Given the role played by advanced glycation end-products (AGEs) in aging, scientists continue to search for ways to destroy or limit the accumulation of these compounds. Regulation generally forces such studies to relate to the treatment of age-related diabetes - intervention in aging is not recognized as a legitimate field of research by the FDA, so therapies will not be approved for use, and thus funding cannot be found for development. "We investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of [diabetic rats] ... LR-90 treatment [reduced] kidney AGE/ALE accumulation and RAGE protein expression ... In vitro, LR-90 exhibited general antioxidant properties ... The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating [diabetic animals] by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis." All of which would be beneficial as applied to normal aging - assuming that this compound is useful in people. Most prospective AGE-breakers coming from animal studies fail to do much good in humans, as the mix of AGE compounds is quite different.
More scientists are weighing in with estimates of the effects of calorie restriction (CR) on humans - estimate being the key word: "in humans there are no life-long studies of CR, only short term trials which indicate that 20% CR acting over periods of 2 to 6 years is associated with reduced body weight, blood pressure, blood cholesterol and blood glucose, risk factors for the major killer diseases of cardiovascular disease and diabetes. In addition recent research has shown that CR acting for 6 months is able to improve biomarkers for longevity (deep body temperature and plasma insulin) and thus should increase life expectancy. The magnitude of the life extension effect of CR in humans can only be estimated. The Okinawans, the longest lived people on earth, consume 40% fewer calories than the Americans and live only 4 years longer. Similarly, women in United States consume 25% fewer calories than men and live 5 years longer. From the survival studies of overweight and obese people it is estimated that long-term CR to prevent excessive weight gain could add only 3 to 13 years to life expectancy. Thus the effects of CR on human life extension are probably much smaller than those achieved by medical and public health interventions, which have extended life by about 30 years in developed countries in the 20th century." The health benefits are still inarguably good, of course.
An interesting exchange of views on longevity research is taking place on the GRG mailing list, as I noted when I posted some of Robert Bradbury's thoughts on the matter a few days ago.
Derya Unatmaz is the researcher behind the Biosingularity blog, and a good illustration of the younger generation of scientists: optimistic, realistic and thoughtful on the topic of longevity research and healthy life extension. You might recall that Unatmaz was interviewed by Attila Chordash of Pimm earlier this year:
I am going to be blunt and say that it is nonsense that we have to make an argument for life! ... Treating or controlling indefinitely all chronic deadly human diseases should be achievable within the next 25-30 years ... I anticipate continuous body regeneration soon after that within the next 40 years.
Here is a mail to the GRG list from Unatmaz, reproduced with permission:
I fully agree that there is no biological reason why human life can not be extended indefinitely and at some point in future (hopefully near one) in my opinion it is almost a certainty this will be achieved.
The point that I disagree with (if I understood correctly) is that the current biological research somehow can be directed, made less wasteful and if the money were to be spent "wisely" we can then achieve the above goal much quicker.
Research by its nature, especially in biological sciences because of enormous complexity, is very wasteful. This is simply because we have not yet identified all the components of the system we are studying, let alone have the capability to put it together from it's individual pieces. I think this is a common mistake made, especially by non-biologists, that the scientists working on biological systems can be more efficient by working on the right solutions and if there was a top down approach on defining the areas to research then we can figure out the solution to aging pretty quickly. This far far from the reality.
It is true that having more money available is critical and advances surely will move much quicker with more funding available, especially nowadays with declining federal support. However, amount of information generated reaches a plateau at some point no matter how much more money is available and you simply start to increase the waste to productive knowledge ratio. Why is that? Because we are still trying to figure out how the system works, and solving difficult problems depend on development of future technologies, which we don't really know where they will come from. There is also limited pool of talent that can work on these problems. For example, as Robert B. pointed out, we would have needed trillions of dollars to sequence all the genomes we have sequenced now if we attempted this just 15 years ago, that would not be the best way to spend your money. You have to let the technology mature and cost come down to reasonable levels before you can ramp up with such advance!
In addition, you simply cannot predict a priori where the major breakthroughs will come from. If they were so obvious, they wouldn't be breakthrough in the first place. Somebody makes a discovery studying fruit fly basic RNA regulation mechanism then that discovery just opens up a whole new frontier of technologies and capabilities (such as RNA interference). Somebody tries to understand how viruses work, then that allows ways to deliver genes into cells using viruses as hosts (retroviral vectors for gene therapy). I can go an with these examples ad nauseam.
My point is this: if you have a lot of money to spend and you want to make a difference in aging research, the best way is still the way NIH grant system works, i.e. distribute your money based on scientific merit to the best scientists and labs you can find who are working in related areas. Don't limit your focus narrowly, they could be working on yeast, worms, turtles, or humans, you or I simply don't know where the next discovery will come from and how it will impact human longevity.
You give out 100 grants to 100 scientists with million dollar each, if 10 of these generate a breakthrough that would be considered spectacular success in research. You can of course look at it as wasting 90-95% of your money, but that's the price you pay to make the major technological discoveries that will leapfrog us forward. What one has to be careful is not to spend too much on brute force approaches in areas where the technology is still not mature (as I gave the sequencing example above). Once you have cost effective ways to look at millions of parameters parallel, as information and other technologies co-advance, then it becomes highly cost effective way of discovery based science, where you look for things without preconceived hypothesis. That's risky science but the payoff can be very big. This can be a especially good area for private funding since even NIH grants are too much dependent on hypothesis and directed research.
Howard Hughes Institute is a great example. Only the best of the best scientists become HHMI investigators. They spend 300-400 million dollars a year, no strings attached, scientists decide what they want to do. In the end you have several breakthroughs every year from HHMI researchers that become the locomotive of biological research. Directed research decided especially by people who are not on the bench doing the science is a bad idea and a great way to waste your money, in my opinion. There is of course merit to highly focused and directed research and that is in development of already identified products. But then that's why we have a whole profit-driven industry for that.... my two cents.
As I see it, this is a perspective on the knowledge problem, but I think it conflates the following:
- an attribute fundamental to research: risk based on lack of specific knowledge
- issues of investment: risk of investing poorly based on having less knowledge of the field than those who work in it
- an attribute of central control of resources: the inability to plan
Scientific research is no more inherently risky or unplannable than starting a company; both are forms of research for those doing the work. Will business plan X work to bring in money; will understanding and intervening in biomechanism A help slow or repair aging. It's much the same thing - and so investment is just as open to planning, risk management and the setting of goals.
The real problem with massive expenditures on research that come from government - as opposed to massive expenditures on research that are sourced from private funds - is an utter lack of accountability for results at all levels of the process. Where there is no accountability, there are no real goals, and thus progress is incidental and slow - relying as it does on individual drive and goodwill rather than more pressing economic incentives.
This is another fundamental difference between the Strategies for Engineered Negligible Senescence and the mainstream of gerontology - for the most part, the mainstream relies on government funding, has not set goals, has no accountability for progress, and hence has no pressure to produce. You can throw as much money as you like into a system with no incentives, but you're not going to get much out it. The NIH is like NASA, or any other huge, unaccountable arm of government - a huge and wasteful sinkhole for resources and talent that could have been achieving great progress if held accountable for their work and inventivized to set a path towards definitive goals.
From PhysOrg.com: "How do adult stem cells protect themselves from accumulating genetic mutations that can lead to cancer? For more than three decades, many scientists have argued that the 'immortal strand hypothesis' - which states that adult stem cells segregate their DNA in a non-random manner during cell division -- explains it. ... [researchers] labeled DNA in blood-forming mouse stem cells and painstakingly tracked its movement through a series of cell divisions. In the end, they found no evidence that the cells use the immortal-strand mechanism to minimize potentially harmful genetic mutations. ... This immortal strand idea has been floating around for a long time without being tested in stem cells that could be definitively identified. This paper demonstrates that it is not a general property of all stem cells." The more we know about the changes that accumulate in cells with age - and the mechanisms by which those changes occur - the better armed we are work towards the repair of aging.
An article by Chris Phoenix of the Center for Responsible Nanotechnology can be found at Nanotechnology Now. Molecular manufacturing (MM) will bring a new industrial revolution, in effect, and one of the areas to benefit greatly will be medicine: "Although the human body and brain are awesomely complex, MM will lead to rapid improvement in the treatment of many diseases, and before long will be able to treat almost every disease, including most or all causes of aging. The first aspect of medicine to benefit may be minimally invasive tests. ... Even with a conservative approach, inexpensive continuous screening for a thousand different biochemicals could give doctors early indications of disease. (Although early MM may not be able to build a wide range of chemicals, it will be able to build detectors for many of them.) Such monitoring also could reduce the consequences of diseases inadvertently caused by medical treatment by catching the problem earlier. ... Today, in advanced arthroscopic surgery, simple surgical tools are inserted through holes the size of a finger; a nano-built surgical robot with far more functionality could be built into a device the width of an acupuncture needle."
"Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime" is out in bookstores, real and virtual, all too soon. The book by Aubrey de Grey and Michael Rae is one of a series of initiatives aiming to illustrate the plausibility of near-term healthy life extension to enough people - and gain enough widespread support and understanding - to spark a revolution in research.
In Ending Aging, Dr. de Grey and his research assistant Michael Rae describe the details of this biotechnology. They explain that the aging of the human body, just like the aging of man-made machines, results from an accumulation of various types of damage. As with man-made machines, this damage can periodically be repaired, leading to indefinite extension of the machine’s fully functional lifetime, just as is routinely done with classic cars. We already know what types of damage accumulate in the human body, and we are moving rapidly toward the comprehensive development of technologies to remove that damage. By demystifying aging and its postponement for the nonspecialist reader, de Grey and Rae systematically dismantle the fatalist presumption that aging will forever defeat the efforts of medical science.
The goal of greatly extending the healthy, vigorous human life span through repairing the damage that causes aging is very plausible. It is plausible to attain that goal within a few decades of work by a large research establishment. But that establishment doesn't yet exist - resources and people must be gathered and persuaded.
So: one step at a time. We must raise support, and we must help make each new initiative to that end more successful than it would have been if we stood to one side and merely watched. What can we ordinary folk do to help make this book successful? Publishing a book is best thought of as two entirely separate activities: a big gala party up front, a burst of publicity and sharing, followed by a long conversation and building of community across years. The publishing industry is all about the party, while the craft of advocacy and activism is all about the years afterwards.
But let's talk about the party, first things first: how can we help to get this book out there and talked about? Well:
- The obvious: pre-order a copy at Amazon.com, as Amazon rankings matter in this gala process
- Tell your friends, write about the book - make some noise!
- Help circulate the popular videos of Aubrey de Grey's presentations
- Post the excerpt at Amazon.com to the noticeboards you frequent
Then a second line of thought began to form in my mind - idly at first, just as a notion. The real issue, surely, was not which metabolic processes cause aging damage in the body, but the damage itself. Forty-year-olds have fewer healthy years to look forward to than twenty-year-olds because of differences in their molecular and cellular composition, not because of the mechanisms that gave rise to those differences. How far could I narrow down the field of candidate causes of aging by focusing on the molecular damage itself?
Well, I thought, it can’t hurt to make a list . . .
There are mutations in our chromosomes, of course, which cause cancer. There is glycation, the warping of proteins by glucose. There are the various kinds of junk that accumulate outside the cell (“extracellular aggregates”): beta-amyloid, the lesser-known transthyretin, and possibly other substances of the same general sort. There is also the unwholesome goo that builds up within the cell (“intracellular aggregates”), such as lipofuscin. There’s cellular senescence, the “aging” of individual cells, which puts them into a state of arrested growth and causes them to produce chemical signals dangerous to their neighbors. And there’s the depletion of the stem cell pools essential to healing and maintenance of tissue.
And of course, there are mitochondrial mutations, which seem to disrupt cellular biochemistry by increasing oxidative stress. I had for a few years felt optimistic that scientists could solve this problem by copying mitochondrial DNA from its vulnerable spot at “ground zero,” within the free-radical generating mitochondria, into the bomb shelter of the cell nucleus, where damage to DNA is vastly rarer.
Now, if only we had solutions like that for all of this other stuff, I mused, we could forget about the “butterfly effect” of interfering with basic metabolic processes, and just take the damage ITSELF out of the picture.
Well, I thought, why the bloody hell not?
Why the bloody hell not, indeed. The aging research establishment needs a kick to the rear and the drive for near-term goals sorely lacking in past years - how else is progress to be made on an aggressive timeline? Over at the Immortality Institute some folk have other good ideas for helping things along:
I contacted of my favorite libraries offering to donate a copy of Ending Aging. I mentioned that Aubrey will be on Good Morning America on September 17th. The library has two sites. After the librarians consulted each other, they checked out the Amazon site then decided that they would match my book contribution, by purchasing another copy or copies so both libraries would have.
They also want to put a display with the book and info about Aubrey and his work in the front of both libraries.
I put together a Powerpoint brief (Attached) for the librarians to help them be informed, and they can use in the display.
Be sure to check out the Powerpoint attached to that post. As is noted, Aubrey de Grey will indeed be on the talk show circuit in September; whatever we can do to increase the buzz before then is grist for the mill.
The more people who learn about de Grey's Strategies for Engineered Negligible Senescence (SENS), the more support we'll see for plausible research to repair the damage of aging. More support means faster progress, and faster progress means a better chance for all of us to live much longer, much healthier lives, bringing an end to the frailty and age-related diseases that presently kill 100,000 people every day.
Chris Patil was kind enough to post on his review of a recent conference on aging science, including the full PDF version: "Nearly 20 years ago, researchers discovered that lifespan can be extended by single-gene mutations in the nematode worm Caenorhabditis elegans. Further studies revealed that the mechanisms governing aging in the smallest organisms have been evolutionarily conserved and may operate in human beings. Since then, the field of biogerontology has expanded considerably, learning from - and contributing to - such disparate fields as cell signaling, metabolism, endocrinology, and a wide range of human diseases including cancer. To date, newly discovered connections and novel interdisciplinary approaches gradually unify what once seemed unrelated observations between seemingly disparate research areas. While this unification is far from complete, several overlapping themes have clearly emerged. At the 95th International Titisee Conference, devoted to 'The Molecular Basis of Aging,' 60 of the world's pre-eminent biogerontologists shared their most recent findings in the biology of aging, and discussed interdisciplinary connections between diverse fields."
Researchers continue to make solid progress in the development of gene therapies to clear out aggregations of unwanted compounds in our bodies: "Alzheimer's involves a protein called amyloid-beta, which makes up gooey clots or plaques that form in the brain. These toxic clumps, along with accessory tangled fibers, kill brain cells and interfere with memory and thinking. The situation has been compared to a build-up of cholesterol in coronary arteries. ... Delivery of genes that led to production of an enzyme that breaks up amyloid showed robust clearance of plaques in the brains of the mice ... The gene delivery technique employed by the research team has been used in several other trials with animals that model human diseases, including cancers. The procedure involves removing cells from patients, making genetic changes, and then putting back the modified cells, which should treat a disease or disability. So far, this approach has produced encouraging results for cancers, blood, muscle, and eye diseases, spinal cord injuries, stroke, Parkinson's and Huntington diseases, and amyotrophic lateral sclerosis."
I noticed today that Rejuvenation Research, the journal of real, actual anti-aging medicine based on the repair of age-related cellular and molecular damage, is going bimonthly next year.
That's a strong continuation of the interest shown in this publication on the scientific path towards reversing aging. Last year, editor Aubrey de Grey noted:
The 2005 impact factors were announced yesterday, including the inaugural impact factor for Rejuvenation Research. I'm pleased to tell you that we obtained the very agreeable ranking of 8.571. This puts us at No. 1 in the "Gerontology and Geriatrics" category by a large margin, even including Aging Cell at 6.013 (which, for whatever reason, is not listed in that category). For a wider comparison, we would be No. 20 in Biochemistry and Molecular Biology and No. 17 in Cell Biology, ahead of such prominent titles as Human Mol Genet, NAR, FASEB J, MCB, MBC, JCS, and Oncogene. ... Moreover, a rough calculation based on available data suggests that this is not a fluke arising from our conveniently small denominator this year -- we will be around the same level next year.
This year, indeed, the impact factor is around the same:
We are pleased to announce that our new impact factor is 8.353 - 2006 ISI Journal Citation Reports
A great showing, and congratulations are due once more:
Aubrey de Grey, at the helm of this multidisciplinary peer-reviewed journal, seeks to understand and ultimately defy the mechanisms of aging. He was featured in a recent 60 Minutes segment titled "The Quest for Immortality"; in a cover story on de Grey, MIT's Technology Review said, "His tireless efforts...have put him among the most prominent proponents of antiaging science in the world. ... De Grey has become more than a man; he is a movement."
Dr. de Grey and his outstanding international editorial board have the opportunity to further explore and advance the science, and perhaps achieve the ultimate goal of slowing or reversing the process of aging.
Rejuvenation Research, the Methuselah Foundation, the SENS conferences - these are all seeds for a mighty research community to come. The future I want to live to see is one in which a massive and thriving longevity research infrastructure exists, flush with the will and resources to match the cancer establishment of today - many overlapping and competing groups taking advantage of and driving the advance of biotechnology in order to defeat age-related suffering and death.
This is very plausible. How fast it comes to pass is up to us, as the speed of this progress depends on our vocal and material support. Do you want to live a much longer, healthier life, untroubled by the conditions that killed your ancestors? Then get up and help do something about it.
The amyloid and tau focus of Alzheimer's research is not universal in the scientific community. From the NYAS: "the well-characterized buildup of amyloid plaques and tangles of tau are not the only biochemical phenomena wrought by this neurodegenerative disease. And this line of investigation, while able to clarify many of the mechanisms that lead to the pathological activity of these proteins, has yet to produce a new drug that successfully treats the disease. ... Aaron Chuang of GlaxoSmithKline characterized this intellectual history of [Alzheimer's disease (AD)] research by referring to a proverb: A frog that grows up in the bottom of a well believes the little sliver of sky he sees is the whole world. Along these lines, the little that we've known about AD until recently has limited the questions that we've asked. While [amyloid beta] and tau are certainly important in the disease, the etiology and mechanisms of AD are probably much broader. Other approaches to thinking about the disease may be essential to unearth new insights and strategies for drug therapies."
You might recall manipulation of myostatin touted as a potential therapy for age-related muscle decline and wasting diseases. EurekAlert! notes that the basic science has already been improved: "mice that lack the gene that makes myostatin have roughly twice the amount of body muscle as normal, mice without myostatin that also overproduce follistatin have about four times as much muscle as normal mice. ... follistatin was capable of blocking myostatin activity in muscle cells grown under lab conditions. When he gave it to normal mice, the rodents bulked up, just as would happen if the myostatin gene in these animals was turned off. He then genetically engineered a mouse that both lacked myostatin and made extra follistatin.... To my surprise and delight, there was an additive effect ... these muscular mice averaged a 117 percent increase in muscle fiber size and a 73 percent increase in total muscle fibers compared to normal mice. These findings show that the capacity for increasing muscle growth by targeting these pathways is much more extensive than we have appreciated."
As Wnt activity increases during aging, muscle cell progenitors switch from a myogenic (i.e., regenerative) mode to a fibrogenic (i.e., inflammatory) mode; this can be prevented with specific blocking antibodies. It is easy to that the resulting increased fibrogenesis, at the cost of regenerative capacity, could cause muscular weakness and sarcopenia in late life.
Here's a few thoughts from elsewhere in the blogosphere a couple of weeks ago:
What does this mean for us? Well, if you block the wnt pathway you could very well promote tissue healing. The truism that you heal slower when you're older would no longer hold true. More interesting however is that many of the obvious signs of aging are due to imperfect cellular maintenance--what if selective wnt pathway suppression could change that? The wnt pathway is crucial so this is something that you're want to only block on a selective basis but it's a very interesting area of research.
This latest round of Wnt-related discussion has focused on aging and cancer, but the last round was all regeneration.
vertebrate regeneration is under the control of the powerful Wnt signaling system: Activating it overcomes the mysterious barrier to regeneration in animals like chicks that can't normally replace missing limbs while inactivating it in animals known to be able to regenerate their limbs (frogs, zebrafish, and salamanders) shuts down their ability to replace missing legs and tails. ... In this simple experiment, we removed part of the chick embryo's wing, activated Wnt signaling, and got the whole limb back - a beautiful and perfect wing
mice have retained incipient potential for continuous tooth generation and that it can be unlocked by activating Wnt signalling. It is reasonable to conjecture that the potential for continuous tooth generation may also have been retained in humans
We've found that we can influence wound healing with wnts or other proteins that allow the skin to heal in a way that has less scarring and includes all the normal structures of the skin, such as hair follicles and oil glands, rather than just a scar ... By introducing more wnt proteins to the wound, the researchers found that they could take advantage of the embryonic genes to promote hair-follicle growth, thus making skin regenerate instead of just repair. Conversely by blocking wnt proteins, they also found that they could stop the production of hair follicles in healed skin.
Human biochemistry is packed with systems like this - vital and influential in regeneration, cancer, aging and other equally important processes and systems. Biology is complex in ways that only an evolved system can be; evolution encourages reuse and multiple purposes for the same component. That in turn leads to balances and trade-offs in longevity, health and evolutionary fitness.
More importantly for us, this complexity makes reengineering our biochemistry a tough job indeed; we're only just getting started, and it's already enough to keep the bulk of the world's medical research community occupied. They won't be finished up any time soon. That's one of the reasons I believe repair strategies like SENS to be a far superior path forward to healthy life extension. Don't struggled through the endless morass of bringing change to the complex systems of our biology: rather, learn how those systems work, and how to repair the specific types of damage that lead to aging. That's a monster of a job in and of itself, but a job that can be achieved rapidly enough to benefit those reading this today.
Tissue engineering and regenerative medicine are starting to see a synthesis of the variety of techniques prototyped in past years. Here's a good example of the type via ScienceDaily, using many of the methods so far developed: "When human heart muscle cells derived from embryonic stem cells are implanted into a rat after a heart attack, they can help rebuild the animal's heart muscle and improve function of the organ ... researchers had struggled to get stem cells to differentiate into just cardiomyocytes, or heart muscle cells - most previous efforts resulted in cell preparations in which only a fraction of 1 percent of the differentiated cells were cardiac muscle cells. By treating the stem cells with two growth factors, or growth-encouraging proteins, and then purifying the cells, they were able to turn about 90 percent of stem cells into cardiomyocytes. The researchers dealt with the other big challenge of stem cell death by implanting the cells along with a cocktail of compounds aimed at helping them grow. The cocktail included a growth 'matrix' - a sort of scaffolding for the cells to latch on to as they grow - and drugs that block processes related to cell death. ... 100 percent of rat hearts showed successful tissue grafts."
Researcher Attila Chordash reminds us that the third Strategies for Engineered Negligible Senescence conference starts on September 6th: "The purpose of the SENS conference series, like all the SENS initiatives (such as the journal Rejuvenation Research and the Methuselah Mouse Prize), is to expedite the development of truly effective therapies to postpone and treat human aging by tackling it as an engineering problem ... SENS3 is not an average conference in any respect and I am really happy to [participate], firstly, as this was the only conference I found where there are both good mitochondrial and stem cell biology sessions and those are my 2 major biological topics. [Secondly] there will be a lot of biogerontology presentations on aging. [Thirdly] because this is the only scientific conference that includes the heavyweight life extension supporter scholar fellows, including the organizer Aubrey de Grey or the practical life extensionist Ray Kurzweil."
Robert Bradbury posts a great deal of very interesting material to the Gerontology Research Group list. Like Aubrey de Grey, he has a "get it done" mindset that focuses on the end goal of healthy life extension, and raised money to make an effort back in the 90s - all of which is somewhat rare in aging research, sad to say. Not enough decisive action, not enough attention to raising funds and changing minds, and far too little straight talk.
It's always worthwhile to note that present best efforts are the next step on a long stairway; looking back, one can always find analagous previous best efforts. Progress is a matter of each round of initiative and fundraising producing greater impact and results than past efforts.
Just recently, Bradbury responded to a fellow looking for advice on fundraising for longevity research in the face of an adverse reactions from potential funding sources ("longevity research is bullshit", "no-one knows why we age," and so forth), from which these thoughts are excerpted:
For example there are books like Caleb Finch's "Longevity, Senescence and the Genome" (922 pages, 160 of which are the bibliography) which clearly documents variances in longevity of many species and goes into some of the causes of aging and why some species may live longer than others. There is Steven Austad's "Why We Age" (244 pages) which explains the evolutionary biology of aging.
Aging and longevity research is not "bullshit", but it should be realized that for a number of reasons one can view "aging research" as a situation similar to that of the 1986 movie with Tom Hanks and Shelly Long, "The Money Pit".
One thing that Aubrey has done a good job of pointing out in various ways is that indefinite longevity does *not* violate any physical laws. And as Steve Austad is good at pointing out (based on Medawar & Williams) there are reasons that "nature" has not handed us a genome which allows us to live indefinitely. And as I like to point out achieving the "impossible" tends to be a matter of timing. No amount of money in the world could buy you your personal genome sequence in 1990, yet today the $1000 personal genome sequence is on the "to be developed" list of the NHGRI (at NIH) (as well as a number of companies who see it as a $$$ milk machine).
I will be more than happy to stand in front of anyone claiming that pursuing "indefinite longevity" is "bullshit" and rip them to shreds (there are some images that were probably cut from Sopranos episodes that come to mind here...).
It is useful to keep in mind that Larry Ellison, through the Ellison Medical Foundation, has probably personally dumped between $100 and $200 million into aging research and it could easily be argued that there is little to show for it. One of the key reasons for that, IMO, is that the money was spent within a "research" framework rather than a business (solution) framework. If we had days for discussion we could examine how much of the money ($500-800 M/year???) being spent by the NIA is being spent "effectively".
One way to prevent money from being spent wastefully is to have a clear goal up front to *produce* a deliverable -- where the deliverable is *not* a set of words on a piece of paper (the byproduct of most "research"). There should be a well defined set of steps to get from the current science to that deliverable. It could be argued that a lot of the "sunk" funding into aging and longevity research was spent before the science was as robust as it currently is so claims regarding "longevity bullshit" (which even I may have made a decade ago) are no longer valid.
I strongly urge you to *not* specify "research of (or on) longevity". The science and theoretical basis of "longevity" is well understood. The mechanics of how it is accomplished in specific species (tortoises vs. sequoia trees) is less well understood. And you could easily dump tens to hundreds of millions of $ into researching how each long lived species achieves longevity (bats, elephants, whales, tortoises, lobsters, geoducks, etc.) and have very little to show with respect to extending human longevity.
A little history of the cancer stem cell theory, and evidence thereof, from the New York Academy of Sciences: "Virtually all cancers are believed to arise from a single faulty cell. But the notion that any cell can be mutated to give rise to new tumors has been replaced by the idea that only a subset of cells, those with self-renewing properties, has the paradoxical effect of conferring immortality to the tumor at the same time they threaten the life of their host organism. ... Before the cancer stem cell theory took hold it was thought that any tumor cell remaining in the body after surgery, radiation, or chemotherapy had the potential to resurrect cancer in its most aggressive form. This model led to treatments, not uniformly successful, that targeted the destruction of every cancer cell regardless of its function. Recently, [scientists] have learned that only a small subset of tumor cells can re-initiate full-blown disease. The implication of the cancer stem cell model is that targeting cancer stem cells, rather than every aberrant cell in the body, might bring about long-term remissions or even cures, and turn many currently deadly cancers into truly manageable diseases."
Here's a report on increasingly sophisticated analysis of genes that contribute to natural longevity: "People who live to 100 or more are known to have just as many - and sometimes even more - harmful gene variants compared with younger people. Now, scientists [have] discovered the secret behind this paradox: favorable 'longevity' genes that protect very old people from the bad genes' harmful effects. The novel method used by the researchers could lead to new drugs to protect against age-related diseases. ... researchers were able to construct a network of gene interactions that contributes to the understanding of longevity. In particular, they found that the favorable variant of the gene CETP acts to buffer the harmful effects of the disease-causing gene Lp(a). ... researchers are greatly expanding their longevity research: From the 66 genetic markers examined in this study, they are now using a high-throughput technology that allows them to assay one million genetic markers throughout the human genome. The goal is to find additional genetic networks that are involved in the process of aging."
The latest Nature Reviews Molecular Cell Biology contains a collection of interesting papers on the biology of aging. Interestingly, nothing on the role of oxidative damage or mitochondria in aging, but many of the other major areas of present mainstream biogerontology are covered.
Over the past 15 years it has become clear that mutations in genes that regulate endocrine signalling pathways can prolong lifespan. Lifespan can be increased by altered endocrine signalling in a group of cells or a single tissue, which indicates that crosstalk between tissues functions to coordinate ageing of the organism. These endocrine pathways might serve as targets for the manipulation of the ageing process and prevention of age-related diseases.
Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time - a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA-protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms.
Recent data suggest that we age, in part, because our self-renewing stem cells grow old as a result of heritable intrinsic events, such as DNA damage, as well as extrinsic forces, such as changes in their supporting niches. Mechanisms that suppress the development of cancer, such as senescence and apoptosis, which rely on telomere shortening and the activities of p53 and p16INK4a, may also induce an unwanted consequence: a decline in the replicative function of certain stem-cell types with advancing age. This decreased regenerative capacity appears to contribute to some aspects of mammalian ageing, with new findings pointing to a 'stem-cell hypothesis' for human age-associated conditions such as frailty, atherosclerosis and type 2 diabetes.
We are complex networks of interacting, self-modifying, slowly damaged systems. Scientists are still in the process of describing human biochemistry in enough detail to manipulate it in ways we would like. Understanding and intervening in the aging process is a task and a half, that much is sure. But what else could be the rational response to suffering and death on a massive scale? We can see that something can be done, and so must act.
The viewpoint driving groups like the Lifeboat Foundation and the Center for Responsible Nanotechnology is illustrated well in this post from Accelerating Future: "There are two sides to living as long as possible: developing the technologies to cure aging, such as SENS, and preventing human extinction risk, which threatens everybody. Unfortunately, in the life extensionist community, and the world at large, the balance of attention and support is lopsided in favor of the first side of the coin, while largely ignoring the second. I see people meticulously obsessed with caloric restriction and SENS, but apparently unaware of human extinction risks. There's the global warming movement, sure, but no efforts to address the bio, nano, and AI risks. ... if we develop SENS only to destroy ourselves a few years later, it's worse than useless. It's better to overinvest in existential risk, encourage cryonics for those whose bodies can't last until aging is defeated, and address aging once we have a handle on existential risk, which we quite obviously don't." I disagree with this viewpoint; I think that history shows people do pay attention and organize to deal with threats of this nature as they become apparent; the Lifeboat Foundation is a part of that process. If anything, the problem is overreaction to perceived threats - and manipulation and exploitation of those who understand such threats poorly - while research and progress towards transformative goals like radical life extension is underfunded, poorly understood and much slower than it might be.
An interesting pitch for the latest research on autophagy and calorie restriction from EurekAlert!: "Cutting calories helps rodents live longer by boosting cells' ability to recycle damaged parts so they can maintain efficient energy production. ... Caloric restriction is a way to extend life in animals. If you give them less food, the stress of this healthy habit actually makes them live longer ... How does it work? During the aging process, free radicals - highly reactive byproducts of our cells' respiration - wreak havoc on our cellular machinery. ... younger cells are adept at reducing, recycling and rebuilding. In this process, damaged mitochondria are quickly swallowed up and degraded. The broken down pieces are then recycled and used to build new mitochondria. However, older cells are less adept at this process, so damaged mitochondria tend to accumulate and contribute to aging. ... The stress of a low-calorie diet was enough to boost cellular cleaning in the hearts of older rats by 120 percent over levels seen in rats that were allowed to eat what they wanted."
Every age-related neurodegenerative condition presents researchers with a vast and complex problem to solve; biochemistry is a real challenge, even in this age of rapidly advancing biotechnology, as illustrated by the vast sums required to build scientific infrastructure and win progress from the mysteries of the brain. Even seemingly simple questions remain unanswered, and there are never enough resources to explore every aspect of a biochemical process as well as we'd like.
Here are a couple of pieces illustrative of that state of research: so much to do, small but significant victories in the form of new knowledge, and the vast spaces yet to be explored.
In prior studies, examination of the brain cells of people with Alzheimer's found some defects in an enzyme produced by the cytochrome c oxidase ( COX) gene, which is important for mitochondrial energy production.
In addition, so-called "free radicals," which cause oxidative stress, are produced in the cell's mitochondria, Moraes noted. "It was assumed that when you have a problem with the COX gene, you have more free radicals being formed," he said.
To see how the gene worked, Moraes's group removed the COX10 gene in mice engineered to develop Alzheimer's disease. "We expected to see that these animals would have more amyloid plaques," Moraes said. "But we got the opposite result," he said. The animals without the COX10 gene actually developed fewer brain plaques than those with the gene, Moraes said. "Those animals also had less free radicals," he said.
"The results are consistent with other evidence that reducing free radicals can limit Alzheimer amyloid plaque pathology," Cole added. "Examples include reducing caloric intake or increasing antioxidant intake. So, even though clinical trials to treat Alzheimer's with [antioxidant] vitamin E have been disappointing, earlier and more effective reduction of free radical damage could mimic the success of this genetic approach and should still be pursued,"
Fischer and his colleagues found that while environmental enrichment did not substantially replace the lost hippocampal neurons, it significantly increased the number of connections, or synapses, between the hippocampal neurons that remained. This increase in connectivity, apparently compensating somehow for the previous death of neurons, led the mice to recover the memories that had apparently disappeared with the loss of the neurons.
Amazingly, the researchers identified a chemical that -- in mice -- mimicked the effect of environmental enrichment. They found that the environmental enrichment modifies the function of proteins that regulate the activity of genes; a substance that blocks an enzyme called HDAC (histone deacetylase) seemed to have a similar impact on the gene activity involved, and tests subsequently showed that this HDAC blocker could allow the recovery of lost memories.
If common forms of neurodegeneration can be repaired from the state of memory and function loss - if memories are stored in ways that persist through the early stages of Alzheimer's, for example - hundreds of millions more lives might be saved at the future cusp between merely advanced medicine and the ability to rejuvenate the aged.
The same would be true if everyone adopted the practice of calorie restriction, by the look of the human studies presently taking place, but I'm not holding my breath waiting for that to happen. Most folk would rather not think about the future, or trust themselves to advances in science; while those advances are certainly on the way, it doesn't seem wise to bet on their arrival soon enough to rescue you from any particular fate.
The 7th Alcor Conference is just around the corner, and I noticed via the Alcor blog that DVDs from last year's event are up for purchase. You'll find a 15-minute sample at the Alcor website: "Is it possible to stop aging? Will nanomedicine and medical nanorobots dramatically extend the human lifespan? Can cryopreserved human beings be revived in the future and what impact would result? Distinguished speakers convened at the 6th Alcor Conference in Scottsdale, Arizona, to present their provocative insights into anti-aging, life extension research, nanotechnology, cryonics, and more. ... Brian Wowk discusses the relationship between cryonics and advanced tissue regeneration technology. Aubrey de Grey shares his opinion about offering a cryonics prize for scientists. Ralph Merkle explains how the cryonics experiment is similar to clinical trials to determine whether cryonics will work. Get a sneak peak of Robert A. Freitas' theoretical nanorobots. Tanya Jones and Steve Van Sickle explain advancements and research projects underway at Alcor."
The prize awaiting us when the scientific community attains even a modest control over the mechanisms and actions of cells is great indeed: regeneration and replacement of injured and age-damaged tissue on demand. From ScienceDaily, a look at one small step on the way: researcher have "achieved an additional step for the potential replacement of damaged brain cells after injury or disease: functional nerve cells can be generated from astroglia, a type of supportive cells in the brain by means of special regulator proteins. ... these glia cells function as stem cells during development. This means that they are able to differentiate into functional nerve cells. However, this ability gets lost in later phases of development ... In order to be able to reverse this development, the team studied what molecular switches are essential for the creation of nerve cells from glial cells during development. These regulator proteins are introduced into glial cells from the postnatal brain, which indeed respond by switching on the expression of neuronal proteins. ... single regulator proteins are quite sufficient to generate new functional nerve cells from glia cells."
The everyday philanthropists of the Methuselah Foundation's Three Hundred will be getting an early look at signed copies of Aubrey de Grey and Michael Rae's "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime". From an email presently sitting in my inbox:
As a major supporter of the Methuselah Foundation, you are set to receive a free advance copy of the new book, "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime" by Aubrey de Grey, Ph.D, and Michael Rae.
I have nearly 100 copies of "Ending Aging" sitting here in my living room right now, all hardcover and signed by Aubrey de Grey. The Methuselah Foundation would like to make sure that all "300" members receive their books as soon as possible.
UPDATE: a picture of the living room in question and thoughts on the book from Anne C.
And the Amazon editorial syopsis:
A long life in a healthy, vigorous, youthful body has always been one of humanity’s greatest dreams. Recent progress in genetic manipulations and calorie-restricted diets in laboratory animals hold forth the promise that someday science will enable us to exert total control over our own biological aging.
Nearly all scientists who study the biology of aging agree that we will someday be able to substantially slow down the aging process, extending our productive, youthful lives. Dr. Aubrey de Grey is perhaps the most bullish of all such researchers. As has been reported in media outlets ranging from 60 Minutes to The New York Times, Dr. de Grey believes that the key biomedical technology required to eliminate aging-derived debilitation and death entirely -technology that would not only slow but periodically reverse age-related physiological decay, leaving us biologically young into an indefinite future - is now within reach.
In Ending Aging, Dr. de Grey and his research assistant Michael Rae describe the details of this biotechnology. They explain that the aging of the human body, just like the aging of man-made machines, results from an accumulation of various types of damage. As with man-made machines, this damage can periodically be repaired, leading to indefinite extension of the machine’s fully functional lifetime, just as is routinely done with classic cars. We already know what types of damage accumulate in the human body, and we are moving rapidly toward the comprehensive development of technologies to remove that damage. By demystifying aging and its postponement for the nonspecialist reader, de Grey and Rae systematically dismantle the fatalist presumption that aging will forever defeat the efforts of medical science.
Why is it that some mammals live far longer than other, quite similar species? The mainstream of aging research is attempting to pin down the answer to that question, on the way to optimizing human metabolism for longevity and resistance to age-related disease: "the specific composition of tissue macromolecules (proteins, lipids and mitochondrial DNA) in long-lived animal species gives them an intrinsically high resistance to modification that likely contributes to the superior longevity of these species. This is obtained in the case of lipids by decreasing fatty acid unsaturation, and in the proteins by lowering their methionine content. Long-lived animals also show low rates of reactive oxygen species (ROS) generation and oxidative damage at their mitochondria. On the other hand, dietary restriction decreases mitochondrial ROS production and oxidative damage to mitochondrial DNA and proteins. These changes are due to the decreased intake of dietary proteins (not of lipids or carbohydrates) of the dietary restricted animals. In turn, these effects of protein restriction seem to be specifically due to the lowered methionine intake of the protein and dietary restricted animals. It is emphasized that both a low rate of generation of endogenous damage and an intrinsically high resistance to modification of tissue macromolecules are key traits of animal longevity." Less damage, longer life - demonstrated very handily by the naked mole-rat, in fact.
Much of Alzheimer's research is focused, rightly or wrongly, on getting rid of amyloid-beta or tau tangles. Immunotherapy has proven promising against amyloid, and EurekAlert! shows these techniques aimed at tau: "The therapeutic approach is based on using fragments of abnormal tau protein as a vaccine. These fragments are studded with phosphate groups, which are thought to promote the aggregation of tau. The antibodies generated by the vaccine are therefore likely to bind to abnormal tau and promote its breakdown. Normal tau, which would be far less affected, has such important biological functions as facilitating transport of chemicals within neurons and maintaining their structure. ... Compared to extracellular amyloid plaques, tau aggregates are confined inside of brain cells, making them more difficult to reach. ... It's likely that there's a synergism in the pathology. Amyloid pathology may cause tau pathology and tau pathology might cause more amyloid ... The vaccine successfully slowed the deterioration of motor abilities produced by excessive amounts of tau in the central nervous system of mice."
With the addition of a generous donation from entrepreneur Brian Cartmell, the Methuselah Foundation now has seven six-figure pledges to its name, the other foward-looking supporters of healthy life extension research being Gary Hudson, Brad A. Armstrong, David Fisher, the Scott B. and Anne P. Appleby Charitable Trust, the Glenn Foundation for Medical Research and one anonymous philanthropist. Above that, two seven-figure pledges, from Peter Thiel and an anonymous philanthropist. Below that, 140 or so $25,000 pledges from members of The Three Hundred, of which twelve have donated five-figure sums already.
I point this out because I realized it wasn't all that long ago that the five-figure pledges were beginning to roll in to the Foundation on a regular basis, and I marked it as a real sign of progress at the time. Six figures are the new five figures as the Methuselah Foundation continues to grow - we should all be pleased to see resources attracted at an increasing rate to the best of efforts to defeat age-related degeneration, suffering and death.
The Methuselah Foundation has a real shot at growing into a large, sustaining, influential and shaping body in aging research, steering not just its own research funds to best effect but lighting the way for millions and then billions of dollars more from other organizations. Convincing the mainstream of research funding that repair of aging is in fact very plausible and comparatively close at hand, given large-scale funding - now there's a goal. Every boulder is a pebble at the head of a larger avalanche, and revolutions start with a single idea spoken out loud and single dollar on the table to fund the first step.
The stranglehold of conservatism on a field of science is broken by obtaining enough independent resources to move down the path ahead - at which point the rest of the field will follow, loudly declaiming that they knew you were right all along. Which I'm happy to suffer, provided they get started soonest; there is a great deal of work to be done if we are to live in good health for as long as we'd like to.
You'll find a respectful article on the Alcor Life Extension Foundation in the latest AzBusiness: "Clearly the freezer is more attractive than the grave, even if one has doubts about the future capabilities of science. With bad luck, the frozen people will simply remain dead, as they would have in the grave. But with good luck, the manifest destiny of science will be realized, and the resuscitees will drink the wine of centuries unborn. The likely prize is so enormous that even slender odds would be worth embracing ... Alcor's challenge is two-fold, with both a reversal of the vitrification process and cures for the diseases suffered by its patients necessary for reanimation to occur. ... there's damage below minus 130 with the vitrification. That damage will still need to be reversed. [There will be] gross fractures that will have to be repaired, and it's probable that molecular nanotechnology and medical nanotechnology will be required to fix people. We also need the cures ... Eventually I believe cryonics is going to be perceived as a common medical practice, maybe not by 2028 but possibly not too far after that. It will be used in cases where if a sudden virus comes up that is killing people, then you're put into a preserved state until a cure is found. This will be an alternative, but that will only occur once this is reversible. There really isn't a realistic timetable yet because we are relying on nanotechnology to develop - we're probably looking at 50 years."
Spam Arrest founder Brian Cartmell has stepped up to donate $100,000 to the Methuselah Foundation: "It's my privilege to be able to financially contribute to the continued and successful operation of The Methuselah Foundation. Too often, people dismiss researchers such as Dr. Aubrey de Grey for engaging in what they consider pie-in-the-sky science, but it's my opinion that Dr. de Grey encourages a creative and intelligent approach towards alleviating the suffering that unnecessarily accompanies the aging process. By focusing research on the damage that occurs at the cellular and molecular levels, the scientists involved with The Methuselah Foundation can potentially offer radical new solutions to our current litany of age-related physical and mental dysfunctions - and I like radical! ... Mr. Cartmell's donation will be invested in SENS-related research. SENS is an engineering approach that aims to obviate the causes of human aging. ... this donation will attract $50,000 in matching contributions from the $3 Million fund established in 2006 by Facebook angel investor Peter Thiel. This new donation will help to extend Methuselah Foundation research into the bioremediation of damaging age-related byproducts in tissue, the protection of fragile mitochondrial DNA and future programs addressing other aspects of SENS, each tackling a specific aspect of age-related biochemical and cellular damage."
I, and many of you folk no doubt, rest my optimism for the potential of longevity medicine atop our hard-won knowledge of physics. The physics of molecules and atoms, the building blocks of our biology is very sound, very proven - and it tells us that there is no reason why we can't build cells from scratch and nanomedical robots to repair the molecular damage of aging in those cells. The path is clear, we can read the nearest waysigns, but we have some walking to do. As Eliezer Yudkowsky puts it:
Consider the statement "It is physically possible to construct diamondoid nanomachines which repair biological cells." Some people will tell you that molecular nanotechnology is "pseudoscience" because it has not been verified by experiment - no one has ever seen a nanofactory, so how can believing in their possibility be scientific?
Drexler, I think, would reply that his extrapolations of diamondoid nanomachines are based on standard physics, which is to say, scientific generalizations. Therefore, if you say that nanomachines cannot work, you must be inventing new physics. Or to put it more sharply: If you say that a simulation of a molecular gear is inaccurate, if you claim that atoms thus configured would behave differently from depicted, then either you know a flaw in the simulation algorithm or you're inventing your own laws of physics.
It is rational to believe, on the basis of solid evidence, that possible beneficial technology will be built. Which is not say that any particular beneficial technology will be built to a defined schedule - schedules, like the work of building, require those notoriously ornery humans to be organized and willful. There are any number of possible technologies that could exist today, but have yet to be built.
And so on to this rather interesting remark:
there are people who apparently believe "Medical interventions aimed at immortality are, therefore, a potential source of evil." That has got to be the worst version of Stockholm Syndrome ever seen. And it's utterly beyond my comprehension. I say to those folks: if you don't want to live a long time, you're free to jump out of a skyscraper any day you want. Please let the rest of us encourage, and maybe benefit from, anti-aging research.
Stockholm Syndrome indeed; we are brutalized by the human condition, yet you'll find its defenders everywhere. The world is seemingly full of people aging to death yet willing you and I to suffer and die on the same schedule:
Nuland also devotes a chapter to the work of Aubrey de Grey and others who believe that aging is simply an engineering problem that can be solved, allowing humans to live for centuries if not forever. He questions the wisdom of striving to extend life beyond its natural limits (approximately 120 years) and stands by the view that "both individual fulfillment and the ecological balance of this planet are best served by dying when our inherent biology decrees that we do."
If one agrees with this perspective (as I do), then the task for each of us is to live a long and healthy life not because we are afraid and want to live forever but because we love life, we embrace the cycle of generations and we value the future of those who will live long after we are gone.
I find it hard to get inside that mindset - "life is good, so die already." Not to mention the odd and entirely false idea that 120 years of life is in any way a natural limit, or the errant Malthusianism and hints of old pagan memes inherent in a concept of "ecological balance" that requires human sacrifice. It suffices as a reminder that our fellow travelers are strange folk indeed.
Via the Immortality Institute forums, I note that "Do You Want To Live Forever?" is now up at Google Video: a "Channel 4 documentary following the revolutionary life-extension and immortality ideas of this somewhat eccentric scientist Dr. Aubrey de Grey ... This show is all about the radical ideas of a [biomedical gerontologist] called Aubrey de Grey who believes that, within the next 20-30 years, we could extend life indefinitely by addressing seven major factors in the aging process. He describes his work as Strategies for Engineered Negligible Senescence (SENS)." I've concluded that "eccentric" actually means "has ideas I would never have" in common parlance. In a world of people who accept the status quo - no matter how terrible - and barely look beyond their noses, we need more visionaries, iconoclasts and driven, unreasonable people. They are the source of progress. The video is well-regarded by the folk at the Immortality Institute; you should take the time to watch.
Of interest today, a paper from Barzilai et al at the open access journal PLoS Genetics: "Human geneticists have only recently begun to use the tools of linkage analysis and association studies to identify alleles contributing to exceptionally long life spans. Interesting candidates have emerged from these studies. There is virtually no information, however, on the genetic basis of differential rates of decline in well-defined physiological functions among human populations. We shall argue that such studies, particularly those that are initiated in middle age, before the onset of complicating comorbidities, should have a high priority for research, as they would have the potential to discover genes that impact on rates of aging within various organ systems. ... Parents of centenarians (born in 1870) were shown to have approximately nine times the odds of living to the tenth decade as compared to controls. Siblings of centenarians were shown to have up to an 18-fold increase in the chance of achieving a similar age. Such data have raised the possibility that some specific genetic modulators of aging in humans can be identified using such populations, and that conserved pathways for exceptional longevity might thus be validated."
As time moves on, scientists continue to add weight of evidence to demonstrate that ever smaller amounts of excess body fat are in fact quite bad for your health and longevity over the years. Here's another example of this sort of research:
For the study, Dr. de Lemos and his colleagues examined data from the ongoing Dallas Heart Study, which is evaluating risk factors for heart disease in a large, multiethnic, urban population with a median age of 45. The new substudy focused on a group of 2,744 participants who had noninvasive imaging tests to look for early signs of plaque build-up in the arteries, which signals an increased risk of developing cardiovascular disease later in life.
Electron-beam computed tomography (EBCT) was used to identify calcium deposits in the arteries of the heart. These deposits indicate the onset of atherosclerosis, or so-called hardening of the arteries, and can be detected years before a person experiences chest pain or has a heart attack. Magnetic resonance imaging (MRI) was used to look for early signs of atherosclerosis in the walls of the aorta.
Researchers then examined the relationship between body shape and early signs of arterial disease. They found that the likelihood of calcium being found in the arteries of the heart grew in direct proportion to increases in the waist-to-hip ratio (WHR). In addition, when they divided the WHR into five groups from smallest to largest, they found that people with the largest WHR were nearly twice as likely to have calcium deposits in their coronary arteries as those with the smallest WHR. The likelihood of atherosclerotic plaque in the aorta was three times as high in those with the largest WHR as compared to the smallest.
The relationship between WHR and arterial plaque remained strong even after other risk factors, such as blood pressure, diabetes, age, smoking and high cholesterol levels were taken into account.
One of the many ways in which calorie restriction benefits healthy longevity is no doubt through minimizing this sort of age-related damage - but avoidance of damage scales with avoidance of fat, as noted above. Pick the level that works for you, but why damage yourself unnecessarily?
An era of growth, change and wonder will commence in the decades ahead, far greater and more glittering than anything seen to date. We will build technology to take us to the stars and bring control over all matter. Disease will be a memory, and we will all have access to capabilities beyond the reach of billionaires today. Youthful lives of centuries and more will be enabled by rejuvenation medicine we can visualize today - but only those of us still alive and healthy for the first steps towards real anti-aging therapies will be able to take part.
The first years of the 21st century are the gentle foot of an exponential curve of wealth, life and technology - up and away. Why increase your risk of missing that ride by failing to keep up with the health basics today?
Why spend time and resources in activities you know significantly damage your health? Doing so steals the most valuable possession possible - years of healthy life that might have let you reach an age of radical life extension - from the person you will one day be. You're picking your own pocket, cutting your future self short. For example: "The smoke of cigarettes represents an important accelerator of the aging process, both directly through complex mechanisms mediated prevalently by excessive formation of free radicals, and indirectly by favoring the appearance of various pathologies ... smoke compromises not only life expectancy, but also the quality of the life, favoring the occurrence of non-autosufficiency. Smoking is an important risk factor for many diseases, such as cancer, cardiovascular and respiratory diseases. ... Non-smokers have a much higher life expectancy than smokers, and the suspension of smoking is accompanied, even in the elderly, by an increase in the survival time due to the reduction of smoke-induced biological damage. ... Among [centenarians], smoking is extremely rare, and even when it occurs among them, it is correlated almost exclusively to bad health conditions and non-autosufficiency, indicating that it compromises health status and the quality of life even in extremely long living subjects."
From Courant.com: "Old people die, but they don't die of old age ... Organs wear down, diseases catch up; there's always a specific reason for a person's death. Though it's assumed that a centenarian didn't die in a rock-climbing accident, vague terms such as 'old age' don't help disease research. ... You're not trying to cure old age, you're trying to cure the conditions that caused the death." Which is at once the right and the wrong focus; right in that there should be no mystery left to aging once the biotech revolution is in full swing - every stone will be turned, every biochemical process recorded, every cellular change catalogued. But this focus is wrong in that we should not fixate on the end stage conditions if we want to make rapid progress in extending healthy life. Rather we should look for common forms of change and damage, and seek to repair them early and often. Our bodies are complex machinery, and the rules of maintenance apply here too. No machinery can last forever when left alone, but effective repair and preventative care can continue for so long as you care to do so - we just haven't developed the necessary technologies to do this for the human body. Yet.
From the perspective our own long-term future as living beings, an understanding of how the mind works - or rather how the biology of the brain supports and enables the mind - is vital. Why is this? Let us start with this: the approach to longevity research I think to be best over the next few decades is SENS or a similar repair strategy. We are clearly going to struggle to rebuild ourselves - even understand our biochemistry - rapidly enough to halt aging within our lifetimes. The repair approach, as illustrated by the Strategies for Engineered Negligible Senescence (SENS), is in effect a way of working around our ignorance of metabolism and biochemical complexity but still achieving results. We focus on what we do know, the forms of damage and change that accumulate with aging, and the plausible methodologies for preventing and repairing this damage.
All fine and well so far. But you have to play the odds. Let's say that we run into problems repairing biomolecular damage of aging in a kidney, say, and the organ continues to fail at advanced age. Suppose the research community runs into a real tough roadblock in kidney biochemistry that might take decades to work through. That isn't so threatening for a kidney; grow a new, young kidney from scratch via the nascent science of tissue engineering, or employ one of the artificial replacements presently in the works.
The brain, on the other hand, is a whole different kettle of fish. It is your foundation and self, plain and simple. There can be no wholesale replacement of tissue, and so the risk of long-lasting roadblocks and tough periods in rejuvenation research for the brain is a serious threat.
What, then, will be the causes of age-related death 30 years from now? The body is an exceedingly complex machine; blocking off one failure mode, or preventing a single mode of death that results from a class of accumulated damage will leave many other possibilities. Behind the neurodegenerative diseases we know lie a hundred, a thousand ever more subtle and devilish ways in which age-related cellular damage can kill us. You can plug as many holes as you like, but eventually you're going to run out of fingers.
From where I stand, the true benefit of metabolic and biochemical research into the mechanisms of human life - at ever increasing levels of detail and complexity - is that it enables and supports the more direct approaches to extending longevity like SENS. The more you know, the more you can do. The better the tools honed in basic research, the better the resulting science and technology. So it is reassuring to see that scientists continue to make progress in understanding the biology of the mind:
What happens in our brains when we learn and remember" Are memories recorded in a stable physical change, like writing an inscription permanently on a clay tablet" Prof. Yadin Dudai, Head of the Weizmann Institute’s Neurobiology Department, and his colleagues are challenging that view. They recently discovered that the process of storing long-term memories is much more dynamic, involving a miniature molecular machine that must run constantly to keep memories going. They also found that jamming the machine briefly can erase long-term memories. Their findings [may] pave the way to future treatments for memory problems.
“This drug is a molecular version of jamming the operation of the machine,” says Dudai. “When the machine stops, the memories stop as well.” In other words, long-term memory is not a one-time inscription on the nerve network, but an ongoing process which the brain must continuously fuel and maintain. These findings raise the possibility of developing future, drug-based approaches for boosting and stabilizing memory.
Inkjet printing and rapid prototyping technologies are finding their place in the field of tissue engineering. Fabrication of bone, for example, is moving forward nicely. From LiveScience: "First, the patient's actual bone structure is scanned with X-ray and CT scanners. The resulting data is combined to make a three-dimensional computer model of the bone; a set of cross-sections is sent to the special 3D inkjet printer. The 3D inkjet printer prints onto thin layers of powdered alpha-tricalcium phosphate (alpha-TCP); the printer 'ink' is a water-based polymer that hardens the alpha-TCP. Successive laydowns of powder and polymer 'prints out' the bone cross-sections to an accuracy of one millimeter. The resulting artificial bone is lightweight and porous; very similar to the original human bone used as a model ... the new artificial bones created from the alpha-tricalcium phosphate powder and polymer are ten times stronger than earlier implants made from hydroxylapatite ... Researchers [have] performed trials on ten people in the past year and a half [and] hope to make the technology commercially available by 2010."
As I'm sure you're all aware, mutations of mitochondrial DNA are an important form of age-related damage - any strategy for extending healthy life span must either repair this damage or make it irrelevant. Here, the Daily Mail has more news on repair efforts: "Defects in this mitochondrial DNA are blamed for a range of rare genetic diseases, including some forms of diabetes, blindness and heart problems. They have also been linked to ageing - suggesting that fixing the flaws could slow down the onset of old age. ... by labelling the functional genes with an "address code" - which effectively tells them where to go - French scientists have succeeded in smuggling them inside the mitochondria. Once there, the pair of genes repaired the damage behind a rare form of blindness and a muscle wasting disease ... In time, the same approach could be used to create injections of genes that will erase flaws thought to be linked to the ageing process. However, while this might slow down ageing, it would not halt it completely, as mitochondria are just one of many factors involved in the ageing process."
Those folk who advise and control vast sums of money can afford few illusions, and certainly no ignorance. So it is that actuaries, financial managers in the insurance industry and similar figures form one part of our culture comparatively well-educated on the prospects for healthy life extension.
Consultancy firm Lane Clark & Peacock has warned that this is due to underestimating future increases in life expectancy and remaining heavily invested in equities.
More than a quarter of FTSE 100 pension schemes updated their life expectancy assumptions in 2006, adding an average 1.5 years to the estimated life expectancy of a pensioner aged 60 in the UK, according to the firm.
Research has shown that people born between 1925 and 1945 were living far longer than expected and actuaries have begun using a "medium cohort" adjustment, which reflects these improvements in mortality rates.
But the consultancy said that even the updated allowances for future life expectancy may not be enough. It added that each extra year of life expectancy adds around 12 billion pounds to pension liabilities.
Any form of betting against increased health and longevity in the decades ahead is looking to be increasingly unfortunate, risky or outright foolish, depending on when the bet in question was first initiated. But we shouldn't feel at all sorry for those taking massive losses - money is a far less valuable or fundamental asset than years of healthy life. Given the latter, it's quite trivial to produce more of the former, after all.
As longevity increases, we all benefit, even those who bet on death.
Sarcopenia, age-related muscle loss, is well known as a common result of aging - and the resulting lack of exercise hastens age-related decline in other ways. Scientists have demonstrated in recent years that adding the amino acid leucine to the diet prevents this progression, based upon a theory of age-related defects in protein machinery. Here, ScienceDaily notes a more general dietary theory, that the elderly consume less protein: "Since nutritional studies show that many elderly individuals eat less protein than the average person, researchers have reasoned that if the elderly simply increased their protein intake, they might slow down muscle loss -- as long as old age doesn't inherently interfere significantly with the ability to make muscles out of the protein in food. ... We wanted to know if there is some reason your grandmother's body, for example, can't stimulate muscle growth in response to eating the same protein-rich meal that you eat, which might over time contribute to muscle loss ... older bodies are just as good as young ones at turning protein-rich food into muscle." Which is interesting when compared with several lines of work suggesting that there are age-related issues with the process of building muscle - it goes to show just how much work is left to do in even the seemingly simple aspects of our biochemistry.
This paper offers a reminder that nothing in biology is as simple as we'd like it to be: "Mitochondrial dysfunction has long been considered a key mechanism in the ageing process but surprisingly little attention has been paid to the impact of mitochondrial number or density within cells. Recent reports suggest a positive association between mitochondrial density, energy homeostasis and longevity. However, mitochondrial number also determines the number of sites generating reactive oxygen species (ROS) and we suggest that the links between mitochondrial density and ageing are more complex, potentially acting in both directions. The idea that increased density, especially when combined with mitochondrial dysfunction, might accelerate ageing is supported by a negative correlation between mitochondrial density and maximum longevity in an interspecies comparison in mammals, and by evidence for an intimate interconnection between cellular ROS levels, mitochondrial density and cellular ageing. ... We hypothesise that increased mitochondrial biogenesis, and possibly also impaired degradation and segregation of mitochondria, if occurring as adaptation to pre-existing mitochondrial dysfunction, might aggravate ROS production and thus actively contribute to ageing."
Rando previously discovered [that] old stem cells will act younger if exposed to younger blood. That's very troubling news for efforts to develop rejuvenating cell therapies. If the whole body is full of chemical signals that suppress growth then just replacing older stem cells with younger stem cells won't yield as much increase in healing and repair as our aging bodies need.
Another research group has just discovered that Wnt is able to suppress mouse stem cell activity because as mice age their bodies make less of another protein called klotho. Well, klotho restrains Wnt and the absence of klotho causes Wnt to suppress stem cell division. ... You might think hey, why not deliver klotho hormone replacement therapy to slow or reverse cellular aging? Good question. Let me put the question another way: Why does klotho production decline with age? Is it just due to accumulation of damage to klotho-making machinery? My guess: the decline of klotho happens in order to reduce the risk of cancer. As cells age they accumulate mutations that could become cancerous. By slowing cell division by reducing klotho the body reduces healing but on average that reduction in healing becomes a net benefit due to avoided cancer.
It's a good educated guess - a number of important mechanisms involved in growth, repair and metabolism in mammals have evolved to a balance between aging and cancer resistance. Simply turning the dial is not a satisfactory solution; you'll either get more aging or more cancer. Solutions at that level of biochemical and genetic engineering have to be smarter - and more complex.
That added level of complexity is one fundamental reason for supporting biomolecular repair research like SENS instead. Don't attempt to change the system, our vastly complex human metabolism, but rather learn how to clean up after it. Repairing the damage and reversing the changes of aging at the level of cells and macromolecules is a much less onerous task that reengineering human biology - while still being a challenge of billions of dollars and tens of years - but one that can bring far greater near-term benefits to health and longevity.
That amyloid levels in the brain are very dynamic is a comparatively recent discovery. Buildup of amyloid beta in Alzheimer's is likely not a matter of slow accumulation, as the amyloid material is constantly generated and destroyed in a matter of days, but rather slow failure of the active mechanisms for removing this toxic substance. Some researchers are taking aim at this process, as noted at ScienceDaily: "The team concentrated its efforts around a protein known as sLRP (soluble low-density lipoprotein receptor-related protein). The team discovered that in healthy people, the protein binds to and neutralizes anywhere from 70 to 90 percent of the amyloid-beta that is circulating in the body. ... Levels of sLRP in people with Alzheimer's were about 30 percent lower than in healthy people, and the sLRP that was present was almost three times as likely to be damaged compared to the same protein in healthy people. ... Zlokovic's group decided to try to reduce amyloid-beta levels in the body by synthesizing an altered, super-potent form of sLRP ... In blood samples from patients with Alzheimer's disease, the modified version of sLRP, known as LRP-IV, soaked up and virtually eliminated amyloid-beta. ... in mice with features of [Alzheimer's] LRP-IV lowered the levels of amyloid-beta in their brains by 85 to 90 percent."
Via GrailSearch, a look at aging from Legendary Pharmaceuticals, a company working on AGE-breakers. Don't miss the huge diagram of aging biochemistry: "Human life is supported by a complex network of biochemical substances and reactions which affect the physical state and vitality of the body and mind. Senescent changes can be seen in the rate and outcome of many of these reactions. However, many of these changes are secondary effects of senescence, rather than primary causes. ... John D. Furber of Legendary Pharmaceuticals has put together a visual model of aging referred to as 'The 2007 Network of Biological Interactions in Human Aging' that shows the interactions between various subcellular, cellular, extracellular matrix and organ system. This is a great representation of aging as it demonstrates no root cause but rather a network of problem areas that are interlinked. The goal of systems biology would be to flush this out in great detail allowing one to zoom in down to the specific genomic and proteomic components of aging."
The science behind the work of groups like Sirtris Pharmaceuticals is based on the study of calorie restriction (CR) and sirtuins - but are sirtuins actually at the root of the biology that drives extended health and longevity through CR? A few contrary positions exist, as is usually the case when research in a field is still dynamic and unfolding. An informative post from Michael Rae can be found in the Methuselah Foundation forums:
Kaeberlein is a former grad student of Leonard Guarente's, and collaborated with him on many studies on "long-lived" mutants of the common yeast Saccharomyces cerevisiae. However, he's become an increasingly vocal critic of the thesis -- first advanced by Guarente, and promulgated even more fiercely by another former Guarente protege, David Sinclair -- that the effect of "CR" on "lifespan" in yeast is mediated by activating the histone deacetylase enzyme Sir2 -- the yeast homolog of the mammalian SIRT1.
The literature of gerontology is littered with alleged models of premature aging, in which the deletion of a gene or the imposition of some stressor leads to what is alleged to be an "accelerated aging" phenotype ... Almost anything that interferes with the normal metabolism of an organism but is not immediately fatal will result in a gradual loss of aspects of organismal function that will bear some analogy to "aging;" the question is what if any relationship they bear to "normal" aging. ... Kaeberlein and Powers present evidence that aspects of the CR/sirtuin hypothesis exhibit the same confusion.
Kaeberlein and Powers put forward a nascent alternative hypothesis which needn't concern us here. The strongest rebuttal is that one does not have to offer an alternative mechanism in order to demonstrate that the original is flawed. At this point, if the hypothesis is "reducing glucose concentration in yeast extends replicative lifespan in budding yeast through the activation of Sir2," then that thesis clearly stands on very weak grounds.
And if the hypothesis is, "compounds that activate sirtuins will act as pharmacological mimetics of life-extending Calorie restriction in humans," then I would say that it is outside of the realm of science, and into the realm of science fantasy, until someone shows me the slim, genetically-normal, 45-month-old, fully-fed but sirtuin-activated mouse.
Punchy, but science doesn't have to be weighed down by decorum. There's more than enough money behind sirtuin research and other biochemical pathways relating to calorie restriction for questions to be settled over the next five years, I would imagine. I expect us all to know exactly how calorie restriction works sometime prior to 2012 - a few years to find the root mechanism, and a couple more to validate it.
Chris Patil looks at recent attempts to find common mechanisms in accelerated aging disorders: "some conditions are best thought of 'segmental' progerias (in that they model aging only in specific organs or cell types), whereas others model the natural aging process very closely in the majority of tissues. Chief among the latter are Werner's Syndrome (WS) and Hutchinson-Gilford Progeria Syndrome (HGPS). The underlying mutation in the two diseases are quite different: WS is due to a mutation in a DNA helicase involved in repair, whereas HGPS is caused by a dominant mutation in lamin A/C, which is critical to nuclear structure (and consequently in gene regulation). While the diseases have distinct phenotypes and ages of onset, they are both widely considered good models of accelerated aging. What, if anything, is the common currency between the two? ... Cox and Faragher argue that premature cellular senescence is likely to be important in both WS and HGPS ... According to this model, senescence (which permanently growth-arrests old and damaged cells) prevents individual cells from forming tumors, but persistent senescent cells embark on a highly anti-social program of gene expression that can [damage] surrounding tissues and may contribute to age-related decline in tissue function."
Biology is information, thus all human interaction with biology is a computational challenge - and so is the quest to defeat aging. The future of biotechnology is entwined with the future of computational power: simulations, complexity management in therapies and tools, and much more. From TechNewsWorld: "while the scientific community knows how to study aging much better than a few decades ago, the idea that aging is a disease is still very contentious. That's because, if aging is a disease instead of a normal phase of life, that implies that something must be done to stop it -- politically a lost cause in many cases ... the best and brightest ought to be looking for ways to fight age-induced disease, and one powerful weapon in this quest is computer-based biological modeling. Computer scientists can make a huge impact on this area of inquiry and should work toward partnering with scientists ... Aubrey de Grey, a well-known leader of the anti-aging movement, started out in computer science and is now applying that knowledge to biology. His example should be emulated. ... Whether or not federal grant makers like it, aging research and practitioners are moving forward. ... The idea that aging is a disease will someday be as common as an online game. In the meantime, important advances in fighting age-related disease are in the works and computer scientists are playing an important role. That role should be allowed to expand, without political interference."
The single gene mutations and targeted antioxidant methodologies for increased longevity are rolling in of late. I expect that the optimization of mouse metabolism will accelerate as the biotechnology revolution continues to pick up speed - that, sadly, is still the goal most research groups are aiming for, rather than identification and repair of age-related damage. Still, at this rate, the existing Mprize champions will be dethroned by the end of 2012.
Here's the most recent example, coming out of focused research into one small part of the grand complexity of mammalian biochemistry:
Genetic deletion in mice of pregnancy-associated plasma protein A (PAPP-A), a recently identified metalloproteinase in the insulin-like growth factor system, extends by 30-40% both mean and maximum lifespan with no reduction in food intake or secondary endocrine abnormalities. Furthermore, these mice have markedly reduced incidence of spontaneous tumors. The findings implicate PAPP-A as a critical regulator of lifespan and age-related diseases, and suggest PAPP-A as a possible target to promote longevity.
More life, less cancer, no obvious downside - for mice, in any case. It is interesting to note that these divergent genetic engineering and other methodologies for tweaking metabolic processes seem to top out at around 30-40% increased longevity in mice, just like calorie restriction. That does tend to suggest a commonality of mechanisms at the base of it all.
As the Methuselah Foundation continues to raise funds for the Strategies for Engineered Negligible Senescence (SENS) research, more young turks will be joining the science group: "Ben Zealley is the newest member of the Methuselah Foundation's scientific team, having joined this summer after completing his degree at Cambridge. He will be working with Dr. de Grey and Michael Rae to expand SENS and develop potential avenues of research. ... I have been interested in the human aging process - and Dr. de Grey's approach to it - for many years, so I'm very much looking forward to being able to work full-time on SENS at last. I'm particularly interested in therapies with rapidly-visible or immediate benefits, since these will be instrumental in swaying public opinion towards the concept of aging as a disease open to effective treatment. Once that's been achieved, the battle will be halfway won!" Funding, time and a group of enthusiastic biomedical researchers will get you a long way - it's good to see SENS ever more on the move.
More on the fading capacity of muscle stem cells with age via ScienceDaily: "as we age, the lines of communication to the stem cells of our muscles deteriorate and, without the full instructions, it takes longer for injured muscles to heal. Even then, the repairs aren't as good. But now that the researchers have uncovered the conduit that conveys the work orders to muscle stem cells, that knowledge could open the door to new therapies for injuries in a host of different tissues. The key to the whole process is Wnt, a protein traditionally thought to help promote maintenance and proliferation of stem cells in many tissues. But in this instance, Wnt appears to block proper communication. ... the ability of muscle stem cells to regenerate tissue depends on the age of the cells' environment (including the age of the blood supplying the tissue), not the age of the stem cell. Although Rando's research focused on the repair of acute trauma to muscles, he suspects that the same sort of problem arises on a lesser scale in repairing damage that results from the normal wear and tear of aging." I've been watching this research over the past couple of years - there are great opportunities there, a chance to take a bite out of degenerative aging, as is true of so much of modern biomedicine.
Early adopters are a form of investor - they provide much needed funds and validation for the continued development of new technologies, taking risks on the comparatively poor first commercial versions. In doing so, these folk play an important role in turning the wheel of progress. Stephen Gordon says it well:
Aubrey de Grey has a related theory about the development of life extension therapy. When asked if these treatments would only be available to the rich, Aubrey has responded that, yes, initially only the rich will be able to afford life extension treatments. But these early expensive therapies wouldn't be very effective anyway.
Later, de Grey argues, the price of these therapies will go down as their effectiveness goes up. There will be some mid-point where moderately money will buy moderately effectively treatments. Ultimately we'll have very inexpensive treatments that everyone can afford that will also be very effective.
I think this movement from "expensive/relatively ineffective" to "cheap/effective" will happen fast with life extension. Once the world sees these therapies as something more than fantasy, we'll pour incredible resources into their development and dissemination. And since technological development is accelerating, progress will be faster by then.
I have been an early adopter several times in the past. Being human (and subject to temptation) I'll probably be first-in-line to buy some cool, marginally-useful gadget again. It might even happen that I'll feel compelled by the risks of age or diminished capacity to shell out big money for life extension version 1.0.
If so, the whipper-snappers who'll benefit later can toast me.
All new technologies - medical technologies included - are hard to produce, comparatively poor in quality and expensive. That is no more than simple economics; creating the new is difficult. Difficult is expensive. Expensive requires investment, and investments in early development must be seen to be recouped within the timeframe of comfort for the investors, or they will not be made in the first place.
Technologies become easily manufactured, of high quality and cheap very quickly if they take off in adoption - commercial revenue opens the door to greater investment in development, expansion of infrastructure for commercialization, and the onset of competition that drives quality up and cost down. The early adoption contingent help to make that process more rapid, and by their actions - and willingness to risk resouces on the new new things in this world - make it more likely that future research and technological development will be funded.
Cancer without metastasis would be that much less threatening of an age-related condition. One effect of ever increasing knowledge of cellular processes will be the elimination of cancer's spread. From EurekAlert!: "For a cell such as a cancer cell to migrate, it first must detach itself from neighboring cells and the intercellular material to which it is anchored. Before it can do this, it receives an order from outside the cell saying: 'prepare to move.' This signal takes the form of a substance called a growth factor ... the team mapped all of the genetic changes that take place in the cell after the growth factor signal is received. As they sifted through the enormous amount of data they received, including details on every protein level that went up or down, one family of proteins stood out. Tensins, as they're are called, are proteins that stabilize the cell structure. ... the growth factor directly influences levels of both [tensin] proteins, and that these, in turn, control the cells' ability to migrate. Blocking production of the short tensin protein kept cells in their place, while overproduction of this protein plug increased their migration." Researchers are in the early stages of evaluating compounds to manipulate tensins; if they work out, tensin inhibitors would be another armament for anti-cancer dendrimer technology.
You'll find a great discussion over at the Immortality Institute forums on the difference between the engineering approach to repairing aging and the metabolic tinkering presently favored by the mainstream: "metabolism is so ridiculously complicated that it could take centuries use such a strategy to achieve negligible senescence in humans, and even then, the damage that you already have wouldn't go away. Research into repairing the damage, rather than slowing it's accumulation, is far more logical. If you can repair the damage once, you can do it again and again. ... The scientists doing this [metabolic work] will swear up and down that aging doesn't have a chance in hell of being fixed in any of our lifetimes, because they know just how complicated metabolism is, and fixing metabolism is the only thing that fits in their conception as being a fix for aging. ... Repairing the damage is massively more beneficial than slowing down aging. Slowing down aging leaves the assumption that natural death related to aging is still inevitable. However, through repair mechanisms, as long as there's a will to repair, you could technically continue to repair for as long as possible. And as technology becomes more advanced, the gaps between the periods required for repair will become longer and longer. It's a win-win in both cases."
We'll all be a fair deal older in 2030, that's for sure. But just how far will we have advanced medical science? The breadth and thrust of modern day medical research is increasing our remaining life expectancy at one fifth of the rate at which we live - but that pace is picking up. What is plausible for 2030? Some thoughts from Advanced Nano:
Achieving three times or more progress in longevity from 2007 to 2030 versus 1984 to 2007 seems very achievable. This will be from public health improvements, disease cures or treatments, lifestyle improvements (from behavior or with medical assistance) and success from direct progress against the processes of aging. This would mean going from a life extension increase of 0.1 to 0.2 years each year to 0.5 years.
I believe that the Strategies for Engineered Negligible Senescence (SENS) is a good plan. SENS could help contibute to a far greater increase in life expectancy. However, SENS success is dependent on both successful science and development and on the funding that it receives.
The future can arrive earlier for you if make the lifestyle adjustments now. You can give yourself a very good chance to live to 90 and the possibility of 100+ with lifestyle and pro-active medical tests and treatments. For the really big gains, help by donating to the SENS project.
Some folk in the systems biology field project a 10 to 20 year increase in life expectancy over the next 20 years. The Longevity Dividend folk are aiming for 7 years over a similar timeframe, and the actuaries are debating models that fall within these ranges. Aubrey de Grey, of course, makes the case that indefinite healthy life span in mice, maintained through repair technologies, has a good chance of success 20 years after large-scale funding is initiated for such a project.
Those in the know agree that more healthy life is possible and plausible, but disagree on how much and how exactly it will be attained. Certainly it will require support and understanding, regardless of the methodology that wins out in the end; science develops to the degree that people desire technology to achieve their ends, and are therefore willing to fund research.
Technorati tags: life extension
The real pace of progress can be seen in improvements in infrastructure - the health of a field in the next decade can be gleaned from the work of the toolmakers today. In regenerative medicine, the tools are improving markedly from year to year, as illustrated by this release from Newswise: "Previously, the system to grow and isolate neurons was very messy and it was unknown whether those neurons were functioning. We're excited because we have been able to purify so many more neurons out of the cell culture and they were, surprisingly, healthy enough to form synapses. These cells will be excellent for doing gene expression studies and biochemical and protein analyses ... The large number of pure neurons produced will allow Sun and her team to study their biological form and structure, the genes they express, the development of synapses and the electric and chemical communication activities within the synapse network. ... We will be able to study the cellular properties of neurons in a very defined way that will maybe tell us what goes wrong in diseases such as Alzheimer's and Parkinson's. We're currently creating many models of human neurological diseases that may provide the answers we're looking for."
Researchers seek to understand the mechanisms of the complex biological machinery that makes up a human with the aim of extending healthy life by reducing wear and tear. We shouldn't forget, however, that this machinery includes a large and significant bacterial component. "humans and some bacteria are known to have mutually beneficial relationships. People gain nutrients and energy with the aid of bacteria, and the microbes are provided with a buffered environment, carbohydrates, and other nutrients ... Since immune function is impaired with age, it might be expected that 'bacterial load' would increase or be otherwise altered as people grow older. Indeed, studies have found shifts in humans' intestinal bacteria with age and evidence that bacteria may blossom in the prostate and other organs of the elderly. To explore the consequences of such changes in bacteria with age in greater detail, the researchers looked to flies." You might recall that calorie restriction has an impact on bacteria in the body - as it seems to have an impact on almost everything that can be linked to aging.
We won't defeat aging in any reasonable timeframe by peeling out named conditions one by one - or tens by tens - and tackling each in turn. There is just too much there:
The dividing line between solemnly named condition and mysterious process of aging is utterly arbitrary; the "normal aging process" only really exists if you want to define it into existence. When you say "normal aging," you are applying a name to a collection of changes, damage, diseases and medical conditions, some of which have their own well-worn taxonomy, and some of which don't.
A recent piece at EurekAlert! makes a similar point, one I wish was made more often:
A broad study of adults ages 65 and older has found that half of them have one or more conditions that can affect their ability to participate in activities of daily living, such as bathing and dressing on their own. ... people with geriatric conditions had about the same level of dependency when performing activities of daily living as older patients with chronic diseases, including heart disease, chronic lung disease, diabetes, cancer, musculoskeletal conditions, stroke and psychiatric problems.
“The focus in medicine has long been on diseases, and how to diagnose and treat them. But that focus often isn’t helpful in regard to older adults; they tend to have one or more of these geriatric conditions, which are not considered diseases and can be missed by physicians."
Degeneration is degeneration, whether or not it has a fancy name and well-established research and patient advocacy communities. The overwhelming focus on naming and patching late-stage conditions - the results of years or decades of chained failures and wear in the overlapping systems of the body - is unfortunate, to say the least.
Dr. Westphal and Mr. Sinclair stress that they are not working to 'cure' aging, a condition that, so far at least, is common to all humanity and that most physicians do not consider a disease. 'Curing aging is not an endpoint the federal drug agency would recognize,' Dr. Westphal says dryly. Instead, both men say, they are working to ameliorate the diseases of aging.
It leads the medical community away from the rational path forward, which is to seek the simplest root causes and intervene at that point. Prevent rather than patch; repair the known forms of age-related cellular and molecular damage at the early stages without needing to understand the ever more complex chains of consequence and failure.
The scientific community and those who fund it could be doing so much more than they are at present to eliminate age-related suffering and death. That must change.
We almost made it through without what seems to be the obligatory reference, but fell at the last hurdle. Via the IEET: "here is the essence of the Voldemort Fallacy: the notion that seeking longevity beyond that which is 'naturally' granted is somehow intrinsically harmful - even if it doesn't look that way at first, and even if harm itself is not the life-extensionist's goal. Some of the conversations I've been involved in on the subject of longevity have been with people who seem to have the idea that the mere desire for personal longevity will somehow indirectly harm others. This, to me, seems to be the result of a particular brand of superstitious thinking - one that is heavily reinforced by literary portrayals of longevity-seekers. Voldemort's direct harm to others can perhaps be seen as a metaphor for the indirect harm that longevity-seeking is often assumed to perpetrate. Nobody really knows what sorts of evils might come about if people could live as long as they liked, but many people assume that evils must be there regardless, and that it takes a certain kind of weakness of character not to passively accept one's demise. ... The hope for a very long life is no different, as far as I'm concerned, from the hope that I will wake up tomorrow morning. The question, 'Why live?' is best responded to by the question, 'Why not live?' It isn't all that complicated."
The modern form of drug design is to identify a biochemical mechanism and design a compound to safely interfere in its progression. An example of the type can be found at ScienceDaily: "Alzheimer's is linked to the build up of amyloid protein which eventually forms 'senile plaques'. The amyloid protein inflicts damage by interacting with an enzyme called ABAD (Amyloid Beta Alcohol Dehydrogenase) and releasing toxic substances which kill brain cells. ... Alzheimer's sufferers produce too much amyloid and ABAD in their brains. Based on our knowledge of ABAD, we produced an inhibitor that can prevent amyloid attaching to it in a living model. We have shown that it is possible to reverse some of the signs associated with Alzheimer's disease. The work is now being continued to try and refine the inhibitor into a potential drug. Our research holds a possible key for the treatment of Alzheimer's disease, particularly in its early stages." Increasing knowledge of our biochemistry opens the field to a wide range of approaches for any particular medical condition: diversity and competition is good.
You might recall some of the pioneers of the field of systems biology (pioneers of defining what the term "systems biology" means, even) see it as a pillar of the next generation of medicine, enabling new technology that will add ten to twenty years to our life expectancy:
It takes five years for people to get anything. The first few times they hear it, they can think of a thousand reasons why it's wrong. Then, after they've heard it a few more times, it starts to sound more logical. If you're a missionary, you've got to be patient with your congregation. We are at the very beginning stages of thinking about this. ... You see what drives the change? Technology. If we invent the technologies that enable this, everything else gets dragged right along. That is one of the fundamental rules of civilization. I think it will make medicine less costly, infinitely more efficient. I think within 20 to 25 years, we'll be living productively 10 to 20 years longer.
The latest issue of The Scientist takes a nuts and bolts, what have you done for me today view of systems biology:
. From early discovery to market, the vast majority of promising pharmaceutical compounds end in failure. Some of these stories end with a whimper or, in the case of something like Vioxx, with a bang.
Enter systems biology. The field has as many definitions as it has practitioners, but Current Genomics puts it simply: "The goal of systems biology is to describe and quantitatively model complete biological systems."
Ideally, systems biology incorporates what Lauffenburger calls the four M's: measurement, mining, modeling, and manipulation. Firstly, scientists catalogue de novo response pathways in order to connect cell-surface receptors with gene expression, or piece together a network from published literature. Next, they pick apart the interaction and cross-regulation of the pathways. All this is captured electronically and integrated into a computer model, which is validated in the lab. If successful, this approach could form the foundation for a rational, hypothesis-based method of identifying new drug targets and biomarkers, while minimizing side effects. The hunt for compounds is a needle-in-a-haystack problem. Systems biology, supporters say, could be our magnet.
Of course, it is hugely hyped; it seems that most new new things in medicine go through the stage of initial hype, collapse of the hype, and then meaningful progress and broad growth of new applications in the years that follow. Expectations always seem to be both too narrow and ahead of reality for the first decade or so - look at the history of gene therapy, for example.
If only it were so simple. It would be, if systems biology were able to "describe and quantitatively model complete biological systems," as Current Genomics so optimistically put it. But that's currently an impossible dream. To illustrate, the full description of just a single pathway in yeast that triggers the first step toward sexual reproduction is taking up the entire activities of a whole research institute, the Molecular Sciences Institute
In the case of systems biology, what's irritating is that the unfulfilled hype and the subsequent disdain has obscured the fact that systems biology can be valuable and is finding a place in drug discovery.
There's a far broader future for systems biology than propping up the dry old drug pipeline mode of medical research - the here and now viewpoint is deliberately limited.
We don't presently have access to the computational capacity and complexity management tools to map processes any faster than speeds measured in man-years. That is rapidly changing, however. In a near future when the computation power to simulate an entire body, cell by cell - and molecule by molecule not so long after that - is next to free, and most research takes place in simulation, systems biology is a lynchpin and design manual.
You'll find an interesting meeting report at the open access journal Immunity and Aging; the full PDF is available. It reflects something of the mainstream view of inevitability, acceptance, and slowing aging as the only path forward - a view that I'd like to see vanish in favor of the SENS approach of working directly towards rejuvenation and repair. "On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life." Despite the defeatism, the science is worth reading.
As I've said before, I have no problem with people who sincerely wish to age and/or die. Nor even to any great degree with those people who fail to think though through the path of future health and suffering, or choose to bury their heads in the sand, and thereby actively hurt the person they will one day be. Individual choice is vital and precious, and these folk are making choices.
There's nothing wrong with education and persuasion aimed at those who don't think much of healthy life extension or SENS research, of course, but in the end the choice of whether to reach for a longer healthy life is up to the individual.
When I point out the callousness of deathists, I am aiming my contempt for those who would force their choice of death and decrepitude upon others. The great evil is not that a person refuses to live longer, nor does it lie in persuading others to choose aging, or in refusing to step up to help defeat age-related degeneration and death. No, the great evil is to attempt to force an early death upon others against their will. There's a name for that, no matter how subtle the actions: murder.
Here's an example of one variety of what I might term acceptable deathism; those who choose to believe they are already immortal, but are generally willing to live and let live. Letting others to their choices and restricting oneself to persuasion without intent of force has always been a sadly thin strand in most religious traditions.
So just what is transhumanism? Well it means what the term implies: going beyond the merely human. Or as the WTA website says, “We support the development of and access to new technologies that enable everyone to enjoy better minds, better bodies and better lives. In other words, we want people to be better than well.” Sounds pretty good, on first reading. But it is not all as rosy as it first appears.
Indeed, some might still ask, what is wrong with all this? Well, there is nothing wrong, as such, with wanting to live longer and healthier lives.
This is all very utopian alright. As I mentioned earlier, this is ultimately about one thing: achieving human immortality. Now if you are a secular humanist, and a philosophical naturalist, as it seems most transhumanists are, you can see why this is such an important and urgent quest. If life ends at the grave, and that’s it, then sure, we may all want to extend this current life by any means possible. But that is the whole problem. Being based on a secular humanist worldview, transhumanism has the whole concept of life and immortality messed up.
The truth is, life extension is already a current reality. Indeed, we will all live forever. But there are just two destinies after the grave, and only one of those we should be striving for. The means to eternal life was accomplished by Jesus Christ 2000 years ago.
Choices, choices. That choice above - the important part of it from this consideration, being to believe that destruction of the brain is not oblivion - is ultimately fatal. From my vantage point, it is the will to self-destruction. No doubt the author might say the same of my point of view and actions. However, I value a world in which we're all free to think and choose for ourselves, and in which choice and consequences are respected.
Even if we could draft the masses to work to defeat aging, we should not do it; that would make us no better than those deathists who would set the agency of government to block research and mandate age-related death to their schedule.
Via Nanodot, a collection of audio recordings of Christine Peterson from the Foresight Nanotech Institute talking on healthy life extension: "One of the Foresight Nanotech Challenges is 'Improving health and longevity'. But to take advantage of these expected advances, we all need to stick around long enough for them to arrive. Here at Foresight we'd like all Nanodot readers to do that, so here are the URLs for audio recordings of my Penguicon talk on current techniques in life extension, sent by Matt Arnold who set up the programming for that meeting." As I've long noted, there is considerable overlap between the go-getters of the healthy life extension community and active folk involved in work and advocacy on advanced nanotechnology (or molecular manufacturing) and the development of general artificial intelligence. It takes the same sort of appreciation for the way in which the world works to see the plausible futures for each of these threads of advancing technology. They will enable very desirable outcomes - so it's not surprising to see people advocating all three paths.
Calorie restriction is known to increase autophagy in at least some cell populations. This process of repair and turnover of materials is of general benefit. "Autophagy often gets overlooked as 'just housekeeping.' [In fact], failures in keeping house likely contribute to diseases such as cancer and neurodegeneration. In addition, autophagy wanes with age for reasons that aren't yet clear [and] is 'mechanistically important' in aging itself." Here is an example of confirming research: "Autophagy is a highly regulated intracellular process for the degradation of cellular constituents and essential for the maintenance of a healthy cell. We evaluated the effects of age and life-long calorie restriction on autophagy in heart and liver of young (6 months) and old (26 months) [rats]. We observed that the occurrence of autophagic vacuoles was higher in heart than liver. The occurrence of autophagic vacuoles was not affected by age in either tissue, but was increased with calorie restriction in heart but not in liver. ... calorie restriction may mediate some of its beneficial effects by stimulating autophagy in the heart, indicating the potential for cardioprotective therapies."
With the growing interest in calorie restriction research and related biomedicine, more scientists are stepping up to theorize on the effects of CR on human life span. "The question has arisen in the literature as to whether dietary restriction (DR) will have a significant effect on human longevity. ... human reproductive costs are high enough to permit a DR response. I then review four different models relating diet and life span, three of which have been previously used to estimate the effects of DR on humans. A review of the pertinent literature suggests that these three models, while plausible, are not capable of making robust predictions that are consistent with human data not used in their development. ... The fourth, or biocultural model, examined combines biologic and cultural factors. Human longevity is more complex than our model systems have led us to believe, and thus any solution will require the development of a new quantitative model. ... If the human cultural pro-longevity practices can be quantified in terms of their effect on energy allocation, then this model may serve in future as a realistic quantitative model capable of identifying pertinent pathways and making robust predictions." I predict that by the time a robust prediction of the degree of extended human life span to be obtained through the practice of CR has arrived, it will be rendered irrelevant by advances in rejuvenation medicine.
Aging is wear at the molecular and cellular level, changes that build up over time and lead to malfunction and failure of the systems built of macromolecules and cells. At the high level, this picture is only slightly complicated by the fact that your biochemistry can repair and reconfigure itself in response to circumstances - repair systems wear, malfunction and fail too.
Some forms of damage are more consequential than others, leading to more rapid or serious failure in capacity. Here is one, for example:
The effects of ageing on progressive deterioration of renal function, both in human and experimental animals, are described elsewhere, but the effect of renal damage on overall survival and longevity is not yet clearly established. The wild-type animals of various genetic backgrounds, fed with regular diet, overtime develop severe age-associated nephropathy, that include but not limited to inflammatory cell infiltration, glomerulosclerosis, and tubulointerstitial fibrosis. Such renal damage significantly reduces their survival. Reducing renal damage, either by caloric restriction or by suppressing growth hormone (GH)/insulin-like growth factor-1 (IGF-1) activity could significantly enhance the longevity of these animals. Available survival studies using experimental animals clearly suggest that kidney pathology is one of the important [non-cancerous form of damage] that could affect overall survival, and that restoration of renal function by preventing kidney damage could significantly extend longevity. Careful long-term studies are needed to determine the human relevance of these experimental studies.
Another good reason to be practicing calorie restriction. While we live in an age in which we can seriously consider engineering the restoration of function in complex organs like the kidney in the near future - or even complete replacement with new undamaged tissue grown to order - we don't know when such goals will be accomplished. Why chance damaging yourself enough to miss out on the arrival of that technology?
A brief tour of the mainstream of aging research can be found at Courant.com - longevity genes, metabolism, drug development. "Once a field crowded with charlatans and hustlers, longevity research has turned up some remarkable insights into why organisms age. And a few scientists have already staked their claims to genes they say are crucial to healthy aging. Almost all of the most promising work on longevity so far has come from a single observation made decades ago - that hungry animals live longer and have fewer health problems than animals that eat more. Scientists studying how the severe restriction of calories imparts such health benefits have zeroed in on a few crucial genes that seem to have very large impacts. ... All the major diseases of aging - cardiovascular, neurodegenerative, cancer, diabetes - they all might fall under the sway of calorie restriction. If we knew which are the critical genes involved in calorie restriction, then we could develop new drugs. That is what we are doing now." I don't see any of this as the path to a future of far greater healthy longevity. The knowledge gained from this research will help, but tweaking metabolism isn't going to rejuvenate those already old. Developing the tools to reverse aging will be no more expensive; we need repair technologies, not metabolic tinkering.
Via the IEET, a transcript of George Dvorsky's presentation at the Longevity Dividend Seminar prior to last week's Transvision 2007 conference: "Life is good, death is bad. That pretty much says it all for life extensionists. There is the general notion that death at 17 is tragic, while death at 87 is natural. That is based on our conditioned response and expectations regarding maximum lifespan. If we could live to 1000, we would consider the death of someone at 350 to be just as tragic. ... A great quote from J.R.R. Tolkien. 'There is no such thing as a natural death. Nothing that happens to Man is ever natural, since his presence calls the whole world into question. All men must die, but for every man his death is an accident. And even if he knows it and consents to it, an unjustifiable violation.' The quote is the obverse to Leon Kass's assertion that the finitude of human life is a blessing for every individual, whether he knows it or not. Another argument is that death is wasteful, destroying memories and experiences. Moreover, it is a terribly thing to have to deal with death. Eliezer Yudkowsky, who experienced the death of his sibling a few years ago, wrote that 'No sentient being deserves such a thing.' Life extensionists are cognizant of the fact that people are dying every day of age-related diseases."
RAGE, the receptor for advanced glycation endproducts ... its name comes from its ability to bind advanced glycation endproducts (AGE), a heterogeneous group of non-enzymatically altered proteins. Besides AGEs, RAGE is also able to bind other ligands and is thus often referred to as a pattern-recognition receptor.
The interaction between RAGE and its ligands is thought to result in pro-inflammatory gene activation. Due to an enhanced level of RAGE ligands in diabetes or other chronic disorders, this receptor is hypothesised to have a causative effect in a range of inflammatory diseases such as diabetic complications, Alzheimer's disease and even some tumors.
RAGE, then, is a part of the biological mechanisms by which an accumulation of AGEs harms you. I'm sure you know just how bad chronic inflammation is over time:
Chronic inflammation spurred by an immune system run amok appears to play a role in medical evils from arthritis to Alzheimer's, diabetes to heart disease.
If you go digging through recent publications, you'll find a fair amount of work ongoing on relating RAGE to various age-related disease states and metabolic processes. For example:
Advanced glycation end products (AGEs) have been proposed as the pathological mechanisms underlying diabetic chronic complications. They may also play a role in the pathogenesis of diabetic osteopenia, although their mechanisms of action remain unclear. We investigated the [protein and gene expression] of two receptors for AGEs, RAGE and galectin-3, as well as their regulation by AGEs, and the apoptotic effect on osteoblast-like cells ... AGEs up-regulated the expression of RAGE and galectin-3 in both cells lines. ... Finally, we demonstrated that a 24 h exposure to AGEs induced apoptosis in both cell lines. Thus, AGEs-receptors may play important roles in the bone alterations described in aging and diabetic patients.
So, more AGEs, more RAGE, more change - decrease in bone strength in this case, as the cells that produce bone are culled. That extra apoptosis may or may not be damage, but it's certainly change that grows with aging and pathology - we can't go far wrong by assuming all change is damage and working to fix or prevent it.
One thing to bear in mind is the processes associated with AGE acculumation are feedback loops; above a certain threshhold matters start to go awry much more rapidly. Repair technologies work very well in circumstances such as these - just keep the level of AGEs below the runaway point, and accumulation will be slow.
AGEs have been implicated in renal disease associated with ageing, diabetes and other age-related disorders. Reactive oxygen species (ROS) promote formation of AGEs, which cause AGE-receptor-mediated ROS generation with activation of signalling pathways leading to tissue injury and further AGE accumulation.
Learning more about your own biochemistry is a strong incentive to help bring forward the day when all these damaging processes of metabolism can be halted and reversed.
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