medical nanorobots. That's still in the future, but you can see that the process is underway: "Scientists have developed nanometer-sized 'cargo ships' that can sail throughout the body via the bloodstream without immediate detection from the body’s immune radar system and ferry their cargo of anti-cancer drugs and markers into tumors that might otherwise go untreated or undetected. ... The idea involves encapsulating imaging agents and drugs into a protective 'mother ship' that evades the natural processes that normally would remove these payloads if they were unprotected ... These mother ships are only 50 nanometers in diameter, or 1,000 times smaller than the diameter of a human hair, and are equipped with an array of molecules on their surfaces that enable them to find and penetrate tumor cells in the body. ... We are now constructing the next generation of smart tumor-targeting nanodevices. We hope that these devices will improve the diagnostic imaging of cancer and allow pinpoint targeting of treatments into cancerous tumors."


Telomeres, Health, and Centenarians

Telomeres are protective lengths of material at the end of your chromosomes. Telomere length and aging are correlated, as are telomere length and health - in both cases the worse your situation, the shorter your telomeres:

Telomeres - the terminal caps of chromosomes - become shorter as individuals age, and there is much interest in determining what causes telomere attrition since this process may play a role in biological aging. The leading hypothesis is that telomere attrition is due to inflammation, exposure to infectious agents, and other types of oxidative stress, which damage telomeres and impair their repair mechanisms. Several lines of evidence support this hypothesis, including observational findings that people exposed to infectious diseases have shorter telomeres.

There are hints that shortened telomeres might be caused by damage to mitochondria, which is in turn a known root cause of many aspects of degenerative aging. In a recently published study, researchers found that telomere length in the oldest humans is still strongly correlated with health - suggesting that perhaps aging is not the primary correlation here.

Association of longer telomeres with better health in centenarians:

Prior animal model studies have demonstrated an association between telomere length and longevity. Our study examines telomere length in centenarians in good health versus poor health. Using DNA from blood lymphocytes, telomere length was measured by quantitative polymerase chain reaction in 38 sex- and age-matched centenarians (ages 97-108).

"Healthy" centenarians (n = 19) with physical function in the independent range and the absence of hypertension, congestive heart failure, myocardial infarction, peripheral vascular disease, dementia, cancer, stroke, chronic obstructive pulmonary disease, and diabetes were compared to centenarians with physical function limitations and >/=2 of the above conditions (n = 19).

Healthy centenarians had significantly longer telomeres than did unhealthy centenarians (p =.0475). Our study demonstrated that investigations of the association between telomere length and exceptional longevity must take into account the health status of the individuals. This raises the possibility that perhaps it is not exceptional longevity but one's function and health that may be associated with telomere length.

This makes more sense if you think of aging as less of a process and more of an accumulation of biochemical damage. Telomere length seems to be a marker for your personal level of damage, possibly by virtue of its connections to one or more of the primary modes of damage. Many questions remain, however, as to where exactly it fits in the grand scheme of cause and effect.

Targeting Cancer Stem Cells

Given that researchers are making strong progress in both understanding the biochemistry of stem cells and in targeted cell-killing therapies, I don't expect the cancer stem cell hypothesis to remain a hypothesis for more than another few years. "After years of working toward this goal, scientists [have] found a way to isolate cancer stem cells in tumors so they can target the cells and kill them, keeping cancer from returning. A research team led [discovered] that a particular protein only appears in stem cells. Until now, researchers knew of proteins that appeared in both regular cancer cells and stem cells, but none that just identified a stem cell. The group has already begun work to use the protein as a target for a new compound that once developed would kill the stem cells and kill the cancer. By targeting the stem cells, scientists and physicians also would be able to stop the cancer from returning. ... Researchers expect to have initial testing completed to begin the first phase of clinical trials within 5 years ... The compound, if successful in human trials, is expected to be available to the public within 10 years."


On Cancer Stem Cells

The Economist looks at cancer stem cells: "The discovery - or, rather, the hypothesis that is now being tested - is that cancers grow from stem cells in the way that healthy organs do. ... Not all investigators support the cancer-stem-cell hypothesis, but the share who do so is growing rapidly. A mere five years ago, few research papers on the subject were presented at big academic meetings. This year there were hundreds at one such meeting alone. Moreover, data from clinical trials based on the hypothesis suggest that it has real value for patients. As a result, drug companies have taken notice and are trying to develop substances that will kill cancer stem cells. ... At the moment, scientists being scientists, few are willing to be anything other than cautious. They have seen too many past cures for cancer vanish in a puff of smoke. The proof needs to come from patients - preferably with them living longer. But if the stem-cell hypothesis is indeed shown to be correct, it will have the great virtue of unifying and simplifying the understanding of what cancer is. And that alone is reason for hope."


I Will Wager That These Mice Live Longer Too

I noticed a paper on the modulation of damaging reactive oxygen species generated by the mitochondria today - this should sound familiar to some of you. Mitochondria are the power plants of your cells, and like all power plants they generate waste as a consequence of their operation. That waste is an important root cause of aging; the rate at which it is produced and your resistance to its damaging effects are strong determinants of longevity.

Even though the researchers in this paper don't have life span data, they are putting together a system very similar to gene-engineered mice that overexpress catalase in their mitochondria. The antioxidant catalase soaks up some portion of the reactive oxygen species - also known as free radicals - before they can wreck havoc with cellular machinery, and the mice live longer as a result. A Russian researcher has crafted a similar demonstration in recent years using biochemistry instead of genetics to localize ingested antioxidants into the mitochondria - there also, longer-lived mice.

Here is the PubMed reference for the paper that caught my eye today:

H(2)O(2) [or hydrogen peroxide] is a major reactive oxygen species produced by mitochondria that is implicated to be important in aging and pathogenesis of diseases such as diabetes; however, the cellular and physiological roles of mitochondrial H(2)O(2) remain poorly understood.

Peroxiredoxin 3 (Prdx3/Prx3) is a thioredoxin peroxidase localized in mitochondria, [which means that this antioxidant chemical can neutralize some fraction of the H(2)O(2) at source, before those free radicals get out into the cell].

To understand the cellular and physiological roles of mitochondrial H(2)O(2) in aging and pathogenesis of age-associated diseases, we generated transgenic mice overexpressing Prdx3 (Tg(PRDX3) mice). Tg(PRDX3) mice overexpress Prdx3 in a broad range of tissues, and the Prdx3 expression is localized exclusively in the mitochondria.

As a result of increased Prdx3 expression, mitochondria from Tg(PRDX3) mice produce significantly reduced amount of H(2)O(2), and cells from Tg(PRDX3) mice have increased resistance to stress-induced cell death and apoptosis. Interestingly, Tg(PRDX3) mice show improved glucose homeostasis, as evidenced by their reduced levels of blood glucose and increased glucose clearance. Tg(PRDX3) mice are also protected against hyperglycemia and glucose intolerance induced by high-fat diet feeding.

I'll wager that these mice also live significantly longer, protected to some degree from the biochemical side-effects of a working metabolism by the enhanced levels of the antioxidant peroxiredoxin 3. That data is a good few years out, however, even if the researchers are working on it now.

I suppose this is a good time to remind folk that ingesting plain old antioxidants is of no demonstrated benefit - they aren't going anywhere near your mitochondria, which is the only place that much matters, so it seems:

Since the early 1990s scientists have been putting these compounds through their paces, using double-blind randomised controlled trials - the gold standard for medical intervention studies. Time and again, however, the supplements failed to pass the test. True, they knock the wind out of free radicals in a test tube. But once inside the human body, they seem strangely powerless. Not only are they bad at preventing oxidative damage, they can even make things worse. Many scientists are now concluding that, at best, they are a waste of time and money. At worst they could be harmful." Mouse studies have shown that carefully directing antioxidants to the cellular mitochondria extends healthy life span on the order of 20-30% - a fairly complex feat of biochemical engineering that no presently available pill can match. Those studies further showed no benefit from the same antioxidants sent elsewhere in mouse biochemistry. Haphazardly throwing chemicals at a very complex problem and hoping for the best does not have the best record of success - when that's all you can do, you do it, but we can do better now.

To recap: a demonstrated 20-30% extension of mouse life span through the very latest methods of engineering antioxidants into the mitochondria, presently available for purchase nowhere. On the flip side, there is zero benefit for mice resulting from the antioxidants presently sold in attractive little jars. Caveat emptor.

The Hostile Wife Phenomenon in Cryonics

I'm not entirely sure what to make of this Depressed Metabolism article: it seems like a refugee from the 1960s in many ways, to put it mildly. Nonetheless, I can see it sparking a healthy discussion on choice, autonomy, and responsibility regardless of what you think of the authors' views. "The authors of this article know of a number of high profile cryonicists who need to hide their cryonics activities from their wives and ex-high profile cryonicists who had to choose between cryonics and their relationship. We also know of men who would like to make cryonics arrangements but have not been able to do so because of resistance from their wives or girlfriends. In such cases, the female partner can be described as nothing less than hostile toward cryonics. ... Hopefully, the forgoing analysis will offer some concrete areas of potential conflict, perceived or real, that can be addressed by both emotional reassurance and reason. Identifying the problems is certainly a necessary first step to resolving them." If there's one lesson coming out of all this, it might be "put more thought into signing contracts of great obligation and responsibility than most people seem to."


Using Signals Instead of Cells

Some first generation stem cell therapies seem to work because of the chemical signals emitted by implanted cells. An obvious next step is to only use the signals and skip the cells entirely. EurekAlert! notes a step along that path: "This method, developed in laboratory research with pigs, is the first non-cell based therapeutic application of human embryonic stem cells (hESCs). It entails using secretions from stem cells. In their studies with pigs, the researchers found that the administration of secretion from stem cells minimized heart injury by enhancing reperfusion therapy (angioplasty and cardiac bypass surgery) and reducing tissue death by another 60%. Heart function was also markedly improved ... Using secretion instead of cells allows us to circumvent many highly intractable problems such as tumour formation, immune compatibility, cell viability, delivery, costs and timeliness." Researchers are still working to understand the signals that drive regeneration, but I imagine that a few years from now we will see tests of artificially produced signal chemicals to stimulate stem cells already present in the body.



The online healthy life extension community came out in force in the past few weeks to vote up and discuss a proposed Amex Members Project focused on longevity science. It was a good calibration for what we can do at short notice when we put our minds to it - we pushed the project into the top 25 by vote count, and created a far larger and more interesting discussion than attended any of the other proposals.

Unfortunately, the punchline is that the Amex advisors punted on the longevity science in favor of other projects for the final 25. Not ready to hear the message perhaps, or looking for a different format in the project description, or carefully estimating the PR effects of A versus B - we'll never know. Via the Methuselah Foundation blog:

Thank you all for turning out to help vote this project into the top 25 by vote count, and leaving so many thoughtful comments - it goes to show just how large and engaged the pro-longevity community has become. We here at the Methuselah Foundation are very pleased with what we've seen in the past few weeks, and view the fantastic community response as another indicator that our efforts are worthwhile.

The real competition - developing medicine to produce engineered longevity - has only just begun. There will be many more initiatives in the years ahead, and many more chances to obtain significant funding.

Serious, long-haul fundraising reason isn't about opportunistically grabbing fruit from the tree - though no-one is going to turn it down when it does happen to show up. You can't depend upon the timetables of other growers. The hard work of fundraising is in setting the stage to grow and harvest your own trees, to culture and create the a backdrop that naturally leads to opportunities for seven-figure investments in progress.

Patient advocacy for research into engineered longevity and the repair of aging is a fundamental part of this process - and that's true at all levels. Whether you are talking about aging research with friends, writing blogs, debating with the scientific community, writing in the established media, or engaging with funding institutions directly, it all goes into creating a zeitgeist in which funding for engineered longevity research is just as expected and understood as funding for cancer science.

We're not there yet. But I've been watching this whole process for a good few years now, and we're a lot closer than we were even five years ago. We push and the wheel turns; we talk, and ever more people listen to what we have to say. The money for research is starting to flow. It's working - so we keep at it.

Another Glenn Foundation Laboratory

The Glenn Foundation is funding a new laboratory at MIT, building upon the Harvard laboratory funded a couple of years ago. "The mission of the Glenn Foundation, founded in 1965 by Paul F. Glenn, is to extend the healthy productive years of life through research on the mechanisms of biological aging. ... The [Foundation] has pledged $5 million over five years to establish a new laboratory in MIT's Department of Biology to study aging. The new Glenn Laboratory for the Science of Aging will be directed by MIT Professor Leonard Guarente, a pioneer in the biology of aging. ... This generous gift from the Glenn Foundation will enable us to expand and intensify the study of critical regulators of aging, such as sirtuins. This work may lead to interventions to extend the healthy, productive period of our lives and forestall frailty and diseases." Laboratories founded with the explicit mission of addressing aging are an important part of the cultural sea change taking place in the aging research community.


Of Monotremes and Mole-Rats

An overview from Existence is Wonderful: "So, what is known so far about longevity in mole-rats and echidnae? Well, perhaps not as much as is known about mice, but certainly a fair amount - and the pool of knowledge is growing all the time. ... One theory regarding exceptional longevity in mammals [is] the "membrane pacemaker" theory of metabolism ... Essentially, what this means is that some findings suggest a relationship between metabolic rate and the health over time of the various fatty-acid membrane structures that comprise animal physiology. Animals are, in a sense, made possible by membranes - life is dependent upon being able to direct functional pathways along specific routes, and to contain chemical materials where they are needed (that is, where they can perform their life-sustaining activities). Longer-lived species, according to the membrane pacemaker theory, are likely to have more peroxidation-resistant membrane lipids than shorter-lived species ... naked mole-rat membrane structure actually remains largely unchanged with age, but that the chemical composition of mole-rat membranes more lipid-peroxidation-resistant than that found in mice."


Why Aren't You Exercising Already?

Scientific evidence for the benefits of exercise is piled deep and high. The benefits for general health, longevity, and resistance to age-related disease are greater and far more broad than anything medical science can do for you today, or is likely to be doing for you over the next decade - first generation calorie restriction mimetics included. Here is one recent example of many studies that show exercise to reduce mortality, extend healthy life, and lower the rate at which age-related degeneration sets in to boot:

Changes in Cognition and Mortality in Relation to Exercise in Late Life: A Population Based Study

On average, cognition declines with age but this average hides considerable variability, including the chance of improvement. Here, we investigate how exercise is associated with cognitive change and mortality in older people and, particularly, whether exercise might paradoxically increase the risk of dementia by allowing people to live longer.


High exercisers (at least three times per week, at least as intense as walking) had more frequent stable or improved cognition [42.3%] over 5 years than did low/no exercisers (all other exercisers and non exercisers) [27.8%] ... People who did not exercise were also more likely to die [37.5%] versus [18.3%].


Exercise is strongly associated with improving cognition. As the majority of mortality benefit of exercise is at the highest level of cognition, and declines as cognition declines, the net effect of exercise should be to improve cognition at the population level, even with more people living longer.

So why aren't you out there exercising already?

Sarcopenia Versus Dynapenia

Is age-related weakness mostly due to the progressive loss of muscle mass called sarcopenia? Some would argue not: "Maximal voluntary force (strength) production declines with age and contributes to physical dependence and mortality. Consequently, a great deal of research has focused on identifying strategies to maintain muscle mass during the aging process and elucidating key molecular pathways of atrophy, with the rationale that the loss of strength is primarily a direct result of the age-associated declines in mass (sarcopenia). However, recent evidence questions this relationship and in this [article] we argue the role of sarcopenia in mediating the age-associated loss of strength (which we will coin as dynapenia) does not deserve the attention it has attracted in both the scientific literature and popular press. Rather, we propose that alternative mechanisms underlie dynapenia (i.e., alterations in contractile properties or neurologic function), and urge that greater attention be paid to these variables in determining their role in dynapenia."


An Update on Catalase in the Mitochondria

You might recall the demonstration of extended healthy longevity in mice by localizing the antioxidant catalase to the mitochondria - a strategy replicated by other researchers to some success. Here is an update on that work: "We describe the effects of mitochondrially targeted catalase (MCAT) expression on end-of-life pathology in mice using detailed semiquantitative histopathological evaluation. We previously reported that the median and maximum life spans of MCAT mice were extended relative to those of wild-type littermates. We now report that MCAT expression is associated with reduced malignant [tumor] burden, reduced cardiac lesions, and a trend toward reduced systemic inflammation ... Combined disease burden and comorbidity are also reduced, and MCAT expression is not associated with any detrimental clinical effects. The results suggest that oxidative damage is involved in aging of [mice] via modulation of a subset of age-associated lesions. Antioxidant interventions targeting mitochondria may therefore be a viable strategy for prevention or postponement of some age-associated diseases."


New Podcasts at SAGE Crossroads

SAGE Crossroads has added a couple of new podcasts since the last brace of material on biomarkers of aging. Take a look and see what you think.

Should longevity science be a priority?

Humanity faces many challenges this century. There are three important considerations that can help us distinguish between the challenges that are truly the biggest problems from those that are less pressing. The first is the magnitute of the harms in question. Second, is their certainty of happening. Last, is the likelihood that we could do something about them. Aging scores very high on all three of these issues.

The sheer number of humans that will suffer the diseases of aging this century is staggering and unprecedented. Aging scores very high on the magnitude of the harm criterion. Secondly, aging scores high on the certainty factor. The scientific consensus is in, senescence causes disease and death. Thirdly, we must ask what is the likelihood that we could actually do something to remedy the situation. The greater the likelihood that we could successfully mitigate the harms in questions, the stronger the case for taking action. We know that aging is not immutable, and thus longevity science could provide us with effective and efficient strategies for dealing with the many problems that the aging populations face.

A great many people within the scientific community do in fact share this view - the most important present debates are over the strategies by which progress is made. What is efficient, what is plausible, how will funds be raised and research prioritized? Meanwhile, outside the scientific community, a great deal of work remains to be done in education and raising awareness: the assignment of resources to specific research goals depends upon a broad base of popular support and understanding. Think of cancer science, for example, or Alzheimer's research. That level of public understanding, appreciation for what is a plausible rate of progress, and support for funding of longevity science is a good goal to aim for.

Is resveratrol the key to unlocking longevity?

KYLE JENSEN: A lot of headlines have been coming out of NIH studies that you’ve been involved in that state resveratrol improves health in mice but not longevity. Do you think there is a chance that resveratrol can increase human longevity?

LEONARD GUARENTE: Absolutely. I think we aren’t going to know that for a very, very long time. In mice so many things have been [improved] by sirtuin activators, and the fact that longevity hasn’t been observed yet I think it just a matter of time before one has the right strain.


KYLE JENSEN: Now do you think this approach, going after drugs like resveratrol, will hold the key to defeating age-related disease and increasing lifespan?

LEONARD GUARENTE: I don’t think we will defeat them, but I think we have a chance to hold them at bay longer and increase the period when we are healthy and disease free. Perhaps as much by a decade. Which, you know, will make a huge difference.

Supporters of drug-based metabolic manipulation will spend staggering sums of money over the next two decades pushing various drugs through the present hideously inefficient system of medical regulation. These are all aimed at slowing aging by inducing metabolic changes discovered in biochemistry of calorie restriction, exercise, and the like. This is the grand, slow, inefficient way forward. Slowing the rate at which age-related damage accumulates does nothing for the old.

It is frustrating at times to see the research community just as close to truly impressive methods of completely repairing specific types of age-related damage as it is to more metabolism-tweaking drugs that can only slow that damage down - and yet all the resources are going to the slower path of drug development that will in all likelihood produce less effective therapies in the end.

Aging Cast As Autophagy Disorder

Enhanced autophagy is clearly important in most - possibly all - of the demonstrated ways to extend healthy longevity in mammals. I noticed this paper today: "Many macromolecules under degradation inside lysosomes contain iron that [makes] lysosomes sensitive to oxidative stress. ... Apart from being an essential turnover process, autophagy is also a mechanism for cells to repair inflicted damage, and to survive temporary starvation. The inevitable diffusion of hydrogen peroxide into iron-rich lysosomes causes the slow oxidative formation of lipofuscin in long-lived postmitotic cells, where it finally occupies a substantial part of the volume of the lysosomal compartment. This seems to result in a misdirection of lysosomal enzymes away from [autophagic vacuoles], resulting in depressed autophagy and the accumulation of malfunctioning mitochondria and proteins with consequent cellular dysfunction. This scenario might put aging into the category of autophagy disorders."


Progress in Bypassing Mitochondrial Damage

Allotopic expression of genes normally found in mitochondrial DNA is a core portion of the Strategies for Engineered Negligible Senescence. It is the process of inserting a copy of vital mitochondrial genes into the cell nucleus, and then figuring out how to get the proteins produced by those genes back to the mitochondria where they are needed. This could eliminate the contribution of mitochondrial DNA damage to aging. A technique for doing all this is now demonstrated in rats: "We obtained a complete and long-term restoration of mitochondrial function in human fibroblasts in which the mitochondrial genes ATP6, ND1, and ND4 were mutated ... ND1 and ND4 are mutated in nearly all cases of Leber hereditary optic neuropathy (LHON). LHON is the most common mitochondrial disorder and is characterized by a loss of vision. ... They introduced the human ND4 gene with the mutation present in the majority of LHON patients into rat eyes. The treatment caused retinal ganglion cells (RGCs) to degenerate significantly when compared to those from control eyes and was associated with decreased visual performance. Importantly, reintroducing normal ND4 led to prevention of RGC loss and visual impairment, effectively rescuing the animals from impending blindness. ... These data represent the 'proof of principle' that optimized allotropic expression is effective in vivo and can be envisaged as a therapeutic approach for mtDNA-related diseases."


Radical Egalitarianism in Defense of Engineered Longevity

Radical egalitarianism is an impossible ideal: that a utopian society could exist in which everyone is equal in some important way - in possessions, ability, or access to resources. Lesser arguments for egalitarianism are usually heard alongside the blandishments of green-eyed socialism: calls for a levelling brought upon anyone with greater wealth or better access to medicine. That type of egalitarian can often be seen speaking out against research into engineered longevity, on the - mistaken - grounds that it will be "for the rich" or otherwise benefit some small group before it benefits everyone. Death for everyone before inequality for anyone is the mantra there:

I find it very strange that apparently intelligent people can field this sort of argument. Replace working anti-aging medicine with, say, working heart transplants, or working kidney dialysis and see how far you get in trying to convince people that suppliers in the developed world are keeping such technologies out of the hands of others, or that we must stop using medicine that is not universally available. Quite aside from the glaring failure to understand simple economics, it is deeply depressing that we live in a world in which people argue for the enforcement of large-scale, preventable suffering and death.


Creating "equality" by taking from the successful ruins the creation of wealth - very much a non-zero sum game - for all. It takes away the vital incentives and rewards for success. At the end of the process, as demonstrated by all that transpired in the Soviet Union, you are left with the same old inequalities, but now taking place amongst ruins, starvation and disease.

In any case, I thought you'd be interested to see the fundament of the egalitarian position turned to support research into ending aging and extending healthy life for a change. Consider this another installment in seeing how mainstream pro-longevity bioethicists think:

Why should the aged have a much greater risk of cancer, heart disease, diabetes, AD, infection and death? The aged do not deserve the cellular and molecular damage that accrues over time; and thus we should seek to mitigate these vulnerabilities. And so I think the aspiration to retard human aging is actually a requirement, not violation, of equality. And this is what I argue at greater length in my paper "Equality and the Duty to Retard Human Aging"

The trouble with radical equality is that the "right" to possess more than you presently own - be it possessions, resources, or young cells - is what's known as a positive right.

Within the philosophy of human rights, some philosophers and political scientists make a distinction between negative and positive rights. According to this view, one's positive right imposes an obligation on another to do something for someone, while a negative right obliges others to refrain from doing something to someone.

A positive right for one person always implies enforced servitude for another person: where do the labor and resources to supply that positive right come from, after all? A system of government that grants positive rights is a system that must be backed up by coercion - taxes, public service, prison, police, and guns. Just try suggesting that you won't supply labor and materials for the postive rights written into law by those who will benefit from them, and see what happens. That is never ethical ... unless you happen to be one of the silent majority who believe it is acceptable to force other people to do what you want them to do. Sadly, if you look outside, you will probably find you live under such a government.

Anyway. It is interesting to see the emergence of attempts to restructure various restrictive philosophies of life to be in favor of engineered longevity, now that the prospect of actually engineering greater human longevity is more plausible. That in and of itself is a sign of progress, I think. Follow the incentives: when people think that they could possibly benefit from a future of rejuvenation therapies, then they will work on the roadblocks they know best. Articles like the one quoted above are a form of vote of confidence in longevity science.

Reactive Carbonyl Species, ALEs, and Aging

Free radicals (such as reactive oxygen species) are increasingly generated with age - this is the end of a long chain of consequences that starts with damaged mitochondrial DNA. How do those oxidizing agents actually cause widespread harm to bodily systems? This paper gives an overview of one broad set of mechanisms, wherein step one is the creation of reactive carbonyl species (RCS) by free radicals: "Most of the biological effects of RCS [are] due to their capacity to react with cellular constituents, forming advanced lipoxidation end-products (ALEs). Compared to reactive oxygen and nitrogen species, lipid-derived RCS are stable and can diffuse within or even escape from the cell and attack targets far from the site of formation. Therefore, these soluble reactive intermediates, precursors of ALEs, are not only cytotoxic per se, but they also behave as mediators and propagators of oxidative stress and cellular and tissue damage. ... The causal role of ALEs in aging and longevity is inferred from the findings that follow: a) its accumulation with aging in several tissues and species; b) physiological interventions (dietary restriction) that increase longevity, decrease ALEs content; c) the longer the longevity of a species, the lower is the lipoxidation-derived molecular damage; and finally d) exacerbated levels of ALEs are associated with pathological states."


Update on the Longevity Science Amex Members Project

From the Methuselah Foundation blog: "I'm pleased to say that the pro-longevity science community rallied to vote the Amex Members Project submission "Undergrads Fighting Age Related Disease" into the top 25 projects by vote totals - and made it the most discussed project of all. Thank you! That discussion is still ongoing, by the way, and people unfamiliar with longevity research have questions about the project. Feel free to jump in and help answer them. What comes next? Well, between now and September 9th - less than a week away - the Members Project advisory panel will look at the projects, votes, and discussions, and announce the final 25. Those 25 projects will be voted on by Amex card holders to determine which 5 will be funded. ... So, all you generous folk who rounded up your friends and spread the word: we're going to do it all again for those with American Express cards starting on the 9th. We here at the Methuselah Foundation are looking forward to it!"


More Evidence For Autophagy as a Good Thing

You might think of autophagy as a form of self-maintenance for your cells: it is the destruction of damaged and older cellular components such that newly built components can take their place. It is an attractive, intuitive idea that an increased level of autophagy leads to consistantly better function in cells, which in turn leads to longer-lived animals. Over the past years, researchers have demonstrated strong links between autophagy and healthy longevity:

The better known life extension mechanisms in lesser animals are all driven by changes in autophagy - or so say the autophagy specialists. It's true that the various hyperspecialized communities of modern biology are overly cloistered and ignorant of one another's research, but the autophagy researchers are assembling compelling evidence for this position.

Some of the most interesting work has been published this year and last. If you want a primer on why autophagy is important, and why it is that some damaged cellular components take a heavy toll of life and health, then look back in the Fight Aging! archives :

What should I find today while meandering through PubMed but another longevity mechanism tied to increased autophagy. You might recall that researchers are achieving impressive results in mice by manipulating p53 - even managing to break the link between cancer protection and aging to give both added longevity and added cancer protection, not one at the cost of the other. In the paper I noticed today, we see that manipulating p53 is another way of manipulating autophagy for beneficial results on health and longevity:

The effects of p53 on whole organism longevity are mediated by autophagy:

The tumor suppressor protein p53 has a major impact on organismal aging. Recently it has become clear that p53 not only controls DNA damage responses, senescence and apoptosis but also plays a major role in the control of autophagy. Thus, deletion, depletion, or inhibition of p53 induces autophagy in human, mouse and nematode cells.

We therefore tested the hypothesis that the mutation of the p53 orthologue CEP-1 might increase the life span of Caenorhabditis elegans through an increase in baseline autophagy. For this, we evaluated the survival of nematodes lacking cep-1, alone or in combination with RNA interference with the autophagy gene bec-1 (which encodes the orthologue of Atg6/Beclin 1).

cep-1 mutants exhibited a prolonged life span. While BEC-1 depletion during adult life did not cause significant modification of the life expectancy of wild type controls, it did reduce the increased life span of cep-1 mutants down to approximately normal levels. These results indicate that the life span-extending effect of the cep-1 mutation is mediated by autophagy. These results lend support to the hypothesis that autophagy has a broad positive impact on organismal aging.

Given the level of funding and interest in calorie restriction mimetics, I imagine that the development of autophagy-enhancing drugs will proceed in the much the same way over the next few years.

Submissions Wanted For Hourglass III

From Ouroboros: "The third installation of Hourglass, a monthly blog carnival devoted to the biology of aging, will appear on September 9th at SharpBrains. We are soliciting entries in the general subject area of aging and biogerontology: Topics of posts should have something to do with the biology of aging, broadly speaking - including fundamental research in biogerontology, age-related disease, ideas about life extension technologies, your personal experience with calorie restriction, maybe even something about the sociological implications of increased longevity. Opinions expressed are not necessarily those of the management, so feel free to subvert the dominant paradigm. If in doubt, submit anyway. Submissions should be emailed to [][at][gmail][dot][com]. (In the meantime, feel free to check out previous editions of the carnival, here and here. Hourglass IV will appear on October 14th at psique.)"


Another Regenerative Strategy For Hearing Loss

Following on from the gene therapy approach for age-related deafness mentioned a few days ago, here's a cell-based therapy via EurekAlert!: "hearing loss due to cochlear damage may be repaired by transplantation of human umbilical cord hematopoietic stem cells ... the team used animal models in which permanent hearing loss had been induced by intense noise, chemical toxicity or both. Cochlear regeneration was only observed in animal groups that received HSC transplants. Researchers used sensitive tracing methods to determine if the transplanted cells were capable of migrating to the cochlea and evaluated whether the cells could contribute to regenerating neurons and sensory tissue in the cochlea. ... Our findings show dramatic repair of damage with surprisingly few human-derived cells having migrated to the cochlea. A fraction of circulating HSC fused with resident cells, generating hybrids, yet the administration of HSC appeared to be correlated with tissue regeneration and repair as the cochlea in non-transplanted mice remained seriously damaged."


A Thought For the Day

I stumbled across a thoughtful blog post earlier today, and thought I would draw your attention to it:

I'm often appalled at the attitudes of others toward the general idea of life extension and toward serious thought, research and development given to technologies that may grant us not years but centuries to live. It is surprising how many among us would not want to live forever. It is their opinion that added years cheapen life by robbing it of what they claim gives it meaning - death. It is my opinion that only a life already and profoundly cheapened in one's own mind is further cheapened by added years.

Their's is, primarily, love of death, not life.

Such individuals seem even more opposed to granting liberty to others to pursue technologies to enable themselves longer lifespans. "How can you dilute the meaning of life", they say. To them, longer life somehow means a life devoid of wonder or surprise.

It is my belief a life loved authentically and completely can only be increased in its wonders if given more time. There is far, far more to be experienced, loved and created than the breadth and depth of the present average lifespan allows. If one's passions are shallow and short-lived, perhaps a short life suits you. However, if one's passions seem to have no limit, additional life can mean only more time to express those passions and to discover new ones.

I'm always pleased to see such sentiments springing up out there in the world. Incremental growth in the community of people who think this way is a necessary foundation for effective activism, advocacy, and fundraising for serious longevity research. As more voices are raised in support for engineered longevity and the defeat of age-related degeneration, more scientists and funding institutions will be persuaded to join the cause - all progress starts with people deciding that they want to see progress.

Metformin as Calorie Restriction Mimetic

This paper is illustrative of the thinking that leads to trying anti-diabetic drugs as calorie restriction mimetics: "Studies in mammals have led to the suggestion that hyperglycemia and hyperinsulinemia are important factors both in aging and in the development of cancer. It is possible that the life-prolonging effects of calorie restriction are due to decreasing IGF-1 levels. A search of pharmacological modulators of insulin/IGF-1 signaling pathway (which resemble effects of life span extending mutations or calorie restriction) could be a perspective direction in regulation of longevity. Antidiabetic biguanides are most promising among them. Here we show the chronic treatment of female outbred SHR mice with metformin (100 mg/kg in drinking water) slightly modified the food consumption but decreased the body weight after the age of 20 months, slowed down the age-related switch-off of estrous function, increased mean life span by 37.8%, mean life span of last 10% survivors by 20.8%, and maximum life span by 2.8 months (+10.3%) in comparison with control mice." Full calorie restriction does better than that (30-40% maximum life span extension), but this is a strong argument for its effects on insulin metabolism to be one cause of enhanced health and longevity.


Another Human Longevity Gene Association

The Telegraph reports on confirmation that a class of longevity genes indentified in lower animals also has an effect on human populations: "The gene linked with better health and a longer life is called FOXO3A and although similar genes have been shown to prolong life span in other species, this is the first time that FOXO has been linked directly to longevity in humans. ... Each gene comes in two copies and the team found the longevity effect of this letter was additive: those with one copy doubled their odds of living an average 98 years ... Men who had two G copies did even better and almost tripled their odds of living nearly a century, and were markedly healthier at older ages ... We screened 213 of the long-lived participants' DNA and 402 of the average-lived, focusing on five genes ... These genes were selected for good reason because they involved in the insulin pathway and signalling, which studies of other animals have shown is linked with longevity." This doesn't tell we laypeople more than we already knew: that insulin metabolism is significant in health and longevity variations within a species.


The Scientific Debate That Will Determine How Long We All Live

Last week, I pointed out an example of researchers who believe engineered longevity must be accomplished by gene engineering and changing the operation of metabolism to slow aging. In that worldview, any significant progress is far in the future, because the task is very complex indeed. Progress in the future is also largely irrelevant to those of us alive today, as slowing aging does next to nothing for people who are already age-damaged to the point of disease and frailty.

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

Fortunately there is a fast boat in addition to the slow boat described above:

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

Today, let me point you to another manifestation of the "we can do no better than slow aging by metabolic manipulation" viewpoint:

The extreme arrogance of anti-aging medicine:

The anti-aging medicine movement proposes to alter the human body in order to achieve extreme longevity. To do this it has to reverse or by-pass the multiple causes of human aging. These include a large number of age-associated pathologies, each of which is being studied in great detail in research laboratories around the world. The protagonists of anti-aging medicine claim that it will be far more successful than the combined efforts of the innumerable scientists carrying out this research. Aging has an extremely long evolutionary history, and the anatomical structure and physiology of animals is directly related to their finite lifespan. The anti-aging movement proposes in a few decades to reverse what has been the result of millions of years of evolution.

The above abstract is wrong-headed, to say the least, but it is an output of the sort of worldview described above: a) that aging can only be slowed, b) that doing so requires the day to day operation of human biochemistry to be changed in non-trivial ways, and c) that this is a very tall order indeed for the medical science of the forseeable future.

So, to point out the errors. Firstly, the causes of aging are not the pathologies of aging. Pathologies are end results - if dry rot is a cause, then failing wooden structural beams are the pathology. Today's prospective longevity engineers talk about causes, about the comparatively few types of biochemical damage that build up in our tissues to create many, many different forms of pathology. Dry rot can make a wooden structure fall apart in any one of a hundred distinct ways - but all are still caused by dry rot.

If you want to tackle aging efficiently - and make no mistake, this whole debate is about efficiency - then pathology is the wrong place to start. If you work on patching up pathologies, then you are Canute against the tide. By failing to stem the underlying cause, your efforts are doomed to inefficiency and ultimate failure. Present day gerontological medicine is largely playing the role of Canute because that has historically been the best medical science can do: throw a huge level of resources at treating the consequences of aging and gain little by it. That little was better than nothing for billions, but it was still little in the grand scheme of things.

We stand in the 21st century now, amidst the early years of a revolution in the capabilities of biotechnology. Scientists can move beyond the historical focus of medical technology on patching end results and instead work on prevention and repair of root causes. Taking a different, more efficient path is why new approaches to longevity engineering will succeed in greatly extending the healthy human life span where decades of scientists and vast expenditures have only slightly raised the bar. Holding out the past as an example of the future is a terrible thing to do. You are rarely going to be right, as the future will be accomplished in a different, usually better way.

I predict that the last sentence in the abstact I quoted above - "reverse what has been the result of millions of years of evolution" - will come back to haunt the author for a good many years. No-one wants to be on record as saying something as bone-headed as that. In the past few decades medical science has reversed any number of evolutionary consequences, some of which have billions of years behind them. As if the number of years a feature took to evolve has any bearing upon the development medicine that acts upon it!

The preceeding point on the structure of living beings, however, is very illustrative of the metabolic manipulation viewpoint: hammering home again that biochemistry will be very hard to re-engineer for greater longevity through slower aging. This is absolutely true, and it would be astoundingly hard to follow though that path to developing longevity therapies. Every biochemical component in our metabolism is a part of many different complex evolved systems - evolution loves reuse and interacting, linked feedback systems. You can't change a thing without having to worry about profound side-effects in every connected process, and the processes important to aging are right in the middle of the engines of life.

But the modern longevity engineers, the heretical minority in the aging research community, are not taking that path forward. Rather, they use the metabolism we have when we are young as the ideal reference model, and seek to reverse all changes away from that reference model that occur with age. No re-engineering, no worrying about how change A affects systems B, C, and D - this is a straightforward repair and restoration strategy. The objective is to restore the metabolism we know works, not create some new metabolism that must be extensively tested and understood.

That is efficiency, and the nature of efficiency in longevity research is the most important debate within the life sciences today, for all that most people know nothing of it. The result of this debate will determine how long we all live in good health.

Towards a Regenerative Cure For Hearing Loss

From ScienceDaily: "scientists have successfully produced functional auditory hair cells in the cochlea of the mouse inner ear. ... researchers specifically focused on the tiny hair cells located in a portion of the ear's cochlea called the organ of Corti. It has long been understood that as these hair cells die, hearing loss occurs. Throughout a person's life, a certain number of these cells malfunction or die naturally leading to gradual hearing loss often witnessed in aging persons. Those who are exposed to loud noises for a prolonged period or suffer from certain diseases lose more sensory hair cells than average and therefore suffer from more pronounced hearing loss. ... One approach to restore auditory function is to replace defective cells with healthy new cells. Our work shows that it is possible to produce functional auditory hair cells in the mammalian cochlea. ... It remains to be determined whether gene transfer into a deaf mouse will lead to the production of healthy cells that enable hearing."


On the Way to Controlling Telomerase

Researchers are making progress in figuring how to control telomerase, and through it influence telomeres, cancer, and aging. From EurekAlert!: researchers "have deciphered the structure of the active region of telomerase, an enzyme that plays a major role in the development of nearly all human cancers. The landmark achievement opens the door to the creation of new, broadly effective cancer drugs, as well as anti-aging therapies. ... Researchers have attempted for more than a decade to find drugs that shut down telomerase - widely considered the No. 1 target for the development of new cancer treatments - but have been hampered in large part by a lack of knowledge of the enzyme's structure. The findings [should] help researchers in their efforts to design effective telomerase inhibitors ... Telomerase is an ideal target for chemotherapy because it is active in almost all human tumors, but inactive in most normal cells. That means a drug that deactivates telomerase would likely work against all cancers, with few side effects." Long-term deactivation will cause massive issues, of course, but that's not the intent for the moment. Given new information about telomerase and mitochondria in aging, there are potentially more interesting end results than good cancer therapies.