If researchers could reproduce the biochemical basis for the health- and longevity-enhancing results of exercise, the resulting drug would no doubt be as popular as calorie restriction mimetics. Exercise and calorie restriction are the two gold-standard items for health: little else even comes close yet. From EurekAlert!, news of small steps on this path: researchers "identified two signaling pathways that are activated in response to exercise and converge to dramatically increase endurance. ... Previous work with genetically engineered mice [had] revealed that permanently activating a genetic switch known as PPAR delta turned mice into indefatigable marathon runners. In addition to their super-endurance, the altered mice were resistant to weight gain, even when fed a high-fat diet that caused obesity in ordinary mice. On top of their lean and mean physique, their response to insulin improved, lowering levels of circulating glucose. ... We wanted to know whether a drug specific for PPAR delta would have the same beneficial effects."
All of the rare accelerated aging conditions appear to be caused by one aspect of "normal" aging exaggerated and run wild to cause great biochemical damage. Researchers now think they understand what underlies another of these conditions: "Sufferers of the disease, called dyskeratosis congentia, tend to have problems in tissues in which cells multiply rapidly - skin, hair, nails, tongue, gut and bone marrow - and usually die between the ages of 16 and 50 from bone marrow failure, or the inability to replenish their blood cells. ... Each time a cell divides, the protective caps at the ends of chromosomes shorten - and when these caps are gone, so are we. Now, by using an unconventional strategy to shorten telomeres in mice, [researchers] have not only created the first faithful mouse model for studying [dyskeratosis congentia], but they have revealed the molecular defect behind the disease. ... these results suggest that in patients suffering from dyskeratosis congenita, the enzyme telomerase can't elongate telomeres as fast as the nucleases chew them away. ... Clearly, the next step is to understand how telomeres are degraded in human cells. We need to identify the nucleases at work and find out how they are regulated."
If many adult tissues and organs are continuously replenished by cells derived from stem cells, then why do they show signs of aging? One possibility is that stem cells themselves age and senesce, resulting in a decreased ability to replace worn-out progeny and/or the fact that they pass on aged phenotypes to their progeny.
Missing in this discussion until now is the effect of the cellular and molecular environment on stem cell properties, although the molecular re-programming of epithelial cells into pluripotent stem cells demonstrates the importance of the intracellular environment. Indeed, ample evidence exists showing that intrinsic and extrinsic regulators are inextricably linked in determining stem cell functional properties. Of special current interest is the extracellular stem cell environment, commonly referred to as the stem cell ‘niche’, as originally coined for hematopoietic stem cells in the bone marrow.
The paper starts with a good review of present thinking on the role of stem cells and their niches in aging. It then moves into the interest of the authors in latexin and modulation of the size of stem cell populations:
The qualitative changes in stem cells and the composition of the stem cell population with respect to qualitatively distinct subclasses is an important factor in stem cell aging. We have shown that amongst mouse strains there is a strong correlation between the rate of early hematopoietic progenitor proliferation and mouse lifespan. Moreover, we and others have observed large strain-specific differences in the maintenance of the [hematopoietic stem cell (HSC)] population during aging, thus suggesting that genetic regulation plays an important role in the way aging affects HSCs.
Using forward genetics, we recently identified a protein, latexin, whose differential expression in stem cells accounts for at least part of these differences in young murine hematopoiesis. We have showed that latexin is a negative regulator of stem cell number and acts through at least two mechanisms to modulate stem cell pool size: a) it decreases HSC cell replication and b) it increases HSC apoptosis. Therefore, in the hematopoietic system, and perhaps other organs, latexin influences aging and perhaps lifespan through its action on stem cells.
You'll recall the ongoing debate on decline in stem cell function: is it fewer stem cells, or is it that the stem cells are less active? Evidence exists to support both sides, but with all the work on age-related changes in stem cell niches over the past couple of years, things seemed to be swinging towards less active stem cells as the dominant explanation. Biology is always more complex than we'd like it to be, however, and the debate continues.
Chris Patil at Ouroboros has dropped two sets of recent research into our laps for consideration, with a focus on continuing efforts to understand the intricacies of human biochemistry as it relates to longevity and aging.
I find most of the work on insulin metabolism and insulin-like growth factor-1 (IGF-1) somewhat heavy going. It's very much down in the depths of metabolic mechanisms, for all that it's related to straightforward demonstrations of single gene longevity mutations in lower animals. It's somewhat analogous to work on calorie restriction mechanisms - in that it draws together energy from food and longevity to a mysterious biochemical middle - but perhaps more opaque because practical applications aren't as advanced at this stage.
Telomeres are more intuitive, however:
Telomeres - the structures at the end of chromosomes - have a long history in biogerontology. Telomeres shorten with every cell division, essentially providing a 'clock' that ticks down until reaching some critical length, at which point the cell will undergo the permanent growth arrest known as senescence. Even though this clock is an important tumor suppression checkpoint (because it prevents cells that have divided many times from continuing to proliferate), senescent cells themselves contribute both directly and indirectly to aging (by diminishing regenerative capacity and secreting deleterious signaling molecules, respectively). Telomere length is also a useful biomarker: it is positively correlated with life expectancy, and appears to respond to environmental influences including chronic infection and psychological stress.
One item of note in the list is that telomerase appears to have other roles beyond lengthening telomeres:
recent studies have led some investigators to suggest novel biochemical properties of telomerase in several essential cell signaling pathways without apparent involvement of its well established function in telomere maintenance. … This review will provide an update on the extracurricular activities of telomerase in apoptosis, DNA repair, stem cell function, and in the regulation of gene expression.
This is important for those groups working on telomerase-based therapies, and has implications for the viability of the proposed WILT strategy that would disable telomerase in order to eliminate cancer. As always, it's a challenge to interfere precisely in human biochemistry when every component has multiple important functions.
Scientists here demonstrate the connection between reduced dietary protein and a better immune response, already known from the practice of calorie restriction: "Manipulation of dietary variables is one the most described events to retard the aging process and maintain immune function. The present study deals with the effect of variable dietary protein-carbohydrate ratios (without caloric restriction) on the alteration of immune response of male albino rats ... These results thus suggest that diets with variable dietary protein-carbohydrate ratios act as an exogenous modulator of immune response with age and [a low protein] diet may be beneficial to slow down/reduce the impairment of immune response in aged individuals." For comparison, you might also look at studies of methionine restriction without overall calorie restriction. Greater control of diet over the years adds up, and every extra year of health gained can make a big difference when the pace of medical development is rapid.
Researchers continue to work on our understanding of the aging brain. From EurekAlert!: "During sleep, the hippocampus, a brain region important in learning and memory, repeatedly 'replays' brain activity from recent awake experiences. This replay process is believed to be important for memory consolidation. [Researchers] found reduced replay activity during sleep in old compared to young rats, and rats with the least replay activity performed the worst in tests of spatial memory. [The researchers] recorded hippocampal activity in 11 young and 11 old rats as they navigated several mazes for food rewards. Later, when the animals were asleep, the researchers recorded their hippocampal activity again. In the young animals, the sequence of neural activity recorded while the animals navigated the mazes was repeated when they slept. However, in most of the old animals, the sequence of neural activity recorded during sleep did not reflect the sequence of brain activity recorded in the maze. ... These findings suggest that some of the memory impairment experienced during aging could involve a reduction in the automatic process of experience replay."
Molecular biologist Attila Chordash recently conducted a short interview with Dave Gobel, co-founder of the Methuselah Foundation. He's been determinedly working away to make this thing a success since the beginning. You can find the interview over at Pimm. His thoughts on the Mprize for longevity research caught my eye:
You put up the money and tell competitors what they need to do. The larger the prize, the more competitors. It's like an inexpensive way of being able to put chips on every single spot on a roulette table. The best way to find a solution to unknown problems is to generate high motivation among the greatest number of thinkers/actors without too much regard to reputation of the competitors - let the best outcome win - I don’t care how they dress.
Incentives make the world go round, which is why research prizes are so effective. The prospect of money and fame are wonderful motivators, as is demonstrated in the business community each and every day. It's a pity that this obvious truth is so often forgotten when it comes to the highly regulated field of medical research and development.
So many, many people still believe that the result of longevity science will be that you are older and ever more frail for more years, with no hope of death. This is absolutely false: the goals are in fact rejuvenation of the old, repair of the biochemical damage of aging, and the extension of healthy, youthful life. But still people have the fate of Tithonus in mind, sunk into the collective consciousness through a hundred similar cautionary tales. So you'll see this sort of doleful op-ed from the Daily Mail: "To some of us, [longevity] seems a ghastly prospect. I am 62, and find life terrific. I get more work done than ever before, because my children have long ago left home and I remain fit. I take pills to keep my blood pressure down and waterworks functioning. ... It seems to some of us terrifying to imagine that we might survive to 100. Surely, the drear misery and loneliness that accompanies such age is not worth it for a birthday party, telegram from the Queen and maybe a paragraph in the local newspaper. Once mobility is gone, once the simplest actions of daily life become dependent upon others, it is hard to sustain self-respect. If science indeed continues to lengthen our lives, I believe that we shall have to be given a choice about opting out." The work of advocacy and education must continue - this is a sign that much remains to be done.
From Canada.com: "Genetic science, stem-cell research and extreme caloric restriction are all part of a burgeoning 'immortality industry' that could soon point the way to a fountain of youth with the potential to stretch the human life span to 125 or 150 years, says a sociologist and consultant on future studies. ... Advances such as nanotechnology - the emerging ability to manipulate extremely small structures - could ultimately make it possible to regenerate every cell in the body ... At that point, we can throw out every idea we have about longevity and even mortality itself. ... The effects of human life-extension will be far-reaching, [potentially] spawning second or third careers in people's extra decades and a society of lifelong students using the gift of more time to continually reinvent themselves with new education. ... The extension of human life will also depend on people's lifestyle [and] the current obesity epidemic, smoking habits and other unhealthy behaviours indicate they don't always make beneficial choices. People can be 'seduced' by breakthroughs they believe will save them from themselves ... I think there is going to be a tremendous chasm between average life expectancy and life potential."
It's a shame that the people most harmed by the existence of the FDA - and the culture of "I have power over you and you shall do as I say" that supports it - are not up in arms. The most vocal opponents of the FDA over the past decade or so are probably folk in the supplement industry. They, despite the threat of jail, losses, and other indignities for doing no more than providing a desired and responsible commercial service, are by no means the most harmed. No, the most harmed are the dying, and we are all counted in that group while the FDA continues in its position that potential longevity therapies will not be approved. No approval means no funds for development, and hence little evidence to show in support of radical change.
The cancer patients, the Alzheimer's sufferers, and all those with other named medical conditions suffer as well: the FDA and associated regulatory bodies form a huge ball and chain that slows progress in science to a fraction of what it might be. When medical development costs much more due to regulation, you will see fewer new medicines. When government employees have greater incentive to deny than approve, you will see fewer new medicines. This is exactly what happens, and the cost is measured in lives.
Back to the supplement industry. One of their voices can be found at the Consumers Against High Drug Prices site, an earnest place that nonetheless seems to me to be missing the real point of the exercise. But it is a supplement industry effort, and that narrows their focus to bottles and herbs - the here and now, rather than what could be, and what might have been in medical research. They would like to largely dismantle the FDA in their neck of the woods - but that sort of renegotiation of the contract with government employees never really works. When was the last time you recall government employees giving up the option to interfere in a given area of commerce? That option to interfere - and cause destruction and mayhem - is how politicians maintain their influence. It's the rule of the sword for a modern age.
You have to keep the incentives in mind. Politicians and government employees have no incentive to play nice and leave you be, no matter what the paper says. So they won't. Trying to redirect or reclassify the power held by others to your benefit is a form of self-delusion: once you're set on that course, the politicians already own your mind. It's a shell game, slightly more complicated and obscure than the voting shell game, but really no different in essence. The only solution to government abuse of power is the absence of that power.
Centralization of power - the state and regulation, in other words - is a form of age-related damage for human societies. It accumulates, piling ever deeper and broader, and leads to degeneration and disease. Look no further than the Soviet Union for an example of where it all leads in the end, but the place we are now is a far cry from the best of all worlds. If you have an interest in a long, healthy life, then you should also have an interest in why modern democracies are greatly slowing progress to that end.
Another Aging 2008 transcript from Future Current: "I have been entranced by the immortality of the species and how it's accomplished. A simple way of putting it: we are made of cells, trillions of them, that have been proliferating backward in time all the way through hundreds of millions of years to the beginning of life on the planet, leaving no dead ancestors in their wake ever - or we would not be here. It is our somatic cells that are destined to die. All the cells in our body have this immortal legacy going backward in time millions of years and will face death for the first time ever in our lifetime. What can we learn about the immortality of the species to transport those observations and discoveries of modern technologies into something that will really do something about human aging? ... How could these cells be used in the next ten years? There are numerous examples I could give you, but one hopeful one - macular degeneration. This is the leading cause of blindness, due to the aging of our retina. These cells have now been made in a form that is appropriate to begin human clinical trials. ... When they become lost or dysfunctional in the back of the retina, they cause this cascade of pathology that is a leading cause of blindness in the elderly. ... It is at least one of the top targets for how we hope these cells will eventually be used in medicine."
From Depressed Metabolism: "The limitation that cryonics procedures can only be started after pronouncement of legal death reflects the unfortunate fact that the current medical establishment does not recognize cryonics as a credible form of advanced critical care. As a result, cryonics is currently practiced as a form of emergency medicine in which conventional resuscitation technologies such as chest compressions and ventilations are used to avoid the kinds of injury that follow after cardiac arrest. Although there will always be a place for cryonics as a form of emergency medicine to treat cases of trauma and sudden circulatory arrest, most patients who currently present for human cryopreservation would benefit from more hospital cooperation in choosing cryonics as an elective medical procedure. Although current cryonics organizations such as Alcor try to make the best of a bad situation by employing standby teams that allow rapid intervention after cardiac arrest to reduce brain injury, much improved quality of care of cryonics patients would be possible if cryonics procedures would start at a point where medical professionals (with informed consent of the patient and/or family) would determine that further treatment of the patient with contemporary technologies would be futile, or even counter-productive."
The brain is a singular organ - our selves are defined by its structure. The aging brain can't be replaced by the same near-future tissue engineering techniques that will give us new hearts and other organs grown fresh from our own stem cells. Thus we are going to have to become very good at repairing the brain in situ, cell by cell, aggregate by aggregate.
One of the biotechnologies needed to achieve this goal is mature regenerative medicine, specifically the ability to manipulate and reprogram stem cells within the brain. Those stem cells must first be found and categorized, and progress continues on that front:
Evidence strongly shows that the true stem cells in the mammalian brain are the ependymal cells that line the ventricles in the brain and spinal cord, rather than cells in the subventricular zone as biologists previously believed. Brain ventricles are hollow chambers filled with fluid that supports brain tissue, and a layer of ependymal cells lines these ventricles.
Knowing the cell source is crucial when developing stem cell-based therapies. Additionally, knowing that these normally dormant cells can be coaxed into dividing lays the groundwork for future therapies in which a patient's own stem cells produce new brain cells to treat neurological disorders and injuries such as Parkinson's disease, stroke or traumatic brain injury.
"With such a therapy, we would know which cells in the body to target for activation, and their offspring would have all the properties necessary to replace damaged or missing cells," said Darius Gleason, lead author of the study and a graduate student in the Department of Developmental and Cell Biology. "It is a very promising approach to stem cell therapy."
Replacing cells is only one part of repairing an age-damaged brain, however. You might take a look at the Strategies for Engineered Negligible Senescence to see the many other issues that accumulate in brain tissue over the course of a lifetime. A lot of work lies ahead.
It's good to see more research groups looking into targeting antioxidants to the mitochondria. From EurekAlert!: "Researchers have taken a first snapshot of how a class of highly reactive molecules inflicts cellular damage as part of aging, heart disease, stroke, cancer, diabetes, kidney disease and Alzheimer's disease to name a few. ... researchers have discovered a tool that can monitor related damage and determine the degree to which antioxidant drugs effectively combat disease. ... Our study provides a better glimpse of why a cell under assault by disease makes 10 times as many reactive oxygen species [ROS] as the same cell when healthy. We have discovered a chemical tool for investigating how diseases cause damage, mitochondrion by mitochondrion ... Efforts to develop antioxidant drugs (e.g. vitamin E) to treat diseases of increased oxidative stress have met with limited success to date because they tried to eliminate ROS, rather than maintain the right amount, Sheu said. He established the Mitochondrial Research & Innovation Group (MRIG) [in] 2002 with the goal of designing therapies to deliver precise amounts of antioxidants to the mitochondria of diseased cells only. MRIG teams are, for example, screening through compounds to confirm that oxidative stress can be reversed by mitochondria-specific drugs."
I can't say I'm sold on recent research that is interpreted as supporting (genetically) programmed aging: "The question of what causes aging has spawned competing schools of thought. One side says inborn genetic programs make organisms grow old. This theory has had trouble gaining traction because it implies that aging evolved, that natural selection pushed older organisms down a path of deterioration. However, natural selection works by favoring genes that help organisms produce lots of offspring. After reproduction ends, genes are beyond natural selection's reach, so scientists argued that aging couldn’t be genetically programmed. The alternate theory holds that aging is an inevitable consequence of accumulated wear and tear: Toxins, free-radical molecules, DNA-damaging radiation, disease and stress ravage the body to the point it can't rebound. So far, this theory has dominated aging research. But the Stanford team's findings told a different story. ... Our data just didn't fit the current model of damage accumulation, and so we had to consider the alternative model of developmental drift." The article oversimplifies both positions, sadly, and the researchers don't appear aware of recent evolutionary explanations for extreme longevity in some animal species.
An interesting post over at In Search of Enlightenment:
Firstly, support for legitimate longevity science is hampered by the vast number of products currently being sold as "anti-aging" therapies without any science to substantiate their claims. See here, for example. And thus one has to be very careful when convincing people that (1) aging is something that ought to be retarded (as it increases our risks of morbidity and mortality); and yet at the same time convince them that (2) we might actually be able to slow human aging and yet (3) none of the current products being sold on the market have been demonstrated to do this (indeed, they might be harmful). The latter point is emphasized, for example, in this excellent piece in the Scientific American by Jay Olshansky, Leonard Hayflick and Bruce A. Carnes.
Now if one is pressing (as indeed I am) (1) and (2), it is of course understandable that people will be want to do something about aging (and thus be tempted to violate (3)). But when asked "So what can I do to slow aging?" my response is "(a) support increasing the amount of public funding we invest in the biology of aging and (b) encourage linkages between different fields of research-- from genetics and evolutionary biology to engineering and statistics". Well, as you can imagine, many people will find that answer rather flat! They want the solution and they want it now (today)! The same is true about climate change. Few people have an interest in being told the best solution is investing in new R&D and might be long-term. Patience never was a human virtue.
There's more in that vein, so take a look. I'm not in the "slow aging by massive government funding of the same community that's strongly resisted progress to date" clade, but the excerpt above is a fair summary of the immediacy problem - that once you've convinced people to think about healthy life extension on the merits, the natural result is a lot of waste and noise in addition to helpful additions to the community. That's the way that humans tend to act; we're given to look for the backsliding easy way out, even when we know it's not going to work. For every person who donates to the Methuselah Foundation's longevity research program, there will be another who decides to look into a new wrinkle cream.
You can lose a lot of sleep over things like this, but I think we advocates are better for accepting that other peoples' choices are not our responsibility. Everyone has free will; our task is to make better information available and persuade those who can be persuaded to help advance the state of longevity science. However well we do, there will continue to be a dubious "anti-aging" snake-oil industry and some number of people making poor choices.
To be filed under "interesting, but not necessarily relevant": "This paper reviews the literature on the effects of hypergravity (HG, gravity levels higher than 1g, the terrestrial gravity) on longevity and aging. The different studies showed that life-long exposures to high gravity levels decreased longevity and accelerated the age-related decline observed on some physiological and behavioral variables. In contrast, chronic exposure to HG increased resistance to heat in young and middle-aged Drosophila melanogaster. A short exposure to HG at the beginning of adult life increased male longevity and delayed behavioral aging in D. melanogaster. All these results show that HG acts as a hormetic factor. Long exposures to HG have deleterious effects on longevity and aging, whereas short exposures have beneficial effects. Some potential mechanisms of action of the beneficial effects of HG are also reviewed here. However, the ones tested so far (heat shock proteins and antioxidant defense) have proven unable to explain the hormetic effects of HG and their mechanisms of action are still unknown."
A nice overview of hormesis: "Aging is characterized by a stochastic accumulation of molecular damage, progressive failure of maintenance and repair, and consequent onset of age-related diseases. Applying hormesis in aging research and therapy is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress. In a series of experimental studies we have shown that repetitive mild heat stress has anti-aging hormetic effects on growth and various other cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects include the maintenance of stress protein profiles, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to ethanol, hydrogenperoxide and ultraviolet-B rays, and enhanced levels of various antioxidant enzymes. Anti-aging hormetic effects of mild heat shock appear to be facilitated by reducing protein damage and protein aggregation by activating internal antioxidant, repair and degradation processes."
I notice that Alcor is hiring: "On June 7th and 8th, 2008, the Alcor board and management held a 2-day strategic planning meeting at the Alcor facility in Scottsdale, Arizona. At that meeting a funding offer brought forward by board member Saul Kent was accepted by the Alcor Board after considerable discussion. The funding offer was made by three donors [who] will each contribute $150,000 a year to Alcor for three years, totaling $1,350,000. The funding provides for searches and three years of salary support for a CEO and a Transport Coordinator, who will be responsible for the early stages of the cryopreservation of Alcor patients. ... The practice of cryonics is controversial because today's methods of cryopreservation cannot be reversed by today's technology and because today's laws require that patients be cryopreserved after they are legally 'dead.' As a result, Alcor has to deal with and counter skepticism at times. The CEO should have the knowledge and presence to deal effectively with negative attitudes towards Alcor and the practice of cryonics. ... Alcor offers a competitive salary and comprehensive benefits package. Employees must reside in the greater Phoenix area, or be willing to relocate to Phoenix."
From FutureBlogger: "I believe that science and technology will make extreme life extension possible for most of us alive today. ... Some argue that humans living longer will cause overpopulation problems ... Some assume that people will continue to exhibit signs of aging and be decrepit into their hundreds ... Some say that scientific conquest of death would not be satisfying. We would be incomplete; we would lack wisdom ... In conclusion: Most arguments against extreme life extension are based on the [preconceived] idea that it can never happen, or that it shouldn't happen. As science and technology advances, these arguments are waning. Life extension is not new [for] humans; look at our past: from avoiding predators to developing antibiotics, we have always sought to extend our lives. Today's technologies simply expand this scope - live long and stay healthy - this is a worthy goal for all of us."
If you're the type who likes to inspect the mechanisms behind the sausage, you should take a look at an article on Alcor's board over at Depressed Metabolism:
In January 2008, Alcor’s self perpetuating Board came under renewed scrutiny after long-time Alcor member and cryonics activist David Pizer tried to raise interest for changing the current system to a member elected Board.
Scrutiny of the board is a fine tradition for stakeholders in for-profit and non-profit initiatives, as is stakeholder activism to produce desired change. The concern voiced in the article is that born of the perceived need for change at Alcor - to better produce growth, increased professionalism, and so forth - and the concern that a self-perpetuating board has little incentive to make the changes that the writer would like to see happen.
Member-voted boards have their own issues, of course, not least that a member (as opposed to stakeholder) has no meaningful ownership right connected to their vote - but the pendulum swings as it chooses.
This is all, I think, I fairly good illustration of the transitionary period from volunteerism to professionalism one sees in any growing industry. The cryonics industry has been going through this phase for a long time, and remaining very small in size, for reasons that are much debated. Is it the fault of the business model, incredulous public perception, heavy regulation, a comparatively undiversified technology base, or the laundry list of other potential factors? Can be solved by changing the way people pay, by changes in regulatory structures, or by increased investment in research and building spin-off technology businesses? And so forth. These are all questions that have been debated at length over the years.
What I think is most telling with regard to where the cryonics industry is at present is that you don't see a lot of discussion focused on change through competition. The traditional solution to undesirable characteristics within an industry is for entrepreneurs to set forth and compete, as "undesirable" usually means "customers will pay for something less undesirable." If you want change, then help to found a new company and do things the "right" way. Ongoing for-profit experiments in any number of different "right" ways are how progress is achieved and benefit brought to customers in the long term.
There needs to be more of that in the cryonics industry if the goal is directed change. The best way to make a board change their stripes is to look like you're going to eat their lunch out from under them; by doing that, you will also have gone a long way towards proving that your "right" way is in fact the right way for progress.
Ouroboros looks at the humble yeast in context: "Our understanding of aging in animals owes a great debt to a large body of careful work in a single-celled organism, the brewer's yeast Saccharomyces cerevisiae. Indeed, as I've argued before, yeast is one of the two organisms with the strongest credible claim to have started modern biogerontology. An unusually large crop of yeast aging papers have appeared over the last few months, and I thought it would be appropriate to spend a few paragraphs describing them - in honor of this humble organism that rises our bread, ferments our beer, and has done so much to open our eyes to the fundamental mechanisms of aging. ... yeast mutants in worm longevity genes are significantly more likely to be long-lived than randomly chosen mutants - suggesting [that] genes that modulate aging have been conserved not only in sequence, but also in function, over a billion years of evolution. ... Given this functional conservation, it is reasonable to use yeast to help answer questions about aging in general, so long as these questions as cell-biological in scope."
The New York Times looks at Sirtris Pharmaceuticals: "The hope is that activating sirtuins in people would, like a calorically restricted diet in mice, avert degenerative diseases of aging like diabetes, heart disease, cancer and Alzheimer's. There is no Food and Drug Administration category for longevity drugs, so if the company is to submit a drug for approval, it needs to be for a specific disease. Nonetheless, longevity is what has motivated the researchers and what makes the drugs potentially so appealing. Dr. Christoph Westphal, the chief executive of Sirtris, said of the potential of the drugs, 'I think that if we are right, this could extend life span by 5 or 10 percent.' He added that his goal was to develop drugs against specific diseases, with the extension of life being 'almost a side effect of our medicine.'" There you have the most serious problem facing longevity science today: that its direct application is not permitted by the FDA. Until this changes no serious investment will be made in the US to bring longevity science to the clinic. This is a tragedy of so great a scale as to beggar belief.
You might recall that the chemical alpha-synuclein is an aggregate that appears to be a proximate cause of Parkinson's disease (and like many biochemical aggregates, its buildup is slowed by the practice of calorie restriction). Researchers are delving deeper into the chain of mechanisms:
Patients with Parkinson's disease (PD) have elevated levels of the protein called alpha-synuclein in their brains. As the protein clumps, or aggregates, the resulting toxicity causes the death of neurons that produce the brain chemical dopamine. Consequently, nerves and muscles that control movement and coordination are destroyed.
The researchers discovered that the activity of three genes that control the synthesis of heme, the major component of hemoglobin that allows red blood cells to carry oxygen, precisely matched the activity of the alpha-synuclein gene, suggesting a common switch controlling both.
The scientists then found that a protein called GATA-1, which turns on the blood-related genes, was also a major switch for alpha-synuclein expression, and that it induced a significant increase in alpha-synuclein protein. Finally, they demonstrated that a related protein -- GATA-2 -- was expressed in PD-vulnerable brain cells and directly controlled alpha-synuclein production.
Researchers are taking a similar tack to that of mainstream Alzheimer's research now that a greater understanding of alpha-synuclein exists. Get rid of the aggregate, in other words:
"Simply lowering alpha-synuclein levels by 40 percent may be enough to treat some forms of Parkinson's disease," says Dr. Clemens Scherzer of Harvard. "So far, researchers have focused on ways to get rid of too much 'bad' alpha-synuclein in Parkinson patients' brains. Now we will be able to tackle the problem from the production site, and search for new therapies that lower alpha-synuclein production up front."
The studies showed that GATA-1 and GATA-2 proteins find the alpha-synuclein gene, stick to it and then directly control it.
"This is not an indirect pathway; it is direct regulation of the gene," says Bresnick. "This directness provides the simplest scenario for creating a therapeutic strategy."
The problem with influencing the production side is, of course, that everything in our biochemistry has many different roles. It's next to impossible to alter any gene or mechanism without causing unwanted side-effects. This is a strong incentive to focus primarily on cleaning up aggregates rather than re-engineering our metabolism, if those are the only two options on the table. Further options will hopefully emerge as researchers progress towards an understanding of why these mechanisms change with age. What form of known age-related biochemical damage is causing changes in GATA regulation - and thus alpha-synuclein levels - and how is it doing that?
How does one determine whether or not an advocacy website is actually working? A firm conviction that benefits are created is all well and good, but that won't get you very far in circles where resources are allocated on performance. The objectives of Fight Aging! are laid out in one of my annual signs of incredulity that I've been doing this for yet another year:
I have sought to bring those who stop by, or who otherwise stumble upon my writings, around to a more productive way of looking at aging, longevity, science and human action.
Sometimes our conversation is hard to find, however. People who might have learned and contributed do not do so; opportunities to broaden the healthy life extension community are lost. ... someone has to be talking on topic to keep the conversation growing, to avoid lapses in which newcomers might miss the party.
A nicely nebulous set of goals upon which to pin metrics. We can look at web statistics (one step beyond damned lies), participation in the healthy life extension community, funds raised for specific goals ... but it's a real challenge to determine what contribution my efforts made to a dynamic community or process of many contributers. Never mind how it could have all be accomplished more effectively or efficiently.
Those of you with longer memories will recall that sometimes people turn up out of the blue, lay down a seven-figure check, and say "yup, it was because of this advocacy initiative that I chose to donate." But it's rare - you can't base an analysis of success on huge checks from the blue. If you have enough of those to start counting, you've already won.
That particular seven-figure check justifies Fight Aging! for a good few more years yet, but vindication isn't really the purpose of metrics. Good advocates are one step removed from fanatics - they'll keep at it until the rest of the world gives in and admits the advocate was right all along. Metrics are about improvement: how can you do better with the resources to hand.
The online metric of first resort is web statistics, the damned lies mentioned above. I'm not all that sure that anything of worth can be derived from web statistics with respect to the goals of Fight Aging!. It's not even clear that more links, more traffic, or more aggregation are necessarily better - this is where those folk who are simply interested in monetizing websites have a much easier time of it. At the end of the day they can look at the dollars and rate of conversions to sale. Meanwhile I ponder the nature of my most popular page for this past year and wonder what most of my page views actually represent.
For Fight Aging!, a "conversion to sale" might be someone who sets off to become a molecular biologist or organize a fundraising conference for the Methuselah Foundation. I might be able to claim partial credit for one or two of those. At the less radical end of the scale, you'll find people who donate to fund SENS longevity research, or discuss healthy life extension with a friend where they might otherwise not have done. You get the idea - and I have no idea as to how well I'm doing there. Realistically, I'm never likely to know. Contributing to the new zeitgeist is not an activity for those who need personal validation, nor those who enjoy a nice, clean balance sheet of expenditure versus result.
So: I'm fairly convinced my work produces a continuing net positive influence, but proving that to anyone's satisfaction - beyond the generous million-dollar donor - is quite another story. In terms of improvement for the future, I'm left with the same old unsatisfactory metric of bulk visits and mailing list membership; I must assume that more is merrier until conclusively proven wrong on that front.
An interesting LiveJournal post: "A person immune to the ravages of old age would still not be immune to death; accident, violence, and other misadventure is perfectly capable of ending even a 25-year-old's life. It simply means that person no longer has a cap on the maximum time he can live, if he so chooses. And that's really what it's all about. Choice. ... If you go into the doctor's office, and he tells you that you have a bacterial infection, which will slowly grow progressively worse until it kills you painfully, then offers you an antibiotic pill that will completely eradicate the infection, I bet you'll take it. Even if you don't fancy the thought of living forever. There's an important point in that. Even folks who don't much want to live forever still probably don't want to die today. Or tomorrow. Someday, perhaps, if that 'someday' is held in the abstract; some future time when things no longer seem interesting. But not today. And that's the point. A solution for aging puts the power to choose in your hands. Old age forces your hand; you don't get the choice to see your grandkids graduate from school, or to celebrate your fiftieth anniversary...the choice is made for you. And I don't see how that benefits anyone."
Researchers continue to work at the blood vessel problem in tissue engineering. From the BBC: "Scientists have used human cells to grow new blood vessels in a mouse for the first time ... The ability to develop swiftly a new network of tiny blood vessels - known as capillaries - would be a prize for scientists. There are dozens of potential applications in medicine, particularly in the treatment of conditions which involve damage to a tissue's blood supply, such as that to the heart muscle following a heart attack. However, the complex structure of these vessels has slowed progress. ... What's really significant about our study is that we are using human cells that can be obtained from blood or bone marrow rather than removing and using fully developed blood vessels. ... It could certainly assist in the connection of other engineered organs to the body's blood supply. Although this approach is not yet suitable for clinical use, it is interesting that they have demonstrated you have all the elements you need to create a functional network of capillaries from a small amount of blood."
Jeriska continues the good work at Future Current, here posting a transcript of Gregory Stock's presentation at Aging 2008 last month:
Dealing with aging and death has always been a challenge. People have different ways of handling it. I see it in four categories: One is to just ignore it. This is pretty easy for awhile - you can just pretend it isn’t happening, particularly when you are young and when the manifestations of aging are not really apparent at all.
Another is, you deny it. "Death is not really real, because our soul will live eternally." Or, we will live eternally through our creations - those sorts of things. A lot of people like to feel that; it makes them feel better about the situation. Another is just to accept it. That is a common practice too, to say it is inevitable, natural, even the best thing. Leon Kass, for example, has said it is life’s finitude that gives it its meaning - as though young people who do not think about their mortality don’t enjoy life.
The final approach is to battle it. This was the strategy of Ponce de Leon, who was wandering around in the jungles of Florida. It could be Aubrey de Grey, too, who is trying to catalyze a serious effort to control the aging process. What is different now, though, is that suddenly, for the first time ever, it is actually quite plausible. As you heard from the comments of earlier speakers, we might actually be able to accomplish that.
What is interesting is that this is not the goal of biogerontology today. Its goal is not to control aging, or extend our natural lifespan, but to somehow compress morbidity, so that we can be healthier for a longer period of time and then fade away quickly. Initially that sounds reasonable, but at its logical conclusion, it really is completely out of sync with our aspirations.
As I've said elsewhere, the most important cultural battle of our time is that which started inside the gerontological community. It is the fight to build a research community whose members eagerly and vocally work to achieve what is possible with the future of biotechnology: the repair of aging and defeat of age-related degeneration.
At present that community is in only its earliest stages. The rest of the field is still mired in the views of yesterday, a place where no-one can talk about healthy life extension for fear of ridicule and loss of funding opportunities. Societies have a way of working themselves into a conservatism that holds back progress. This is slowly changing, but that change must continue and accelerate if we are to see significant progress within our lifetime.
As an addendum to prior discussions of the plasma membrane theory of longevity and related metabolic rate correlations: "Metabolism is a defining feature of all living organisms, with the metabolic process resulting in the production of free radicals that can cause permanent damage to DNA and other molecules. Surprisingly, birds, bats and other organisms with high metabolic rates have some of the slowest rates of senescence begging the question whether species with high metabolic rates also have evolved mechanisms to cope with damage induced by metabolism. To test whether species with the highest metabolic rates also lived the longest I determined the relationship between relative longevity (maximum lifespan), after adjusting for annual adult survival rate, body mass and sampling effort, and mass-specific field metabolic rate (FMR) in 35 species of birds. There was a strongly positive relationship between relative longevity and FMR, consistent with the hypothesis. This conclusion was robust to statistical control for effects of potentially confounding variables such as age at first reproduction, latitude and migration distance, and similarity in phenotype among species because of common phylogenetic descent. Therefore, species of birds with high metabolic rates senesce more slowly than species with low metabolic rates."
Researchers have demonstrated an Alzheimer's therapy that removes amyloid plaque, but that doesn't halt or reverse neurodegeneration: "The theory was that dementia could be slowed or reversed once the plaques were cleared, and experiments in animals have shown that removing these plaques improves brain function. ... long-term follow-up of Alzheimer's patients treated with [the therapy] did show, 'a reduction in the number of plaques in the brains of patients -- in some cases there was a virtually complete removal of plaques. Crucially, there was no evidence that the patients benefited by the removal of plaques and even those subjects with virtually complete removal continued to deteriorate and had severe end-stage dementia prior to their death.' ... [researchers now believe] that removing plaques - at least by this method - is unlikely to make a significant difference to the clinical outcome of patients with established Alzheimer's disease ... it strongly suggests that plaques are not sufficient on their own to account for disease progression."
There are a lot of people who believe in the technical feasibility of cryonics and intend to make cryonics arrangements ... when necessary. As cryonics observers know, this is an extremely risky attitude because when people need cryonics the most, they often are unable to communicate their wishes, may meet resistance from relatives who benefit from their not making cryonics arrangements, or lack financial resources because life insurance is no longer an option to fund cryonics.
The best time to make cryonics arrangements is when it seems least likely that you need them soon.
Which is true of all preparation. As de Wolf also points out, cryonics - in the pleasant future in which for-profit cryopreservation concerns are established with solid business models and a sizeable presence - will remain an important critical care option even in the era in which science has conquered aging. Having rapid access to cryosuspension in the event of traumatic accident will be an important item of preparation for ageless individuals.
Many bridges remain to be crossed to reach that stage, not least in the expansion of the cryonics industry to a form in which greater growth and sustainability are ensured. For the moment, it's important to remember that thinking positively about cryonics isn't enough to ensure your cryosuspension. Some effort in preparation is required to ensure that you have the best possible chance of taking advantage of this alternative to the grave and oblivion.
For all the obvious reasons, actuaries would love to be able to predict human longevity with accuracy. But is that possible with present or near-future tools, even setting aside considerations of rapid progress in biotechnologies of rejuvenation? Researcher Leonid Gavrilov here excerpts some of a recent paper on that subject: "Who has a better chance to become a centenarian - a taller or a shorter person? Is it better to be slender or stout? We know that most centenarians are both short and slender in their body build, but these measurements made at older ages could be misleading because they might only reflect body shrinkage as a result of aging. We were also intrigued by other possible predictors of long life. Is it better to be a farmer or an actuary in order to survive to 100? Does the number of children a person has affect their chances to celebrate their 100th birthday? Is it better to have dark eyes or light eyes? All these personal characteristics could be useful for actuaries if a strong association between them and exceptional longevity were to be established."
The MIT Technology Review looks at continued attempts to understand the degree to which present healthy human longevity is influenced by genes: "An ambitious plan to sequence 100 genes in 1,000 healthy old people could shed light on genetic variations that insulate some people from the ailments of aging, including heart disease, cancer, and diabetes, allowing them to live a healthy life into their eighties and beyond. Rather than focusing on genetic variations that increase risk for disease, scientists plan to focus on genes that have previously been linked to health and longevity. ... advances in genetic screening technologies have allowed scientists to start searching the genome for clues to healthy aging and a lengthy life span. That work has revealed that the genomes of healthy old people are not blemish free. ... These people have genetic susceptibility markers for many serious diseases [but] they don't get any of these diseases. What is the explanation? What might account for their insulation from these diseases?" Genes are not fate - evidence to date suggests that lifestyle choices have much more weight for all but the most genetically unlucky, and those choices are reflected in epigenetic variations, not genetic variations.
The MIT Technology Review looks at a promising strategy in tissue engineering: "Tissue engineers are ambitious. If they had their way, a dialysis patient could receive a new kidney made in the lab from his own cells, instead of waiting for a donor organ that his immune system might reject. Likewise, a diabetic could, with grafts of lab-made pancreatic tissue, be given the ability to make insulin again. But tissue engineering has stalled in part because bioengineers haven't been able to replicate the structural complexity of human tissues. Now researchers have taken an important first step toward building complex tissues from the bottom up by creating what they call living Legos. These building blocks, biofriendly gels of various shapes studded with cells, can self-assemble into complex structures resembling those found in tissues. ... This will be an effective way to put the cells where we want them to be. You can probably generate a tissue with a higher complexity [using] the new method than is possible with a scaffold that has to be seeded with cells." Compare and contrast with the use of whole-organ cell matrix templates, another recent development aimed at solving the same problem.
Chronic stress correlates with shorter telomeres, as well as with worse health. Via EurekAlert! researchers are proposing a mechanism by which telomere length is reduced by stress, leading to a worse immune response: "Short telomeres are linked to a range of human diseases, including HIV, osteoporosis, heart disease and aging. ... an enzyme [called telomerase] keeps immune cells young by preserving their telomere length and ability to continue dividing. ... the stress hormone cortisol suppresses immune cells' ability to activate their telomerase. This may explain why the cells of persons under chronic stress have shorter telomeres. ... When the body is under stress, it boosts production of cortisol to support a 'fight or flight' response. If the hormone remains elevated in the bloodstream for long periods of time, though, it wears down the immune system. We are testing therapeutic ways of enhancing telomerase levels to help the immune system ward off cortisol's effect. If we're successful, one day a pill may exist to strengthen the immune system's ability to weather chronic emotional stress."
The ability of immune system cells to identify and kill cells of a particular type of cancer varies enormously from person to person, even with medical interventions designed to point the immune system in the right direction. This is demonstrated in the variability of some forms of cancer vaccine:
When a tumor is surgically removed, proteins are collected, cultured and introduced in a Petri dish to dendritic cells taken from the patient's blood. The new, "educated" dendritic cells are then injected into the patient where they are intended to recognize and destroy lingering tumor cells. Patients receive three vaccinations at two-week intervals. A fourth vaccination is given six weeks after the third.
This study centered on the immune responses of 32 patients enrolled in a Phase II clinical trial. Seventeen patients had a significant positive response after three vaccinations; 15 showed no such responsiveness.
Forty-one percent of vaccine responders, compared to seven percent of non-responders, survived at least two years.
It is this variability that led to the work of Zheng Cui in transferring cancer fighting immune cells between mice, which you might recall from past SENS conferences:
the simple transfusion of the cancer-fighting immune cells from the resistant mice effectively transfered the same remarkable protection to the normal mice. And even more excitingly, the treatment didn't just prevent cancers from forming, but actually fought off existing cancer: when researchers transfused the anti-cancer white blood cells into normal mice with existing skin tumors, the tumors regressed completely in a matter of weeks. Moreover, a single dose of the cancer-fighting immune cells gave the normal animals a cancer immunity that often lasted for the rest of their lives.
A recent article looks at Cui's work and attitudes towards getting the job done - if you have something that demonstrably works, getting it to the clinic should run in parallel with figuring out how it works. That's a tough sell these days, however, yet another consequence of rabid over-regulation of medical research and development.
First, we had cancer-resistant mice and asked, 'What can we learn from it?' The reason it’s resistant is because it has very different white cells. So then that immediately prompted the concept of therapy, because you can easily transfer white cells. You can extract them as a therapeutic agent and give them to another mouse. It’s a therapy. It’s much better than to find the gene. If you find the gene, then you have to understand the mechanism, and you have to find a way to put the gene into the cell, into all the cells you want to, and that would not work very easily. The technology as we speak right now is not really mature for that area. You might have to wait another 10, 20 years before that technology catches up with the concept. However, what we found is a cell as a therapeutic agent, so why not go ahead and see how it works. It worked really well in mice, so the next question, very obviously, is can we find a similar cancer resistance for humans as a donor for a therapeutic agent. And the answer is yes, we did find quite a few of them
A lot of people don’t like this because they said I have not a single idea of how it works. And I said, "Why should I?" If I can already go into therapy, why should I spend so much time now to find out how it works? That dispute was with the establishment, that’s why this trial has not been funded.
Here's another Future Current transcript of biomedical gerontologist Aubrey de Grey at Aging 2008: "Aging is bad for you. It is a degenerative condition, and thus a theoretical target of regenerative medicine. What I have come here today to tell you, and what my scientific colleagues will be telling you over the next hour or so, is that it is no longer simply a theoretical target of regenerative medicine. It is on its way to becoming a practical one. Why is that? Really it comes down to this definition of aging that I have written down. This is something that gerontologists and people who study the biology of aging have known for a very long time, but it has not always been stated quite so explicitly. Aging is very definitely a side effect of being alive in the first place. You accumulate various types of damage, just in the same way that a simple man-made machine like a car will accumulate damage as a side effect of its normal operation. Again, just like man-made machines, the human body can tolerate that damage with more or less no loss of function or performance for a very long time. The damage only starts to really matter when it reaches a threshold of abundance that is prejudicial to the optimal performance of metabolism."
A Future Current transcript of one of Aubrey de Grey's presentations at Aging 2008: "Some people say, 'I don't want to live to a thousand.' I don't want to live to a thousand, necessarily. I don't even know if I want to live to a hundred. But I do know I want to make that choice when I am 99, rather than having it gradually removed from me by declining health. This is what it comes down to. The extension of lifespan by the defeat of aging is not the point - at least it is not the main point for me, and I do not think it is the main point for most people who are engaged in this crusade. The purpose is to alleviate the suffering that goes with getting decrepit, frail and dependent. Of course, this includes not just those who are suffering that, but the suffering of their loved ones. The extension of average lifespan is essentially a side benefit. It is something that will happen because the way that we are going to do this, using regenerative medicine, will also mean that you have only the same probability you did when you were a young adult of dying peacefully in your sleep without any of these diseases. In other words, a very low probability indeed. You will indeed on average live a great deal longer, and I don't think you’ll complain if you do. However, that is not the purpose. The purpose is to alleviate suffering."
Via Marginal Revolution:
If [cryonics] works, the benefits are high, and the probability of it working is greater than zero. Yet few people sign up for it. I think that we are afraid of looking weird if we sign up for it.
The way to think about how and why people make decisions is to look at costs and benefits - which go far beyond mere money, of course. The discussion in the post revolves around "looking weird" as a cost. That's important for we folk descended from apes, possessed of a deep-seated and hardwired need for peer validation. Other costs exist, such as the need to get up and sort out paperwork - people die and become sick in many ways through similar laziness, especially in health matters stretched across the years. I think the comments to the post demonstrate that the more important costs are the perceived financial ones, however.
I suspect the eccentric childless millionaire demographic is overrepresented. Who else can afford it?
People look at the pay-at-the-door cost of cryonic suspension and decide they can't afford it, that cryonics is only for the rich. That is very much not the case, however. Next to no-one pays for their suspension in a lump sum at the door. Instead it's done via assignment of a life insurance policy for a very small number of dollars per month. There have been very few cryosuspensions of extremely wealthy people.
This suggests to me that if cryonics organizations want to grow, they should stop outsourcing organization of payment. Cryonics should be marketed from the very first touch to the potential customer as an insurance service you pay for monthly: people understand that, and do it all the time. What you are buying is cryosuspension should you be unfortunate enough to die, and the cryonics company handles the mechanisms of insurance - or however else the finances are sorted out - behind the scenes.
Monthly income for a company also allows for the sort of growth and professionalization that has been a challenge in the cryonics industry under the present model of funding for research and development. All in all, a potential win-win situation. One might ask why it hasn't been tried yet.
Biology is always more complex than first appears. I noticed a good example a few days ago, and have been mulling over what to say about it. You may have noticed that research into the biochemistry of progerias - accelerated aging conditions - has been picking up in recent years. The same is true of research into the mechanisms of calorie restriction, such as the importance of enhanced autophagy to health benefits conferred by the practice of calorie restriction. Progress has been made on both fronts, with the possibility of beneficial medical advances in longevity science resulting in the future. Much remains to be understood, however.
It is widely-assumed that the autophagic activity of living cells decreases with age and probably contributes to the accumulation of damaged macromolecules and organelles during aging. Over the last few years, the study of segmental progeroid syndromes in which certain aspects of aging are manifested precociously or in exacerbated form, has increased our knowledge of the molecular basis of aging. We have recently reported the unexpected finding that distinct progeroid murine models exhibit an extensive basal activation of autophagy instead of the characteristic decline in this process occurring during normal aging.
Further studies on Zmpste24-null progeroid mice, which are a reliable model of human Hutchinson-Gilford progeria, have revealed that the observed autophagic increase is associated with a series of metabolic alterations resembling those occurring under calorie restriction or in other situations reported to prolong lifespan.
So, what does this mean? That we've reached the point in the capabilities of biotechnology at which there is little more to be learned about "normal" aging from progerias? That progeroid mice eat less? That the stress effects of progeria upon cells trigger the same sort of response as the stress of calorie restriction?
Of such challenging questions is fundamental research made.
I've seen a lot of nonsensical, willfully obtuse objections to living a longer, healthier life through technology in the past five years. I think this Wall Street Journal piece tops them all, however. "As for recurrent rejuvenation [it] it fares poorly in a comparison with reincarnation, its closest analogue. According to a basic Hindu understanding, reincarnation involves a succession of new bodies - human, perhaps, but also animal or insect - for the same soul, one that has not yet improved sufficiently to break out of the cycle of life and death and enter the realm of enlightenment. Recurrent rejuvenation, though [keeps] the same body in a continuous loop from youth to age and back again, while the mind is free to accumulate and store all its successive experiences. So a question: Wouldn't [you] be a bit of a wreck after the preserved pain (physical and psychological) of having lived so many years and gone through the aging process 10 or 20 times? A soul in the Hindu reincarnation cycle might not have attained Nirvana, but at least the bad karma carried over from one life can be expunged in the next." Some people are just never going to get it - which is fine, a choice on their part. It's somewhat saddening to see so many slow and painful suicides in the making, however, when compared to the alternative of enhanced healthy longevity that researchers are working towards.
The Daily Bruin talks to some of the folk who were at Aging 2008: "Defeating the effects of time by finding a cure for aging has become the focus of multiple areas of research, bringing the possibilities of achieving immortality from fantasy into the realm of science. The new possibilities offered by regenerative medicine illustrate how advancements in therapy on the molecular and cellular level may be able to extend the healthy human life span within the next 20 years ... Finding a cure for aging is no longer a theoretical target or a fantasy, but on the way to becoming a practical target. Aging is the most universal degenerative condition and is now becoming the target of regenerative medicine ... The body is a really complicated machine, but it's still a machine, so its healthy lifespan can be extended indefinitely by sufficiently comprehensive repair and maintenance, just like simple man-made machines. ... Aging is a complex phenomenon that affects many different systems ... understanding it and fixing the damage as it comes can potentially cure the harmful effects of aging and as a result, elongate the healthy human lifespan."
A number of folk from the longevity science and radical life extension advocacy communities were at last month's Idea City conference in Canada. A typically "balanced" but otherwise helpful article from the press showed up recently at the National Post:
The idea of youth restoration and life extension has long captivated the human imagination, from Dorian Gray's cursed portrait and Ponce de Leon's fountain of youth to cryogenic freezing and Botox.
Nowadays, the solutions range from the practical, such as Mr. Rae's extreme caloric tightrope, to the theoretical, which include scientific advances in tissue regeneration, biological tinkering to delay reproduction, and advancing the use of nanotechnology to repair the inner workings of the body with tiny cell-sized robots.
These kinds of futuristic solutions were a major focus of a recent conference in Toronto organized by Moses Znaimer, the 66-year-old media mogul who built his career on youth-driven television channels such as CityTV and MuchMusic and is now bent on rebranding 50-plus as the new watershed age for hip and active lifestyles.
"If you are having a good time and you are not in discomfort or disarray, we all want to live forever. Who wouldn't want to extend a happy and productive life?" he said.
But such a mission - life without end - is not without its detractors.
I can only imagine: "I'm writing an article on how good it is to breathe steadily and repeatedly - quick, find me someone to speak for the contrary viewpoint." Along those lines, here is an argument offered later in the article in favor of standing aside and letting billions of people suffer and die, who might otherwise have been saved:
"It's part of the natural cycle of things that life passes through these rhythms, one generation gives way to the next," he said. "We should be very careful about throwing that out.
"The world goes through change ... but we don't necessarily want to be the agents of some of that change."
Which is the same argument then marshalled by those who want to employ government force to make people suffer and die on a centrally-determined schedule - by blocking medical research and deployment of new technologies. Sometimes it's a challenge to live in peace with the asylum of would-be mass-murderers next door.
Long-lived naked mole-rats are little goldmines of information on how metabolism and membrane composition relates to species longevity. From Ouroboros, a new twist: "Stress resistance at the cellular level is correlated with longevity at the organismal level, to such an extent that one can screen for longevity mutants by first identifying stress-resistant animals. ... It would therefore come as a surprise if a long-lived organism turned out to be unusually sensitive to stress - and in particular, sensitive to particular stresses. In one fell swoop, this would falsify both the general, well-accepted correlative pattern (stress resistance = longevity) and the somewhat more fanciful model of a central [stress resistance mechanism related to longevity]. ... Short version: naked mole rats are more resistant than mice and rats some stressors, but not all of them. Heat and starvation, two of the classic and longest-known types of stress known to correlate with longevity, work in the expected direction, with the mole rat more resistant. Beyond that, curiously, it’s hard to find patterns." If you have to bet on biology, always bet that it's going to turn out to be more complex than presently thought.
From TechNewsWorld: "More than 200 scientists and longevity activists gathered at UCLA recently to discuss advancements in repairing humans. New technology is making it possible to imagine a world with ever greater life spans, but old world issues pervaded the discussions. ... 'We should mount a war on aging where it is not a disease, it is THE disease,' said Gregory Stock, Ph.D., director of the UCLA Program on Medicine, Technology and Society. To do this, Stock proposed an 'aggressive publicly funded program.' While no one challenged this idea on the panel, during the two days of the conference, it was clear that some questioned the efficacy of such a plan. Indeed, in a less formal setting, [Bruce] Ames lamented the fact that under the mostly government-run system of science grants, the 'true visionaries are not getting funding.' This is not surprising, given that government agencies are by nature political, making decisions with an eye toward public opinion, not necessarily the best and brightest ideas. Agencies like the U.S. National Institutes of Health and particularly the Food and Drug Administration typically become risk averse over time, as it's easier to deny approval for an idea or product that no one ever finds out about than it is to take a chance on a revolutionary idea and have it flop."
With all the results arriving from comparative study of biochemistry in species of varied longevity, the membrane pacemaker theory is gaining support. For example:
The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. We tested this hypothesis by comparing the fatty acid composition of heart phospholipids from long-living Procellariiformes (petrels and albatrosses) to those of shorter living Galliformes (fowl).
The 3.8-fold greater predicted longevity of the seabirds was associated with [a] significantly reduced peroxidation index in heart membrane lipids, compared with fowl. Peroxidation-resistant membrane composition may be an important physiological trait for longevous species.
It is possible that this has a lot more to do with ways in which differential membrane composition correlates with metabolic rate - which in turn correlates with life span - than with oxidative resistance. It is also possible that these results are a sign that dramatically reducing the oxidative load produced by mitochondria, and thereby reducing the molecular damage that follows to mimic the effects of more resistant membranes, could extend life in mammals much further than the 20-30% demonstrated through targeted antioxidants.
It's certainly worth looking into. Something interesting is lurking in the triangle of mitochondria, metabolic rate, and membrane composition.
Anne C. ponders long-term maintenance of the brain: "One of the most fascinating things about the brain is how it must simultaneously change constantly over time (in response to new information and other inputs) and maintain the aspects of its structure that permit it to keep functioning as a person wants it to as he or she ages. This is true for the body as a whole, of course, but particularly interesting to consider in the case of the brain, as (unlike other organs and parts, which can be transplanted or replaced by prostheses) the brain is unique to each individual in such a way that you wouldn't ever be able to replace it with another and expect to get 'the same person' as a result. ... It is this uniqueness and irreplaceability of brains that makes them of special concern in thinking about healthcare across the lifespan. ... I [think] it more than reasonable to surmise that the conditions presently grouped together as 'the dementias' will likely someday: (a) subsume the phenomenon of milder memory loss and progressive cognitive difficulty currently considered 'normal aging', and (b) become amenable to preventative, maintenance, and rejuvenation treatments."
A research group is proposing that buildup of advanced glycation end-products (AGEs) causes DNA damage in addition to known other issues: "The scientists studied semen samples from men with diabetes who were receiving insulin therapy. ... when we looked for DNA damage, we saw a very different picture. Sperm RNA was significantly altered, and many of the changes we observed are in RNA transcripts involved in DNA repair. ... Diabetics have a significant decrease in their ability to repair sperm DNA, and once this is damaged it cannot be restored ... We found a class of compounds known as advanced glycation end products (AGEs) in the male reproductive tract. These [accumulate] during normal ageing. They are dependent on life style - diet, smoking etc - and in many diabetic complications are centrally implicated in DNA damage. ... The scientists intend to follow up their work by trying to determine how AGEs cause and contribute to DNA damage. They believe that they may have uncovered a new role for AGEs, and that their influence goes far beyond diabetes and its complications." I think that this is proposed on a fairly weak correlation, but we'll see where it goes.
The next Slashdot interview is with Aubrey de Grey, biomedical gerontologist and advocate for radical life extension. So if you have things you'd like to ask, get over to Slashdot and write up a question:
There may be such a thing as a conventional scientist - but Aubrey de Grey is not one. Instead, biogerontologist de Grey has spent much of the last 20 years investigating the science of aging by considering the aging process as a multifaceted disease whose manifestations can be mitigated, rather than an inevitability to merely accept. That might not be unusual in itself, but de Grey believes that by addressing the causes and symptoms of aging, human life can be extended to at least 1000 years - a stance has earned him accolades and contempt in various degrees. (He might not especially mind being called names like "rogue" and "maverick," though.) De Grey is also chairman and chief science officer of The Methuselah Foundation, whose M-Prize for extending the lifespan of mice has been mentioned on Slashdot before. Ask de Grey about his research below; he'll answer the top-rated questions, and we'll publish them in this space. The usual Slashdot interview rules apply - so ask all the questions you'd like, but please confine yourself to one per post..
Some interesting and possibly useful questions - in the sense of illustrating important misunderstandings or areas in which existing answers haven't yet made it into common knowledge - are forming already:
From the studies I've looked at, and the differing oppinions of the popular media, there seems to be a lot of misconceptions on the effects (or lack thereof) of telomerase on aging. Could you give a brief discussion of that (and possibly other factors/nonfactors and relative importance)?
Has any research been done on how extreme longevity affects a person psychologically?
If you had 60 secs to get a college student excited about wanting to study and research life extension, what would you say besides the obvious 'live-forever' meme?
Given that the most promising research to-date on life-extension (resveratrol and caloric restriction) can produce about a 40% increase in maximum lifespan at best, how do you estimate that we can achieve a lifespan of 1,000 years (about a 10-fold increase in current maximum lifespans)?
If the average human lifespan were extended to 1000, would the average human age at a normal speed (i.e., like now), then hit a certain specific age and remain at that age until the end (everlasting youth), or would the aging be constant?
If I gave you a lab rat today, how long could you extend his life? What about me - is there anything I can do (other than a healthy lifestyle), or could have done, today, to start extending my life? How long before the answers to either of these questions change significantly? 5 years? 10? 20?
Others have listed potential problems, I'm interested in the follow-up question to those: what do you look for to say "this won't work"? Simply stating "I believe it can" is the realm of religion. What evidence would it take to convince you that it isn't possible after all?
Via EurekAlert!, advocacy from those who believe that engineering metabolism to slow the accumulation of age-related damage is the only way ahead: "The traditional medical approach of attacking individual diseases -- cancer, diabetes, heart disease, Alzheimer's disease and Parkinson's disease -- will soon become less effective if we do not determine how all of these diseases either interact or share common mechanisms with aging ... all living things, including humans, possess biochemical mechanisms that influence how quickly we age and, through dietary intervention or genetic alteration, it is possible to extend lifespan to postpone aging-related processes and diseases. ... We believe that the potential benefits of slowing aging processes have been underrecognized by most of the scientific community. We call on the health-research decision-makers to allocate substantial resources to support and develop practical interventions that slow aging in people." Meanwhile, initiatives to raise funding to develop the means to repair - rather than just slow - the damage of aging continue. I believe those initiatives to be the superior path forward, as they seem likely to be less complex, less costly, and more effective.
How far we've come in the past five years, from the days in which the mainstream media poured scorn on the practice of calorie restriction. If there is a lesson here, it is to observe the way in which the Calorie Restriction Society engaged and encouraged the research community: progress in science is a necessary accompanyment to progress in advocacy for a cause. From MSNBC: "While the quest for the proverbial Fountain of Youth is endless and typically fruitless, one method known to extend the human lifespan by up to five years has quietly become accepted among leading researchers. The formula is simple: Eat less. It could add years to your life, several experts now say. And done in moderation, it could at least help you live a more healthy life. The only question is: Will the average person do it? ... Here's a rough rule of thumb that many experts generally agree on now: Eat 15 percent less starting at age 25 and you might add 4.5 years to your life ... Eating fewer calories also reduces age-related chronic diseases such as cancers, heart disease, and stroke in rodents. That's important because it suggests ways to not just make us live longer, but to allow us to age more gracefully, healthwise."
An interesting paper: "In higher organisms dependent on the regenerative ability of tissue stem cells to maintain tissue integrity throughout adulthood, the failure of stem cells to replace worn out, dead, or damaged cells is seen as one mechanism that limits lifespan. In these organisms, tumor suppressors such as p53 are central participants in the control of longevity because they regulate stem cell proliferation. Several recent reports have identified p53 as a longevity gene in organisms such as Caenorhabditis elegans and Drosophila melanogaster, which lack proliferative stem cells in all but the germline and have relatively short lifespans. This has forced us to reevaluate the role of p53 in the control of lifespan. We discuss how p53 might regulate longevity in both long- and short-lived species by controlling the activity of insulin-like molecules that operate in proliferating and non-proliferating compartments of adult somatic tissues. We also discuss the hierarchical structure of lifespan regulation where loss of p53 has lifespan extending effects. Finally, we suggest a molecular mechanism by which p53 might facilitate the response to severe nutrient deprivation that allows metabolically active cells to survive periods of starvation. Paradoxically, loss of p53 function in these cells would compromise lifespan."
Biotechnology is improving rapidly: taking sets of individual cells and looking in the state of DNA inside the mitochondria of those cells is a reasonable exercise for a modest research group nowadays. As expected, neurons in old brains have a bunch of deletions:
Mitochondrial dysfunction is a consistent finding in neurodegenerative disorders like Alzheimer's (AD) or Parkinson's disease (PD) but also in normal human brain aging. In addition to respiratory chain defects, damage to mitochondrial DNA (mtDNA) has been repeatedly reported in brains from AD and PD patients. Most studies though failed to detect biologically significant point mutation or deletion levels in brain homogenate.
By employing quantitative single cell techniques, we were recently able to show significantly high levels of mtDNA deletions in dopaminergic substantia nigra (SN) neurons from PD patients and age-matched controls. In the present study we used the same approach to quantify the levels of mtDNA deletions in single cells from three different brain regions (putamen, frontal cortex, SN) of patients with AD (n = 9) as compared to age-matched controls (n = 8). There were no significant differences between patients and controls in either region but in both groups the deletion load was markedly higher in dopaminergic SN neurons than in putamen or frontal cortex (p < 0.01; ANOVA). This data shows that there is a specific susceptibility of dopaminergic SN neurons to accumulate substantial amounts of mtDNA deletions, regardless of the underlying clinical phenotype.
Deletions are much more important than point mutations when it comes to degrading function in mitochondria, and thereby causing a follow-on chain of issues in a cell and surrounding tissue. You might recall recent work showing mice loaded up with point mutations and perfectly fine for it, for example. Deletions, however, have a much greater chance of knocking out one of the few genes necessary for the effective function of mitochondria.
You can look back in the archives to see what happens when mitochondrial DNA is damaged, and the important contribution this makes to degenerative aging. We should all be supporting and encouraging work on the slate of potential technologies to repair, replace, augment, and move mitochondrial DNA:
- The MitoSENS approach - move it to the nucleus
- Replacement via protofection
- Restore function via the (tRNA) mechanisms of Leishmania
- Another tRNA approach
Other potential methods exist in a more speculative state, such as using engineered bacteria to consume damaged mitochondria, or xenotransplantion of new mitochondria from other species. The breadth of potential approaches is growing, which is a good sign, but the field isn't moving fast enough for my liking at this time. More funding and attention is needed.
The inaugural Hourglass carnival of aging and longevity science is hosted at Ouroboros: "Welcome to the first installation of Hourglass, a blog carnival devoted to the biology of aging. This first issue corresponds with the second blogiversary of Ouroboros, but mostly I consider it a celebration of the excellent (and growing) community of bloggers who are writing about biogerontology, lifespan extension technologies, and aging in general ... BrainHealthHacks writes about recent evidence that smarter people live longer. This is true whether your metric of intelligence is education (which could be problematic, as education levels are often correlated with lifelong affluence and access to medical care) or whether you're looking at individual genetic variations correlated with both longevity and intelligence. It's a giant post that quotes several articles from the primary literature as well as studies by international organizations." You'll find an interesting view of ongoing calorie restriction studies too.
Are you participating in the Immortality Institute's Folding@Home competition? You should be - there are prizes, after all. It's a group effort to move the Longevity Meme Folding@Home team up in the rankings, with modest sums of money for the best contributers in each new quarter.
I was reminded by the organizers that the new quarter of competition kicked off this month - it's not too late to jump on in:
Many thanks to all of the visionaries and contributors who made the inaugural quarter of the F@H Prize a resounding success! The Longevity Meme folding team rose from rank 199 to 172 (as of June 24th) while increasing its point per day output by 150 percent!!
The 2nd quarter of competition is beginning on July 1st (all competitor’s scores will be reset to zero) and even more cash is up for grabs thanks to a generous donation by Maciek K. So get ready to rev up your PS3s, overclock your CPUs and, max out your GPUs.
***Special Note: Even though the starting date of the 2nd quarter of competition is July 1st, you can join at any time and your points will start accumulating from the date you register***
When I head on over to the team stats online, I see we're at rank 166 with an impressive trendline on the results chart. Moving up the ranks is tough going in the upper levels; congratulations are due to the contributers.
Folding@Home has been a success. In 2000-2001, we have folded several small, fast folding proteins, with experimental validation of our method. We are now working to further develop our method, and to apply it to more complex and interesting proteins and protein folding and misfolding questions. Since then (2002-2006), Folding@Home has studied more complex proteins, reporting on the folding of many proteins on the microsecond timescale.
More recently (2006-present), we have been putting a great deal of effort into studying proteins relevant for diseases, such as Alzheimer's and Hunntington's Disease.
We feel strongly that a Distributed Computing project must not just run calculations on millions of PC's, but DC projects must produce results, especially in the form of peer reviewed publications, public lectures, and other ways to disseminate the results from FAH to the greater scientific community.
FuturePundit comments on the latest resveratrol research: "Surprisingly, resveratrol extends life of those on the calorie restriction diet. I say 'surprisingly' because calorie restriction is already causing most of the changes that resveratrol causes. But note that mice on the middle range calorie diet did not live longer as a result of resveratrol treatment. ... Maybe on the [every other day feeding] mice the resveratrol worked by mimicking the effects of calorie restriction on the feeding days? ... My reaction to this study is mild disappointment. Resveratrol did not work nearly as well as calorie restriction in extending life. You still need to starve yourself to assure a longer life." It's convenient verbal shorthand, but the practice of calorie restriction is not "starving yourself." It's important to be correct in these matters - calorie restriction is elimination of calories above those needed to be healthy, while still obtaining an optimal level of micronutrients. Many slim, healthy people are already practicing a form of mild calorie restriction when measured against commonly recommended dietary intake. Still, my fervent hope is that calorie restriction will become irrelevant and outstripped by the first medical interventions to extend healthy life, hopefully within the next 20 years. My money is on technologies of mitochondrial replacement and repair.
From the Methuselah Foundation: "Are you an undergraduate interested in the Strategies for Engineered Negligible Senescence and other avenues of longevity science? Have you considered volunteering with the Methuselah Foundation to help advances towards the repair of aging? Then you should visit the MFURI website to learn more about the Methuselah Foundation Undergraduate Research Initiative. ... the initiative provides students with the knowledge and logistical support to develop their own projects to further the agendas of the Methuselah Foundation, a non-profit organization which supports research and advocacy for radically extending healthy human life. As a means for promoting student interest, thousands of dollars in scholarship funds, grants, and man hours are provided annually. These support mechanisms, coupled with the logistical support of numerous dedicated, professional volunteer coordinators, provide unprecedented opportunity for student development and success in most any academic discipline. In addition to becoming eligible for scholarships and general support, MFURI students are also given the choice to perform projects and initiatives for university credit virtually anywhere within the United States."
Researcher Attila Chordash is back from last weekend's Aging 2008 conference, and he's posted his video of biomedical gerontologist Aubrey de Grey's presentation from a vantage point at the pre-conference public event.
This is how my Macbook saw Aubrey de Grey’s talk exactly 1 week ago on the [preconference] at UCLA.
I am minded of the concert bootleg scene, except with scientists instead of musicians, and no bouncers chasing down the camcorders - you'll see what I mean when you watch it. I am told that conference video will be forthcoming from the Methuselah Foundation in due course - it takes a little time for the volunteers to pull all that raw footage together and get it online.
The conference was a great success, just like prior conferences under the Methuselah Foundation umbrella, and congratulations are due to the volunteers who worked very hard over the past months to make it so.
From the PHG Foundation: "a new publication in the journal Cell Stem Cell has claimed that countries with less restrictive regulatory regimes account for a disproportionately high level of scientific publications, supporting concerns cited by many prominent US researchers that without easing of current legislation such as current restrictions on the use of federal funding for stem cell research [the] country will lag behind in this area of medicine. Countries dubbed 'overperforming' in stem cell publications were Singapore, the UK, Israel, China and Australia, whilst 'underperformers' included the US, Japan, France and Switzerland ... The author concludes that the most highly performing countries had generally permissive policy environments for [embryonic stem cell] research, whilst those lagging behind were characterised by 'protracted policy debates and ongoing uncertainty, regardless of their current policy environment'." No great shock there. The more you make it hard to move forward, the less moving forward there will be. This has little to do with degrees of public funding, and everything to do with levels of regulation.
We're a fair way from being able to produce a complete replacement for the functions of human body - a very sane goal if you'd like to live a lot longer - but the checklist of what can be replaced is getting longer by the month. From the New Scientist: "More and more of the body is becoming, if not obsolete, then certainly replaceable. But which of our body parts can be engineered today, and which will we have to make do with? ... Implants that copy the simple structural job of skeletal tissue are the easiest to build ... by culturing normal or stem cells it is now possible to grow pretty much any type of tissue. Some complete organs have already been grown from scratch. ... Other parts of the body's plumbing network, such as the lymphatic system, are becoming replaceable too. Last year, mice were implanted with an artificial lymph node made from collagen and cells taken from a gland in newborn mice. ... Implants can also help the blind see, by stimulating the retina, optic nerve or the brain's visual cortex. ... Other research seeks to replace entire limbs with robotic replacements."
The latest issue of Rejuvenation Research is online. You'll find a few more esoteric items on calorie restriction biochemistry, but one paper on methionine restriction is more accessible and interesting. By way of a reminder, recall that there's a fairly good argument for the beneficial effects of calorie restriction to largely stem from lowering the intake of methionine, one of the eight essential amino acids in your diet.
Rats and mice, when subjected to methionine restriction (MetR), may live longer with beneficial changes to their mitochondria. Most explanations of these observations have centered on MetR somehow suppressing the effects of oxygen free radicals.
It is suggested here that MetR's effects on protein metabolism should also be considered when attempting to explain its apparent anti-aging actions. Methionine is the initiating amino acid in mRNA translation. It is proposed that MetR decreases the protein biosynthesis rate due to methionine limitation, which correspondingly decreases generation of ribosomal-mediated error proteins, which then lowers the total abnormal protein load that cellular proteases and chaperone proteins (mitochondrial and cytoplasmic) must deal with.
That's an interesting thought. All cells carry some amount of damaged and malformed proteins as a result of errors in normal operation. The more abnormal proteins, the worse the cell performs - it makes sense that slowing the rate of operation also slows the rate of damage. You can read a little more about that in the context of bacterial reproduction, cell divison, and aging back a way in the Fight Aging! archives. The question is whether this is significant compared to the effects of mitochondrial generation of damaging free radicals.
The other paper that caught my attention is a nice demonstration that the benefits of calorie restriction don't necessarily have anything to do with insulin-like growth factor 1, IGF-1. For those who have been following research into IGF-1 metabolism and aging, a field with at least as much interest as investigations into mitochondria and aging, that might be a counterintuitive result.
It is known that dietary restriction (DR) increases maximum longevity in rodents, but the mechanisms involved remain unknown. Among the possible mechanisms, several lines of evidence support the idea that decreases in mitochondrial oxidative stress and in insulin signaling are involved but it is not known if they are interconnected.
It has been reported that when C57BL/6 mice are maintained on an every other day (EOD) feeding their overall food intake is only slightly decreased and plasma insulin-like growth factor (IGF)-1 is even somewhat increased. In spite of this, their maximum longevity is increased, analogously to what occurs in classic DR. Thus, this model dissociates the increase in longevity from the decrease in IGF-1 observed in classic DR.
These results support the possibility that EOD DR increases maximum life span at least in part through decreases in mitochondrial oxidative stress which are independent from insulin/IGF-1-like signaling.
As I said yesterday, metabolism is a complicated affair.
Over at Ouroboros, comments on SENSE, Michael Rose's consideration of his research as it impacts the "repair damage to cure aging" viewpoint of the Strategies for Engineered Negligible Senescence (SENS): "Rose concludes that life-extension therapeutics must address the issue of age-specific adaptation in order to be effective ... In the evolutionary view, increasing risk of mortality is the consequence of a failure to adapt to the selection-pressure landscape specific to a particular age; because post-reproductive lifespan is largely (but not always) masked from selection, it is easy to see how such age-specific failures of adaptation might occur. The 'mortality plateaus' to which the author refers are life-history periods of constant, rather than increasing, mortality risk. Rose argues that the existence of these plateaus in the survival curves of many species imply that accumulation of irreparable damage is - at the very least - not the whole cause of aging. Therefore, the argument goes, reversing this damage cannot be sufficient to prevent or reverse aging as such."
From EurekAlert!: "Scientists have found that the compound resveratrol slows age-related deterioration and functional decline of mice on a standard diet, but does not increase longevity when started at middle age. ... Dietary restriction has well-documented health benefits in mammals, and the study of possible mimetics of it, such as resveratrol, are of great interest. ... Resveratrol did not have a significant effect on lifespan in animals fed standard chow, suggesting that the intervention did not affect all aspects of the basic aging process. Mice on a high-calorie diet without resveratrol lived the shortest length of time and mice on an every-other-day regimen lived the longest, regardless of resveratrol treatment. However, for mice on a high-calorie diet, mean and maximum lifespan increased for mice on resveratrol when compared with the control mice. Researchers found that resveratrol's effects on longevity could be completely uncoupled from changes in body weight, meaning that mice on a high-calorie diet with resveratrol did not necessarily lose weight but did experience a longer (and healthier) life than mice on the same high-calorie diet not taking resveratrol. They speculate that improved cardiovascular health and reduced fatty changes in the liver may have contributed to the increased lifespan of resveratrol-treated mice."
Proteins widely believed to protect against aging can actually cause oxidative damage in mammalian brain cells. [The] findings suggest that the proteins can have both proaging and protective functions, depending on the circumstances, the researchers said.
"Sirtuins are very important proteins," said Valter Longo of the University of Southern California, Los Angeles. "Overexpression can protect in some cases, and in other cases, it may do the opposite. It has to do with the fact that they do so many things."
Longo urges caution to those developing SirT1-boosting drugs intended for human consumption.
" [Such drugs] could have beneficial effects for certain diseases, but again, these proteins do a lot of things," he said. "I would say the idea that there is a conserved action of sirtuins to cause major life span extension - the foundations for that are weak or very weak. Until we have more data to show that chronic treatment to increase SirT1 activity does not do damage, I don't think it's a good idea."
Metabolism is very complex, and the sirtuin story is a good illustration of that point. What might have seemed straightforward a few years back, at the opening of serious movement towards commercial calorie restriction mimetics, is anything but.
When it comes to the source of longevity in mammals, the finger is pointing to the mitochondria. Either the mitochondria are more efficient, or as is shown to the be the case in the mole-rat and now the echidna, the surrounding biochemistry is more resistant to damage. The echidna "is exceptionally long-living. Its documented maximum lifespan of 50 years is 3.7 times that predicted from its body mass. Other exceptionally long-living mammals (naked mole-rats and humans) are known to have peroxidation-resistant membrane composition .... The peroxidation index (=peroxidation susceptibility) calculated from this membrane composition was lower-than-expected for their body size, indicating that the cellular membranes of echidnas would be peroxidation-resistant. Additionally when the calculated peroxidation index was plotted against maximum lifespan, the echidna values conformed to the relationship for mammals in general. These findings support the membrane pacemaker theory of aging and emphasise the potential importance of membrane fatty acid composition in aging and in the determination of maximum longevity." Mitochondrial damage is the first domino in a long and spreading line of follow-on processes of damage. Ongoing research into mitochondrial repair, replacement and damage resistance deserves far more funding, given the potential payoff for human healthy longevity.
Chris Patil of Ouroboros is organizing a blog carnival for aging science and longevity research topics: "There's enough good science blogging about the biology of aging that the community deserves its own monthly carnival (along the lines of the general-biology carnival Tangled Bank, or the neuroscience carnival Encephalon, both of which we've hosted here before). So let's start one. I thought long and hard about names and settled on 'Hourglass,' which is topical enough to be appropriate, but general to be inclusive. ... 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. About the only sorts of things I'm going to turn away are quackery or promotions of a commercial product."
Welcome to AnAge, a curated database of ageing and life history in animals, including extensive longevity records. AnAge was primarily developed for comparative biology studies, in particular studies of longevity and ageing, but can also be useful for ecological and conservation studies and as a reference for zoos and field biologists.
You might recall that de Magalhaes is one of the folk pushing for genetic sequencing of long-lived mammals:
Among mammals alone there is at least a 40-fold variation in maximum longevity. We still do not know why different species of similar body plan, biochemistry, and physiology can age at such different rates, but these differences must be seated in the genome.
So go and take a stroll around the AnAge toolset. Those of you looking for a quick and interesting result can jump straight to the list of species ordered by current best estimate or record of maximum longevity:
Scolymastra joubini, Hexactinellid sponge: 15,000 years
Pinus longaeva, Great Basin bristlecone pine: 4,731 years
Cinachyra antarctica, Epibenthic sponge: 1,550 years
Arctica islandica, Ocean quahog: 400 years
Balaena mysticetus, Bowhead whale: 211 years
Sebastes aleutianus, Rougheye rockfish: 205 years
Strongylocentrotus franciscanus, Red sea urchin: 200 years
I've mentioned the urchins recently, and clams and whales are back little in the Fight Aging! archives. I'm sure you're all familiar with the bristlecone pine, but what is this 15,000 year sponge? From the AnAge entry:
Animals of this and similar species of Antarctic sponges grow extremely slowly in the low temperatures. Estimates based on growth rates suggest a very long lifespan in this and similar animals. One two meter high specimen in the Ross Sea was estimated to be 23,000 years old, though because of sea level fluctuations in the Ross Sea it is unlikely that such an animal could have lived for more than 15,000 years. Even if 15,000 years is an overestimate, which may well be the case, this specimen appears to be the longest-lived animal on earth.
The Wikipedia entry provides a little more background as to what sort of beast this is. You learn something new every day.
EukekAlert! reports on a mechanism that may reverse half of all cancers - assuming that the cancer cells don't promptly evolve their way around it, that is. "Researchers identified a precise threshold level of the signaling molecule Myc that determined the fate of tumor cells in a cancer of the immune system in mice. Above the threshold, high levels of Myc drove immune cells to grow too large and multiply uncontrollably. When the researchers lowered Myc levels below the threshold, the same cells shrank to normal size, stopped multiplying and began dying normally. ... But Myc is essential, at lower levels, for normal cell function. So, switching Myc all the way off is not an option for treating cancer. ... In the past, scientists have shown that cancer signals such as Myc are 'like light switches' [and the] idea that this is a threshold is really not the way we were all thinking ... We were able to experimentally prove that we can turn Myc off a little bit, or for a little time, and that's enough to have a profound effect on cancer."
Chronic inflammation raises the risk of pretty much everything you don't want to happen to your body and mind as you age. In effect, it is a source of damage to your biochemistry - and damage has consequences. Here, The Future of Things looks at what inflammation does to your risk of cancer: "It is well known that inflammation produces cytokines (immune response chemicals that encourage cell proliferation and suppress cell death), which could lead to cancer if proper cell monitoring mechanisms are not activated. In addition, another process that is evoked during inflammation has been suspected as a possible cancer inducer. During the inflammatory response to infection, immune cells, such as macrophages and neutrophils, release reactive elements, such as oxygen and nitrogen, often damaging the DNA. When DNA repair mechanisms function properly, the damage caused by inflammation is repaired before it can develop into cancer. However, the MIT team showed that once the mechanisms are not intact, the damage to the DNA can develop into mutations, possibly leading to cancer." Don't forget that packing on the visceral fat is in essence agreeing to suffer a lifetime of enhanced chronic inflammation.