Life expectancy is increasing, and the rate of increase is accelerating. People live longer than they expect to live. If you lay the foundations of your future - savings, investment, work - with an eye to your grandparent's lifespan and strategies, then you're not planning well. "As greater longevity is increasingly becoming a fact of life, people are leaving themselves vulnerable to financial hardship at a time when they are most in need ... Nearly half the population of the UK said they were only expecting to live to the same age as their parents' generation ... Interestingly, whilst people do not realise the possibility of themselves living longer than their parents, they do recognise that their children will live longer lives than they will. However, 18-24 year olds grossly underestimate this, with only 25% of them thinking that their children will live longer, whilst 44% 55 year olds thought this. ... People acknowledge increased longevity for younger generations but do not realise that this is a very real issue for them today." Plan for an interesting future - and recognize that you have more than enough time to save and invest all you will need, even in the best scenarios of radical life extension.
The Understanding Aging conference will be held in Los Angeles in late June, and the early registration and abstract submission deadlines are only two weeks away. By mail from conference organizer Aubrey de Grey: "The program has over two dozen confirmed speakers, all of them world leaders in their field. As for previous conferences I have [co-] organised, the emphasis of this meeting is on 'applied biogerontology' -- the design and implementation of biomedical interventions that may, jointly, constitute a comprehensive panel of rejuvenation therapies, sufficient to restore middle-aged or older laboratory animals (and, in due course, humans) to a youthful degree of physiological robustness. ... registration for the conference includes preferential admission to the free public preconference 'Aging: the disease, the cure, the implications.'" You'll recognize many of the names on the conference agenda - an assembly of leaders in their fields and people of influence.
Scientists are making real inroads into replicating and controlling the cells and mechanisms of our immune system. Producing immune cells, directing their actions, deciphering the biochemistry of pathogens - all these pieces are waiting to be put together as a bioartificial immune system, many times more selective, efficient and resistant to damage than the basic version we're all equipped with. For added effect, it will also slay cancer cells and degrade the buildup of dangerous compounds, such as the amyloid beta associated with Alzheimer's disease.
A large component of age-related frailty stems from decline and malfunction in the immune system - chronic inflammation and loss of function due to overpopulation of memory cells are at the top of the list. But what if your immune system were augmented, pruned, and more controlled? Recurring viruses like CMV dealt with without the resulting bloat of useless memory cells; artificial antigens released as need to vastly improve defenses against invaders; a library of antigens kept in waiting, as large as you need, so that no new invader catches you unaware; hyperefficient destruction of known cancer cell types long before they can become a threat. The list goes on. The present problems of immune system aging could be eliminated, and the immune system made vastly more powerful, by the technologies just one or two steps down the road from what is taking place in laboratories and clinical trials today.
researchers describe a method that can identify and clone human antibodies specifically tailored to fight infections. The new technology holds the potential to quickly and effectively create new treatments for influenza and a variety of other communicable diseases.
When an infection invades, the immune system goes to work manufacturing antibodies to fight it. Most of the antibodies created will have no effect, but a very few will bond to the invader and replicate to neutralize the enemy.
The new process develops a "smart bomb" for the immune system, using fully human monoclonal antibodies specifically designed to fight the infection without doing any harm to the body.
"We can recognize which cells are made and then make antibodies from them directly," Wilson said. "It's a rapid and efficient way to make fully human antibodies."
The key to a superhumanly quick response to pathogens is access to an evolving library of ready-made antibodies. One might imagine the future providers of immune system technology looking a lot like today's providers of anti-virus software for your computers, harvesting information on potential infections and streaming update information to bioartificial antibody manufactories in your bloodstream.
All of this isn't so far away. With the underlying technology in hand, it only takes a decade to build an information and delivery infrastructure like the one I've described above, and I can't imagine it taking more than two decades to complete and commercialize the presently nascent science. The only thing really holding us back is the ball and chain of oppressive regulation in the medical development field.
Reason Magazine is running an interview with VC, trader and philanthropic investor Peter Thiel. It's of interest to those who would like more insight into the thinking that leads Thiel to support the activist outgrowth of the transhumanist community - specifically the Singularity Institute (hundred of thousands of dollars focused on development of general artificial intelligence) and the Methuselah Foundation (millions of dollars focused on radical life extension). The interview focuses far more on the former than the latter, but the reasoning is applicable across the board. On the one hand information technology, on the other hand biotechnology, both accelerating hard towards the promise of amazing future technologies:
I think [the Singularity Institute is] a group of really smart people working on an important problem. I think that the basic rule on philanthropy that I have is that I want to donate money to causes that are worthwhile but where there are no market-based mechanisms for them. There is a category of things that would benefit all of humanity but where the benefits are very diffuse and the costs are concentrated. Maybe it’s very long-term. So I focused my philanthropy on things with a 20-, 30-, 40-year horizon. The horizons are too long for a for-profit company to take advantage of, and the government and universities are not pushing things because maybe it’s too unconventional or it doesn’t easily fit into a particular political agenda or vision of the future. Those areas are probably systematically underfunded. It may be the only area of philanthropy that’s underfunded. ... I also have been doing some work on radical life extension, which I think is similarly underfunded.
I certainly think living longer is not a generally bad thing. I think that making sure the technology arc is positive rather than negative is not generally a bad thing. I think it probably would be somewhat mistaken to frame it in too narrowly selfish a way. It may be the case that the work being done on life extension is going to benefit people 100 or 200 years from now, but I think it still is a good thing to do it. My own guess is that I will live to age 100 to 120, so I'm frustrated that the technologies aren't going as quickly as they should because of government interference.
The question's not an abstract question about “Is it desirable for people to live X years?" It's "Is it good to have a cure for this form of cancer? Is it good to do something where your bodies and minds stay younger and healthier for longer than they otherwise would?" The [Leon] Kass approach encourages the rest of the society not to reflect about this. In the United States life is getting longer and longer, but we’re not thinking about it. If we’re actually going to live to age 100, the effect of Kass will be to encourage people to have a very unhealthy last 30 years because they will not have thought about and will not have prepared for it.
The future is what we make of it: either a golden era, realized through foresight and planning, or a wasted opportunity. The more people of influence to realize just how great the potential, the better.
Correlations are pointers - they indicate where future research and development may best be directed. Here, researchers demonstrate a strong correlation between mammalian life span and various mitochondrial characteristics: "In animal cells, mitochondria are semiautonomous organelles [with] their own code and genome (mtDNA). The semiautonomy and restricted resources could result in occasional 'conflicts of interests' with other cellular components, in which mitochondria have greater chances to be 'the weakest link,' thus limiting longevity. ... (1) to what extent the mammalian maximum life span (MLS) is associated with mtDNA base composition? (2) Does mtDNA base composition correlate with another important mitochondria-associated variable - resting metabolic rate (RMR) - and whether they complement each other in determination of MLS? ... Analysis of 140 mammalian species revealed significant correlations ... To the authors' knowledge, it is the highest coefficient of MLS determination that has ever been reported for a comparable sample size. Taking into account substantial errors in estimation of MLS and RMR, it could mean that [this explains] most of the MLS biological variation. [This leads us to] mitochondria as a primary object for longevity-promoting interventions."
This paper proposes that the next step for recent advances in engineering pluripotent stem cells is to create these cells directly, inside the body: "Stem cells are the major factor ensuring mammalian regeneration. Cell replacement therapy is an attempt to follow this natural process. Another strategy suggests a controlled de-differentiation of somatic cells to a stem-like state with subsequent re-differentiation. Indeed, the cultured mammalian somatic cells may be reprogrammed to a pluripotent state by the induction of a specific set of genes. The next logical step toward the goal of organism rejuvenation is to test the possibility of inducing the pluripotent state in somatic cells in vivo. Such an approach has the potential to improve upon and overcome several obstacles facing today's cell replacement therapy." This is an interesting line of thinking; why not simply create new stem cells right where they are needed?
If you've been following along, you'll recall that many of the most interesting biotechnology demonstrations in recent years work because they target very specific parts of the cell. For example, targeting antioxidants to the mitochondria extends life in mice where straightforward application of antioxidants does not. Here, the Telegraph reports on a related approach for an Alzheimer's therapy: hitting a part of the disease mechanism that's already been tried, but this time localizing the action of the drug to a specific structure within the cell. "The drug targets the membrane of brain cells, focusing on compartments in the membrane, called 'rafts', that play a central role in many cellular processes. Although this drug is not the first to target the enzyme, called beta secretase, it is the first to do so in the right place, in the 'intracellular membrane compartment' where the enzyme triggers the protein deposit build-ups. The team has devised a way to anchor the drug to the membrane to stop the harmful deposits."
The latest issue of Rejuvenation Research is available online, with a strong focus on the mechanisms of Alzheimer's and other neurodegenerative processes. One of the more interesting papers describes the use of DNA vaccines in place of viral vectors in Alzheimer's immunotherapy. From Wikipedia:
DNA vaccines are third generation vaccines, and are made up of a small, circular piece of bacterial DNA (called a plasmid) that has been genetically engineered to produce one or two specific proteins (antigens) from a micro-organism. The vaccine DNA is injected into the cells of the body, where the "inner machinery" of the host cells "reads" the DNA and converts it into pathogenic proteins. Because these proteins are recognised as foreign, they are processed by the host cells and displayed on their surface, to alert the immune system, which then triggers a range of immune responses.
The early days of reprogramming our cells to do our bidding are starting to look quite sophisticated. Most immunotherapies for Alzheimer's disease (AD) seek to draft the immune system into destroying the accumulation of amyloid plaques thought to cause neurodegeneration. From the paper itself:
Although the clinical trials of active vaccination for AD patients were halted due to the development of meningoencephalitis in some patients, from the analysis of the clinical and pathological findings of treated patients, the vaccine therapy is thought to be effective. Based on such information, the vaccines for clinical application of human AD have been improved to control excessive immune reaction. Recently, we have developed non-viral DNA vaccines and obtained substantial [amlyoid beta] reduction in transgenic mice without side effects.
This issue of Rejuvenation Research is a weighty one, a little under twice as big as February's issue, and there's far too much of interest to list it all here. Head on over and take a look.
ShrinkWrapped expands on the terrible cost imposed upon progress by the FDA: "The development of our cumbersome and onerous regulatory environment that will slow the availability of drugs to those who would benefit from it is a sad story of missed opportunities and risk aversion ... the FDA was established and set up a framework for approving drugs only after they were shown to be safe and effective. The terrible problem for medicine is that there is no such thing as a drug that can be proven to be completely safe. ... On every level it makes sense for us to develop anti-aging treatments. Losing the abilities of those who are most skilled and experienced on a regular basis is wasteful of human resources. Yet our current regulatory environment not only precludes developing drugs that could slow aging, but makes studies to show their safety and effectiveness impossible to perform. ... as in any bureaucracy, the FDA is not going to be able to modify its mandate without a tremendous push from those most likely to be effected by their conservatism."
Sirtris Pharmaceuticals is something of a figurehead for the resources flowing into calorie restriction research at all levels over the past few years. As I'm sure you saw in the media, Sitris was recently acquired by GlaxoSmithKline for a fair chunk of change; in an age of oppressive regulation and the enormous investment in time and money required to satisfy that regulation, this is the preferred exit strategy for investors, as it's the only one likely to happen rapidly. Some thoughts from those who watch the industry below:
Sirtris has focused on the commercial development of clinically useful sirtuin activators, which are predicted to be useful as anti-diabetic drugs. Data from academic labs have suggested they could be of even wider use, e.g., in increasing exercise tolerance or treating inflammatory disease. Underneath it all, of course, is the knowledge that the the sirtuins were initially identified as longevity assurance genes; the subtext of all discussions of sirtuin activators is that they may mediate their beneficial effects by slowing aspects of the aging process itself.
The acquisition of an small company at a large premium (the offer was more than 80% higher than Sirtris' market cap) by a pharmaceutical giant is one of the first demonstrations that the drug industry is taking seriously the idea that there's money to be made in treating aging per se rather than all of the associated conditions separately
Sirtris, as you'll recall, is centered on the exploration and manipulation of sirtuins such as SIRT1. Ouroboros also provides an overview of what is presently known about the role of SIRT1.
Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. ... Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this - I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word "transformational" around, you know that they’ve thought beyond a replacement for Avandia.
That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?
Notice that the largest problem for the future of longevity medicine in the established research and development community is the FDA and its heavy-duty, risk averse structure of trials after trials after trials. The cost is immense, and in most cases utterly out of proportion to any rational cost-benefit analysis of a new medical technology. So those technologies simply aren't commercialized, joining the vast sea of wasted potential that attends all imposition of regulatory cost.
The simple answer to the questions in the quote above is that you don't run a Phase II trial for life extension strategies. It doesn't make sense to talk about these structures and strategies rigidly applied to this case, but the present weight of regulation doesn't allow for the sort of free competition and innovation under pressure that always produces working, practical answers.
Since the FDA will never approve an intervention into the aging process - as aging is not recognized as a disease, and the FDA only approves treatments for disease - the underlying technologies are not applied to that end. No-one invests in medicine that cannot be sold due to government prohibition. Instead, the promising science is diverted into the same old process of patching up the very end results of age-related damage. It's that simple and that wasteful.
Absent a very overdue revolution, change to this sorry state of affairs will be slow and expensive, a matter of lining the pockets of politicians to re-order some of the destruction they've caused. A part of that long change process is the assimilation of potential new longevity science into organizations large enough to influence the FDA's mandate. Here, we see one of the first acts in that play.
Dry wit from Ouroboros on the very long-lived PEPCK-Cmus mice: "It's become reflexive to ask whether a long-lived mutant is living longer because it's calorie-restricted for some reason, incidental to the main phenotype conferred by the mutation, but this is not the case here: In order to preserve their enviable bods, PEPCK-Cmus mice eat 60% more than controls - so they're not extending their lifespan by dieting. If anything, they're anti-dieting: their increased metabolic efficiency means they’re harvesting more calories per gram of carb or fat than normal animals. No word yet on what happens if you do try to calorie-restrict them; I can imagine it going either way but am holding out hope for tiny explosions. ... The PEPCK-Cmus seem to have it all: great bodies, long lives, extended reproductive and sexual lifespans, and no need to limit their appetites. The down side? Apparently, they are complete assholes: the mutants are aggressive and hyperactive, traits heretofore unheard-of among muscular, fit humans (and, indeed, in the field of biogerontology)."
MSNBC is running an op-ed by Arthur Caplan on a few of the more common knee-jerk objections to engineering greater human longevity: "arguments that we should not live a lot longer because we will grow decrepit are simply silly. No one proposes that we spend a lot of money on biomedical research to pursue a longer life of decrepitude and suffering. The idea behind radical life extension is that we live a decent quality of life for a lot longer. If all that is in store is frailty and mental decline, then the debate is over before it starts. But that is not what the debate is really about. ... As for violating some natural limit if we live a lot longer - what limit? We have already doubled our lifespan since the days of the Hittites, Israelites, Greeks, Babylonians and Egyptians, all of whom were lucky to make it to 35. Are we already living unnatural, and thus immoral, lifespans? ... Evolution cares not a whit how long you or I live, only that we survive to reproduce. There is no such thing as a 'natural' lifespan - only what we can do with agriculture, engineering, medicine and public health."
A review paper I noticed today reminded me of the relationship between body temperature and longevity. Calorie restriction leads to lowered body temperature - as well as extended healthy life - in mice, but unrelated methods of lowering body temperature over the long run also seem to extend longevity to some degree. For example, see this research from a couple of years ago:
Was calorie restriction itself responsible for longer lifespan, with reduced body temperature simply a consequence? Or was the reduction of core body temperature a key contributor to the beneficial effects of calorie restriction? Conti and colleagues wanted to find out. To tackle the problem, the scientists decided to try to lower core body temperature directly, without restricting food intake.
Conti and colleagues decided to focus their efforts on the preoptic area of the hypothalamus, a structure in the brain that acts as the body’s thermostat and is crucial to temperature regulation. Just as holding something warm near the thermostat in a room can fool it into thinking that the entire room is hotter so that the air conditioning turns on, the Scripps Research team reasoned that they could reset the brain’s thermostat by producing heat nearby.
To do so, they created a mouse model that produced large quantities of uncoupling protein 2 in hypocretin neurons in the lateral hypothalamus, which is near the preoptic area. The action of uncoupling protein 2 produced heat, which diffused to other brain structures, including the preoptic area. And, indeed, the extra heat worked to induce a continuous reduction of the core body temperature of the mice, lowering it from 0.3 to 0.5 degrees Celsius.
The scientists were then able to measure the effect of lowered core body temperature on lifespan, finding that the mice with lowered core body temperature had significantly longer median lifespan than those that didn’t. While this effect was observed in both males and females, in this study the change was more pronounced in females - median lifespan was extended about 20 percent in females and about 12 percent in males.
Some researchers would like to pin temperature-dependent longevity on the rate of chemical reactions in the body (reaction speeds generally being proportional to temperature), but I suspect that's too simplistic. An alteration in the rate at which mitochondrial processes generate damaging free radicals sounds more plausible, driven by some temperature-sensitive signaling and control process.
The interesting question with regard to this is what proportion of calorie restriction benefits stem from this mechanism - as opposed to, say, the loss of visceral fat, changes in metabolic control pathways, increased autophagy, other regulatory changes in cells, and so forth. None? A tenth? A third? What? As we look at ongoing work to produce calorie restriction mimetic drugs, based on manipulating the biochemical pathways researchers discovered through research into calorie restriction, how much benefit will these mimetics provide for people who still have visceral fat and a high body temperature?
If you eliminate germline stem cells in flies and nematode worms, they live 20-50% longer. From ScienceDaily, an explanation of the biochemistry: "When reproduction is delayed, animals live longer. Why? Our research suggests that signals from the reproductive system can regulate aging in animals - including, possibly, humans ... speculated that these flies might live longer because they are insensitive to the effects of insulin. ... animals such as flies, worms and mice live longer when they produce or receive less insulin. ... [but] when germline cells were eliminated, and flies lived longer, insulin-producing cells in the fly brain actually make more - not less - insulin. ... How can flies be longer-lived when they're making more of a life-shortening hormone? ... Even though the brains were making more insulin, the bodies were responding as if there was less insulin present. ... In reaction to the flies' brains boosting insulin production, the insects' gonads - their ovaries or testes - produce a protein that acts like a sponge. This protein binds to the insulin and blocks its signals throughout the body. So the flies respond as if there is low, not high, insulin circulation inside their bodies."
AMPK is one of the more important regulatory components in our metabolic machinery, activated by lower energy intake - such as calorie restriction - and diminishing with age. As such, AMPK signaling changes are prime target for investigation. From EurekAlert!: "when cells are kept hungry in a culture dish, a watchdog enzyme called AMPK jumps into action and attaches a chemical phosphate group to a target protein named raptor. As a result, raptor, whose job is to cradle a growth-promoting protein called mTOR, is disabled, inactivating mTOR and halting cell division. Cells then safely switch into energy conservation mode until plentiful times return. ... Simply the most rudimentary information that any cell needs is to know whether there is food around - that's what AMPK senses. If there is not, you need to turn off factors that make cells grow." mTOR is another party of interest for calorie restriction research - is there a good way to achieve the beneficial health and longevity benefits of calorie restriction by directly manipulating the controls our biochemistry?
As I mentioned over at the Longevity Meme, SAGE Crossroads seems to be putting forth new material on policy and longevity science once more. Looking at some of the podcasts uploaded this year, I notice one on the Longevity Dividend initiative with Daniel Perry of political advocacy groups Alliance for Aging Research and CAMR, amongst others.
All you have to do is go into any bookstore in this country and go to the health section and you’ll see lots of titles about ending aging or immortality or stopping aging in its tracks. I think there is a lot of debate over whether that’s conceivable, but I think there is an emerging belief that we can slow down the processes of aging and make real achievements within a reasonable period of time, the next 10-15 years, that could buy back for people now living 5-7 years of healthy, productive life. As one gerontologist said, it ought to take 80 years to get to 60. Now that may be a bit more ambitious that what I’m talking about. I’m talking about seven years not 20 years, but there is a growing feeling among leading scientific authorities that based upon what we know works in laboratory animals, including apparently based on recent data, rhesus monkeys, a very close cousin to human beings. It could be possible that we could engineer healthier, more vital, more satisfying life for people in their 70s, 80s, and 90s in our lifetime.
Institutional outlooks are usually incrementalist, aiming for the smallest set of changes possible under present circumstances, as the incentives within institutions discourage any other course. In that respect, the Longevity Dividend is the output of institutional thinkers. What you see above this is more or less the view from inside the government funding monolith, where suggesting even a modest target for increasing healthy life span is a major advance, hurdle and negotiation.
Meanwhile, outside the institutional gates is where you'll find the serious attempts to create revolutionary change in the aging research community and develop disruptive technologies from the latest longevity science. As I said at the time the Longevity Dividend was first put forward:
this proposal is late to the party, fails to acknowledge those who have been advocating similar approaches for some years, and touts a target for gains in healthy life span that is somewhat less than the actuaries and system biologists think will be attained in the next 10 to 20 years by present trends and research directions.
The Longevity Dividend proposal is primarily a political position - which should instantly explain most of its deficiencies to those who follow the way in which funding politics works. It's the first step in a long engagement with large-scale government funding sources (such as the National Institute on Aging) in an attempt to steer future funds into the sorts of moderate programs supported by its authors. That Miller, et al, are doing this at all illustrates, amongst many other things, a concern that future funding will dry up in favor of groups presently moving to advocate healthy life extension - such as those system biologists, or supporters of the Strategies for Engineered Negligible Senescence.
My prediction for the next decade: the trail to radical life extension, and to increasing public understanding and support for medicines to repair aging, will be blazed by philanthropic and private venture funding.
What should I find in my in-box today, but an email from SAGE Crossroads, a professional site on aging science and policy (far too much policy for my taste) that ceased updating a while back. It seems they've risen from the dead this year, and are once again putting new content online in the form of Sagecast videos - see the right hand side on their home page: "Many have argued that when it comes to advances from longevity research - the science is there, but the policy's not. Dr. Richard Miller discusses policy barriers and solutions including insight into the issues faced by FDA, CMS, and NIH when it comes to longevity science. ... In addition to the regulatory and other policy hurdles that longevity science must face, the 'politics' also play a role. Dr. Robert Butler chatted with SAGE Crossroads about the environment, attitudes, and perceptions that challenge the translation of longevity science." For my part, I suspect that the spheres of policy and government research institutions are the last places to look for the signs of rapid, revolutionary progress in enhancing human longevity.
Researchers continue to work on the infrastructure for practical tissue engineering, here succeeding in "growing large numbers of stem cells from adult human hearts into new heart muscle cells. A breakthrough in stem cell research. Until now, it was necessary to use embryonic stem cells to make this happen. ... The cells grew into fully developed heart muscle cells that contract rhythmically, respond to electrical activity, and react to adrenaline. ... We've got complete control of this process, and that's unique. We're able to make heart muscle cells in unprecedented quantities, and on top of it they're all the same. This is good news in terms of treatment, as well as for scientific research and testing of potentially new drugs. ... Stem cells from the hearts of patients with genetic heart defects can be grown into heart muscle cells in the lab. Researchers can then study the cells responsible for the condition straight away. They can also be used to test new medicines. This could mean that research into genetic heart conditions can move forward at a much faster pace. In the future, new heart muscle cells can likely be used to repair heart tissue damaged during a heart attack."
I've been meaning to mention that molecular biologist and healthy life extension advocate Attila Chordash is in the midst of blogging the construction of his PhD thesis. His long term interest is in what he calls partial immortalization (or, alternately, systemic regenerative medicine) - as much healthy life extension as possible attained through period replacement of organs and vital cell populations, as well as via manipulation of stem cells in situ. I have been varyingly skeptical of the degree to which this alone is sufficient for radical life extension:
But it is still an interesting concept, and will clealry be explored in the years ahead, given the massive levels of funding and research interest justifiably directed towards stem cell science.
But back to the thesis, which is a good insight for those interested in what is presently going on down in the trenches of the research community:
During my PhD work I’ve done various stem cell transplantations (local and systemic) into brain, heart, muscle tissues using different stem cell sources, just like freshly isolated bone marrow derived cells (hematopoietic, mesenchymal stem cells), murine embryonic stem cells, cultured hematopoietic stem cells. And I was heavily involved in the mechanisms by which exogenous stem cells can contribute to host tissues and the way these exogenous cells and lesion models can motilize the built in endogenuous stem and progenitor cell populations.
So for me the unifying concept behind is a kind of systemic approach, that is to collect many stem cell data from various tissues, organs, compare them to each other and derive some unifying principles from them that could be adapted to other tissue environments too.
Chordash is not the only person engaged in online thesis building in the regenerative medicine space. I view this as a facet of the overall trend in scientific work towards more open access, meritocratic open review, a gift economy of information, and incremental publication by release. The present information infrastructure in the scientific community - much of it still geared to and informed by an era of paper libraries and hand-delivered mail - isn't up to the task of enabling efficient management and utilization of data at scale. Change is underway, and must go a lot further if the pace of research is to keep up with the pace of data generation. As Chordash puts it:
after all, scientists should conduct nice experiments and publish their results in short, inforich and accessible research papers in order to share it ASAP with the research community, not in book-length, otherwise unaccessible PDFs
The ideal infrastructure would look - from above the API layer - something like a vast distributed and cross-referenced database, constantly updated and constantly accessible to automated discovery and correlation agents, raw data neatly split out from conclusions and theories about that data. As even small fields grow far beyond the ability of one researcher - or one small team - to encompass and understand, automation of the time-consuming parts of academic research will become increasingly necessary.
Judging by this MSNBC article, it takes three to four years for new information to percolate into the mass media to the point at which it appears in general interest pieces on a particular topic. So this article on longevity science looks something like a refugee from late 2004, but I'll take it as a sign of progress that this is the worst thing I can find to say about it. "Public imagination has been sparked by researchers such as Aubrey de Grey, the British scientist who claims that aging is an 'engineering problem' that can be solved by identifying basic causes of aging and creating nuts-and-bolts medical and biomedical solutions. These may include growing new organs or tissues for use in aging bodies, or other techniques promised by the burgeoning field of regenerative medicine. But some scientists who study the underlying causes of aging say such benefits aren't likely to extend lifespan in the near future. 'It's easy to say that aging is an engineering problem, but we're pretty elaborate pieces of engineering,' says longevity researcher Brian Kennedy ... Nonetheless, leading anti-aging researchers are pursuing several approaches that they hope may one day extend lifespan." The article goes on to mention some of the better-known fields, such as research into the biochemistry of calorie restriction.
MSNBC looks at the "anti-aging" marketplace, as busy selling snake oil and muddying the water as ever: "dozens of businesses set up displays to market everything from horny goat weed dietary supplements to wands containing dirt that supposedly align water molecules so the H2O will get into your cells. Many of the products and services attempt to capitalize on recent science buzzwords. Terms like 'stem cells' [were] flung about, but mostly it was a case of putting old wine in new skins. 'ADULT STEM CELLS are the BEST-KEPT SECRET in today's wellness...' boasted a flyer for a dietary supplement ... Take it and increase 'the number of circulating stem cells in your body.' Not only can it 'replace diseased cells with healthy cells' and provide 'anti-inflammatory and immune system support' but also give users 'mental clarity and mood elevation.' But the products are really just a repackaging of a supplement that has been marketed aggressively since the 1980s, a form of blue-green algae called aphanizomenon flos-aquae. The science behind the claimed benefits for aphanizomenon is slight - whether the claim is for immune boosting as it was 20 years ago, or stem-cell enhancement as it is today. In fact, there has long been concern about the presence of toxins in blue-green algae products, though you wouldn't know it from the marketers at the trade show." The level of utter nonsense and falsehood in the marketplace is quite amazing at times.
Every once in a blue moon, I'll participate in a blogmeme. Blink and you'll miss it, right back to longevity science and advocacy the next day. This is a small one put forward by Michael Graham Richard:
Here are 7 questions that I would like to ask to the following people: Michael Anissimov, Jamais Cascio, Tom McCabe, George Dvorsky, Steven Smithee, Randall Parker, and Reason of Fight Aging.
1. What would you nominate as the best idea that anybody has ever had? Why?
From a utilitarian point of view, the formalization of the scientific method that produced the present long-surviving community able to sift and preserve truth from the great foaming sea of lies and mere belief. This is more than a matter of the method, but also the way in which the method is presented, and the way in which scientific communities govern and propagate themselves. We'll put Francis Bacon forward as the figurehead originator for the modern world, though it was an idea whose time had come (once again) in his lifetime.
Men have sought to make a world from their own conception and to draw from their own minds all the material which they employed, but if, instead of doing so, they had consulted experience and observation, they would have the facts and not opinions to reason about, and might have ultimately arrived at the knowledge of the laws which govern the material world.
Imagine a world in which a community as devoted to the practice and protection of the scientific method had emerged and sustained itself as early as seems possible, say perhaps 2,000 to 3,000 years ago in China. How much further could we have advanced by now?
2. What non-fiction book do you think everybody should read? Why?
Anything that provides a solid, readable overview of the Austrian school of economics as it applies to everyday life, modern democracies and the choices we make. Widespread and profound economic ignorance - meaning ignorance of the way in which our world really works, leading to an inability to identify and address the many problems and evils that exist - is at the root of the yawning chasm between what is and what might be.
The very advanced class should go straight to the online edition of Mises' Human Action, while everyone else might consider starting with the very readable and recently released "The Revolution: a Manifesto" by Ron Paul, or perhaps Economics for Real People.
3. What fiction book do you think everybody should read? Why?
Atlas Shrugged - though I imagine that if you're were ever going to read it, you probably have already. Still, put aside anything you know about the author and read it as a work in isolation. The most important lessons in life revolve around the following triad: that choices matter deeply, self-knowledge is power, and hard, honest work is required to attain any goal worth having. Rand's writing will make you think about these things, and you will be the better for it.
4. What technology has most changed your life in the past 10 years and why? What technology do you think will have the biggest impact on your life in the next 10 years and why?
In both cases, the communication and computation infrastructure that sustains the internet; it opens up myriad opportunities and economic niches that were impractical in earlier ages. Bandwidth and information density in component peripherals matters, which is why, I imagine, that the mobile communication revolution hasn't really changed matters for me all that much. The next interesting phase transition, for people like me at least, will occur when you can carry the all the function and utility of a home office and high bandwidth connection in your pocket for a reasonable amount of money. This is more a matter of sorting out the peripherals than the bandwidth, or at least it looks like the peripherals have further to go, but at that point a truly nomadic lifestyle is quite plausible once again for a significant section of the populace.
5. What piece of music would you want with you on a desert island (that has a functioning stereo, of course)?
A spoken word piece on how to build a decent transmitter from the components of a stereo. For the rescue request. It can be set to sparse drum and flute accompanyment if you like.
6. What is the most interesting thing you are working on/reading about/writing about these days?
In terms of what I am watching from the sidelines, even more than the advancing science of longevity, I think it is the ongoing cultural upheaval in the gerontology community that is most engaging. We are witnessing a sea change of paradigm and transfer of influence, from a community that dared not even talk about extending healthy life span, to a vocal and engaged community that now spars in public over how best to do it, and how long it will take.
This is of great importance. The science is just work and money - large amounts of both, of course, but that can always be found if the will to progress exists. The real battle is over whether the science will be turned to the purpose of longevity in any significant way at all.
7. Looking ahead, are you an optimist or a pessimist? Why?
One has to be an optimist about the progress of science and technological capabilities. It's a fast uphill ride, and the next three decades will see the advent of powerful technologies like molecular manufacturing, affordable orbital lift capacity, enormously powerful computers for the cost of sand, organ regrowth and the absolute control of human cells.
I am very pessimistic about the influence of dominant forms of political organization in the developed world and the corrosive influence upon culture that follows - the vanishment of ambition, education, self-sufficiency, responsibility and accountability. Progress will be hindered and shackled, especially in the world of medicine. All the incentives are horribly misaligned, towards stagnation and poverty of service, and - short a long overdue revolution - will only get worse.
You might recall the PEPCK-Cmus mice reported last year: great health and lots of positive improvements in their metabolic biochemistry. They eat hugely, don't put on weight, are very active, and live long. That last item is starting to look impressive indeed: "A second surprising result was the apparent extended longevity of the PEPCK-Cmus mice; they lived almost 2 years longer than the controls and had normal litters of pups at 30-35 months of age (most mice stop being reproductively active at 12-18 months). We use the word 'apparent' because we have not as yet carried out a detailed aging study, involving multiple mice, which are followed at regular intervals over their lifetime; this type of study is currently in underway in our laboratory so hopefully we will be able to state unequivocally that the PEPCK-Cmus mice do live longer than controls." The present longevity record holder is a touch under 5 years for growth hormone manipulation, but this PEPCK-Cmus method leads to much more robust mice. The underlying mechanism is up for debate - it seems to be a polar opposite of longevity induced by calorie restriction biochemistry.
From Ouroboros yesterday, and well said: "Forty-five years ago, Aubrey David Nicholas Jasper de Grey was brought into the world. Today is his birthday, and it seems appropriate to briefly reflect on Aubrey's achievements to date and what he represents to biogerontology. At times brilliant, at times exasperating, Aubrey is unquestionably the world's most energetic popularizer of the idea that there is something we can do about aging - and not just a little something, mind you, but a very big something: we can end it, once and for all. In particular, he argues, we can take an engineer's approach to reversing or repairing several types of damage that characterize aging, and thereby eliminate the process of aging itself. ... it is good and right that we appreciate Aubrey for his energetic efforts in pushing a radical idea - that aging might someday be vanquished - out of the fringes and into the mainstream of modern biological thinking. Despite his differences with individual scientists (and sometimes with large groups of them, waving torches) he remains biogerontology's most prominent popularizer, and therefore in some sense the field's biggest fan." If Aubrey de Grey didn't exist, it would be necessary to invent him.
You can compare and contrast the views of biomedical gerontologist Aubrey de Grey (chair of the Methuselah Foundation, originator of the Strategies for Engineered Negligible Senescence) and gerontologist Robert Butler (president of the International Longevity Center and one of the folk behind the Longevity Dividend initiative) in a series of short videos available at Big Think. A small sampler can be found at the Big Think blog:
What is the point of knowing your own genetic code? For many scientists, the genomic era promises to entail the ultimate type of "preventive medicine," preventing not only biological disease, but aging itself. [Biomedical gerontologist] Aubrey de Grey suggests that an ending to aging would limit suffering since "aging just doesn’t kill people. It kills them horribly." It’s something we may not quite be prepared to deal with "because aging has been considered inevitable for so many millennia."
Dr. Robert Butler too believes that in a hundred years, we’ll be living much longer, better.
The rest of their video segments can be found elsewhere in the site:
Aging to death is a terrible fate, but human ingenuity and application of the scientific method have banished many other horrible fates from most lives in past decades. We live in an age of revolution and accelerating prowess in computation, biotechnology and medicine. So much is possible today that could not even have been planned two decades ago. Scientists know more than enough now to work to prevent and repair the root causes of age-related suffering, degeneration and frailty - all that's needed is the public support and will to move forward, to seek a cure for degenerative aging.
Keeping pace with the identification of normal stem cell populations throughout the body, researchers are also isolating the errant stem cells that drive cancer. From EurekAlert!: scientists "have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer's recurrence and its resistance to chemotherapy. ... These results bring us closer to more effective and targeted treatment for epithelial ovarian cancer, one of the most lethal forms of cancer ... Present chemotherapy modalities eliminate the bulk of the tumor cells, but cannot eliminate a core of these cancer stem cells that have a high capacity for renewal. Identification of these cells, as we have done here, is the first step in the development of therapeutic modalities." With a clear understanding of the biochemical differences that identify cancer stem cells, researchers can unleash the array of targeted therapies presently performing so well in the laboratory. The elimination of cancer as a threat of old age is very much underway.
An overview and update on the latest cancer stem cell research, via the Economist: "The cancer-stem-cell theory, though plausible, was based on animal experiments and its relevance to humans was untested. But a series of studies reported this week [has] changed that. They suggest both that cancer stem cells are very relevant indeed to survival, and that going after them is an excellent idea. ... [Researchers] looked at samples from 268 people with pancreatic cancer and found that the pattern of stem cells in their tumours predicted how long they would live. Those whose tumours had stem cells at their edges (the 'invasive margin' in the militaristic jargon of the cancer-warriors) lived on for an average of 14 months. Those who did not lived an average of 18 months. Not a huge difference, but confirmation that cancer stem cells have an impact on the outcome of disease." The path to effective destruction of cancer stem cells - with none of the harm caused by untargeted chemotherapy - is the use of targeted delivery vectors, keyed to the biochemical differences between cancer stem cells and other cells, a technology presently showing great promise in the laboratory.
You might recall that mice engineered not to express the protein p66Shc live 30% longer, but it's not entirely settled as to why this is the case. The protein p66Shc is required for some methods of programmed cell death in response to damage and failing function, so removing it lowers the rate at which cells destroy themselves in response to stresses:
Free radicals (a category that includes reactive oxygen species) lead to oxidative stress, a term for damage caused to cellular mechanisms by these chemicals. Cells destroy themselves via apoptosis in response to excess oxidative stress, a process initiated in the mitochondria, so as to prevent their own failing mechanisms causing further damage to the body - but the processes of identifying just when is most advantageous to do so are quite varied and complex. The protein p66Shc [is] an important part of one scheme by which a cell starts in on destroying itself.
p66Shc knockout mice exhibit higher catalase activity [and] removing p66Shc extends life - but is this because of a lowered rate of apoptosis with oxidative stress, or is it in fact the higher levels of catalase, an antioxidant that helps soak up the free radicals before they break things? As I'm sure regular readers recall, engineering mice to have more catalase in their mitochondria is good for a 20-30% boost in life span.
There's more on the mechanisms of p66Shc over at ScienceDaily today:
Activated by cellular stress, four p66Shc molecules form a stabile complex via Cystein-Cystein interactions. Only this complex can introduce the controlled cell death by causing the mitochondria to burst. The p66Shc activity can be arrested by the Glutathione and Thioredoxin cellular protective systems, which are capable of breaking down stress damages, substances that cause stress and the activated p66Shc complex. "p66Shc acts in this capacity as a stress sensor", explains Dr. Steegborn.
"The cell's suicide program is apparently only started when these protective systems can no longer handle the cellular stress, and are subsequently also no long capable of deactivating p66Shc that has already been activated."
Mice in which the gene for p66Shc, which is closely related to the human equivalent, has been removed do in fact live some 30% longer than normal mice, but the suspicion is that this gain in lifespan is achieved at the expense of correct function; i.e., that the organism is more susceptible to malfunctions due to cell damage.
Which is interesting, but my money is still on the catalase theory.
From Ouroboros: "The soluble protein Klotho appears to be an anti-aging factor, since mice deficient in the Klotho gene show signs of premature aging. However, the validity of Klotho-/- mutants as a model of progeria is controversial: many of the pathological features of the mutant phenotype can be attributed to hypervitaminosis D, and can be reversed by eliminating vitamin D from the diet. (Biogerontologists are generally more skeptical of progeria than increased longevity, since there are lots of ways to shorten lifespan that don't involve bona fide accelerating of the aging process, whereas there are far fewer ways to lengthen lifespan without slowing that process down.) Another blow against the idea of Klotho as a regulator of lifespan comes from Brownstein et al. ... from a biogerontological perspective, it's both interesting and sad: Specifically, it’s a strike against the idea that we might be able to supplement aging mammals (like ourselves) with increased levels of Klotho in order to forestall aging."
Researchers continue to follow the chained mechanisms by which calorie restriction confers health and longevity benefits. From EurekAlert!: "Previous research has shown that the lifespan-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation ... The big question then became what's happening in these translation-deficient cells to slow aging. That's when [we] had the idea to look at Gcn4 ... Gcn4 is a specialized protein called a transcription factor, which helps transfer genetic information during cell growth. The protein is activated when a cell is starving for amino acids. ... To make the link between Gcn4 and longevity, the scientists then asked whether preventing the increase of Gcn4 would block life span extension. In every case, cells lacking Gcn4 did not respond as strongly as Gcn4-positive cells. ... Although scientists don't yet know whether Gcn4 plays a similar role in organisms other than yeast, Kennedy points out that worms, flies, mice and humans all have Gcn4-like proteins that appear to be regulated in a similar way."
It's a matter of common sense that putting your skin out in the sun is not good for its longevity. As it turns out, the way in which the sun damages your skin is more subtle than a blunt effect of direct radiation. Here's a look at one part of the way in which that happens:
Cutaneous aging occurs through 2 biologically distinct processes: intrinsic and extrinsic aging. The first is a naturally occurring process that results from slow tissue degeneration. In human dermis, intrinsic aging is characterized by 3 features: atrophy of the dermis due to loss of collagen, degeneration in the elastic fiber network, and loss of hydration.
In contrast to intrinsic aging, extrinsic aging is due to environmental factors. Since ultraviolet (UV) exposure is the principal cause of extrinsic aging, it is often referred to as photoaging. At the microscopic level, the distinguishing feature of photoaging is a massive accumulation of elastotic material in the upper and middle dermis, a process termed solar elastosis. Using recombinant DNA technology, it has become possible to demonstrate that UV radiation can activate the human elastin promoter. This provides a mechanism for enhanced elastin biosynthesis, which contributes to the clinical and morphologic changes observed in photoaged skin.
In other words, solar radiation changes the way skin is programmed to form and repair itself - for the worse. So much of aging is caused by malfunctions in the signal and control mechanisms of the body, processes necessary to the normal function of tissue run awry or amok, causing damage or - as in this case - changes in the structure of tissue that reduce its ability to function. Inflammation in the skin brought on by solar radiation is another example that contributes to aging of the dermis; necessary mechanisms subverted to set damaging processes in motion.
Genetic research suggests that Parkinson's disease is not a matter of wear and tear in the brain, but more of an inherited susceptibility to damage: "Inheriting one or both of these mutations doesn't mean that a person will develop Parkinson's disease, but that an individual's risk is increased. The basis of population genetics is that disease is familial; people are so distantly related that they don't know they may have inherited specific genes. While there may be an environmental component to development of the disease, none have been identified that have risks as large as those seen by the LRRK2 gene mutations ... even though there are familial mutations in different locations of the gene, it produces the same effect, the same disease. ... It seems like mutations are occurring in a few founders, and that these founders have a lot of offspring over generations that carry the mutation. Even in sporadic disease, then, familial genes are inherited but symptoms may skip some generations, making the disease appear sporadic." Which suggests that much of Parkinson's could be eliminated via use of a mature gene therapy technology.
A metastudy weighs in to demonstrate that antioxidant supplementation has no effect on human life span. Statistics is a dangerous beast, meaning one should never consider this sort of study in isolation, but its far from the only research to show that the standard array of antioxidant supplements don't do much. "The findings of our review show that if anything, people in trial groups given the antioxidants beta-carotene, vitamin A, and vitamin E showed increased rates of mortality. There was no indication that vitamin C and selenium may have positive or negative effects. So regarding these antioxidants we need more data from randomised trials. The bottom line is that current evidence does not support the use of antioxidant supplements in the general healthy population or in patients with certain diseases." If you engineer your antioxidants (or your genes) to target the mitochondria inside your cells on the other hand - the heart and starting point of the mitochondrial free radical theory of aging - then a slowing of aging results. But that doesn't happen when you swallow those supplement pills.
Longevity science advocate Barbara Logan has organized an evening with biomedical gerontologist Aubrey de Grey at the Orlando Science Center in Florida this May 12th, sponsored by the Millard Foundation, and boasting a slick mini-website. Good work - I'm always pleased to see hardworking members of the healthy life extension community doing more to move matters forward:
Engineering an End to Aging, an evening with Dr. Aubrey de Grey
Find out why MIT's Technology Review, the New York Times, the Economist, Fortune Magazine, Popular Science, Barbara Walters, 60 Minutes, even Stephen Colbert think Dr. Aubrey de Grey may have found the way to end aging.
If you're in Florida this May, this is an excellent chance to hear de Grey speak and ask your questions about his Strategies for Engineered Negligible Senescence, the longevity science book Ending Aging and the ongoing research funded by the Methuselah Foundation.
Enjoy Dr. de Grey's engaging and entertaining speaking style. Get a chance to talk to this pioneer in the world of longevity research. Learn about the latest breakthroughs in life extension. Network with influential individuals interested in the future of bio-tech here in central Florida.
You'll find PDF fliers and a press release at the website for the Orlando event. If you live in that part of the world, do your part and pass the promotional material along to those who would be interested.
Given the right cues, our stem cells are capable of far greater feats of healing than take place naturally. Scientists are searching tirelessly for the controlling signals that can put stem cells to work without the risk of cancerous growth. Via ScienceDaily: "researchers screened about 147,000 molecules to find one that could transform human blood stem cells into a form resembling immature heart cells. When they implanted blood stem cells activated by this compound into injured rodent hearts, the human cells took root and improved the animals' heart function. .. Despite medical advances in treating and preventing heart attacks, once the heart is damaged it cannot repair itself ... After a week, the function of the rats' hearts had significantly improved, and after three weeks, the organs contracted as strongly as they did before the damage. Tests showed that the human cells were alive and had incorporated themselves into the heart tissue ... this drug can act on blood stem cells that are already being used in other clinical trials. This may speed its movement into clinical trials for heart repair." Note that screening 147,000 molecules for the one you want is an unremarkable feat these days - biotechnology continues to accelerate, leading to a rate of analysis and progress that would have been impossible 20 years ago.
EurekAlert! reports that the practice of calorie restriction reduces the risk of pancreatic cancer, in much the same way as it reduces the risk of epithelial cancers: "Prevention of weight gain with a restricted calorie diet sharply reduced the development of pancreatic lesions that lead to cancer [in] a strain of mice that spontaneously develops pancreatic lesions that lead to cancer. ... analysis points to a connection between calorie intake and a protein called Insulin-like Growth Factor (IGF)-1, with obesity increasing and calorie restriction decreasing levels of IGF-1. IGF-1 is an important growth factor known to stimulate the growth of many types of cancer cells. Inflammatory signaling proteins also were found to be reduced in the blood of the calorie-restricted mice. ... The decline in blood levels of inflammatory proteins in the calorie restricted mice makes sense [because] fat tissue is a major source of inflammatory factors such as cytokines."
So very many people will die before the advent of working rejuvenation medicine, largely from aging, and including many of you reading this now. The only viable option open to these folk is cryopreservation, the low-temperature storage of the brain and body after clinical death. This process can preserve the fine structure of the brain sufficiently well for plausible future technologies to revive a preservee; everything that makes you the person you are is in the structure of your brain. Preserve that, and you can wait as long as needed for the expanding future of medical nanotechnology - and even more advanced science beyond that - to develop the needed tools for revival.
Very low temperatures create conditions that can preserve tissue for centuries, possibly including the neurological basis of the human mind. Through a process called vitrification, brain tissue can be cooled to cryogenic temperatures without ice formation. Damage associated with this process is theoretically reversible in the same sense that rejuvenation is theoretically possible by specific foreseeable technology.
Injury to the brain due to stopped blood flow is now known to result from a complex series of processes that take much longer to run to completion than the 6 min limit of ordinary resuscitation technology. Reperfusion beyond the 6 min limit primarily damages blood vessels rather than brain tissue. Apoptosis of neurons takes many hours. This creates a window of opportunity between legal death and irretrievable loss of life for human and animal subjects for cryopreservation with possibility of future resuscitation. Under ideal conditions, the time interval between onset of clinical death and beginning of cryonics procedures can be reduced to less than 1 min, but much longer delays could also be compatible with ultimate survival.
Although the evidence that cryonics may work is indirect, the application of indirect evidence is essential in many areas of science. If complex changes due to aging are reversible at some future date, then similarly complex changes due to stopped blood flow and cryopreservation may also be reversible, with life-saving results for anyone with medical needs that exceed current capabilities.
If you're interested in living to see the bright future of humanity, but unlikely to survive into the near-future era of rejuvenation medicine and enhanced longevity, then cryonics is the only practical way forward. Nothing in the laws of physics prohibits medical technologies capable of restoring a cryopreserved person to life and function - if the structure of the preserved brain is intact, it's just a matter of waiting.
Mitochondrial damage and loss of function with age is an important contribution to many forms of age-related disease, dysfunction and degeneration. Here, an overview of some of the nuts and bolts of that damage: "high-throughput transcription profiles of genes coding for mitochondrial proteins in ventricles from adult (6-months) and aged (24-months) rats were compared using microarrays. Out of 614 genes encoding for mitochondrial proteins, 94 were differentially expressed with 95% downregulated in the aged. The majority of changes affected genes coding for proteins involved in oxidative phosphorylation ... gene expression changes in aged hearts translated into a reduced mitochondrial functional capacity ... aging induces a selective decline in activities of oxidative phosphorylation complexes I and V within a broader transcriptional downregulation of mitochondrial genes." Recall that oxidative phosphorylation is the more efficient mode of operation for mitochondria, and that loss of oxidative phosphorylation is the first step in the mitochondrial free radical theory of aging.
Amongst all its other health benefits, calorie restriction appears to also reduce the risk of certain types of cancer: "A restricted-calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development ... An obesity-inducing diet, by contrast, activated those pathways ... These results, while tested in a mouse model of skin cancer, are broadly applicable to epithelial cancers in other tissues ... Epithelial cancers arise in the epithelium - the tissue that lines the surfaces and cavities of the body's organs. They comprise 80 percent of all cancers. ... Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R). These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR. ... Calorie restriction, which we refer to as negative energy balance, inhibits this signaling, and obesity, or positive energy balance, enhances signaling through these pathways, leading to cell growth, proliferation and survival."
An interesting short paper on glucose metabolism and aging caught my eye today; the full PDF is also freely available for those who like more detail.
There is an ever increasing scientific interest for the interplay between cell's environment and the aging process. Although it is known that calorie restriction affects longevity, the exact molecular mechanisms through which nutrients influence various cell signaling/modulators of lifespan remain a largely unresolved issue.
Accumulating evidence shows that among the important regulators of aging process are autophagy, sirtuin activity and oxidative stress. In light of recent work indicating that glucose availability decreases lifespan whilst impaired glucose metabolism extends life expectancy [in nematode worms], the present article deals with the potential role of glucose in the aging process by regulating - directly through its metabolism or indirectly through insulin secretion - autophagy, sirtuins as well as other modulators of aging like oxidative stress and advanced glycation end-products (AGEs).
Drench your diet in glucose and calories and pay the price, in other words. For all that various studies have shown that much of the interesting biochemistry of calorie restriction hinges on protein restriction - rather than cutting the carbohydrates like glucose - this paper is an argument for a specific set of calorie restriction benefits to stem from cutting down glucose.
I think that it's plausible based on what we know today to divide the results of calorie restriction into two parts, one relating to protein intake and the reaction of various controlling machineries of metabolism, and the other to the interconnected fat-levels-and-insulin-signaling systems. Sirtuins, a well-funded area of research at the moment, seem to lump into the latter rather than the former in the view put forward in this paper.
If you read around the past few years of calorie restriction research, you'll see a lot of interesting contradictions and poking of holes in tentative theories as new data arrives at a fast rate. That's the way science moves forward, and metabolic biochemistry is a fearsomely complex beast. I suspect researchers will find some presently strong hypotheses to be wrong or incomplete, or that calorie restriction does in fact work differently in important ways when comparing yeast, flies, mice, worms and humans. In many ways, this field is coming to the interesting part - enough data, funding and hard working researchers to pull it all together within the next five years.
The free radical theory of aging - which evolved into the mitochondrial free radical theory of aging - has been around for a while. Via Ouroboros: "Understanding the molecular mechanisms underlying the ageing process may provide the best strategy for addressing the challenges posed by ageing populations worldwide. One theory proposing such molecular mechanisms was formulated 50 years ago. Harman et al. suggested that ageing might be mediated by macromolecular damage through reactions involving reactive oxygen species (ROS). Today, a version of the free radical theory of ageing, focusing on mitochondria as source as well as target of ROS, is one of the most popular theories of ageing. Here we critically review the status of key principles and concepts on which this theory is based. We find that the evidence to date shows that many of the original assumptions are questionable, while on some critical issues further refinements in techniques are required. Even so, it is becoming evident that mitochondria and [mitochondrial DNA] integrity may indeed be crucial determinants of organismal ageing."
EurekAlert! notes that researchers have "successfully identified stem cells within articular cartilage of adults, which although it cannot become any cell in the body like full stem cells, has the ability to derive into chondrocytes - the cells that make up the body's cartilage - in high enough numbers to make treatment a realistic possibility. The team have even been able to identify the cells in people over 75 years of age. Osteoarthritis [occurs] when changes in the make up of the body's cartilage causes joints to fail to work properly. At its worse it can cause the break up of cartilage, causing the ends of the bones in the joint to rub against each other. This results in severe pain and deformation of the joint. One current treatment to treat damaged cartilage due to trauma in younger patients is to harvest cartilage cells from neighbouring healthy cartilage and transplant them into the damaged area. Unfortunately, only a limited number of cells can be generated. ... We have identified a cell which when grown in the lab can produce enough of a person's own cartilage that it could be effectively transplanted. There are limitations in trying to transplant a patient's existing cartilage cells but by culturing it from a resident stem cell we believe we can overcome this limitation."
Every year you can extend your natural healthy longevity is a year more for the scientific community to develop working rejuvenation medicine. Regular exercise certainly helps, but be wary of hype like "chop a dozen years off the biological age." Exercise is not proven to do any such thing, but it does make some biomarkers of fitness return to the levels of a person 12 years younger. Exercise also helps to avoid damage caused by a sedentary lifestyle through a variety of processes, varying from dropping excess visceral fat to changing the regulation of metabolism: "aerobic fitness may indirectly delay dependency by preventing other conditions that are likely to diminish functional capacity, including obesity, diabetes, hypertension, myocardial infarction, stroke, some forms of cancer, and osteoporosis. Exercise also hastens recovery from injuries and any additional muscle power may prevent falls, he said. ... There seems good evidence that the conservation of maximal oxygen intake increases the likelihood that the healthy elderly person will retain functional independence."
The publishers of the Rejuvenation Research journal have thoughtfully started to list the fast track articles that become available online ahead of publication. I would imagine that the general trend in journals will be to move away from the existence of "issues," a bundle of publications released in one go, as publishing infrastructure becomes increasingly removed from the old school of print and paper. Looking at what's up ahead of the second the issue this year, I notice a paper by researcher Michael Rose on his SENSE thesis, a critique on the goals and methods of the Strategies for Engineered Negligible Senescence (SENS) from the perspective of his work in evolution and aging:
Thirty years ago, in 1977, few biologists thought that it would be possible to increase the maximum life span characteristic of each species over the variety of environmental conditions in which they live, whether in nature or in the laboratory. But the evolutionary theory of aging suggested otherwise. Accordingly, experiments were performed with fruit flies, Drosophila melanogaster, which showed that manipulation of the forces of natural selection over a number of generations could substantially slow the rate of aging, both demographically and physiologically.
After this first transgression of the supposedly absolute limits to life extension, it was suggested that mammals too could be experimentally evolved to have greater life spans and slower aging. And further, it was argued that such postponed-aging mammals could be used to reverse-engineer a slowing of human aging. The subsequent discovery and theoretical explanation of mortality-rate plateaus revealed that aging was not due to the progressive physiological accumulation of damage. Instead, aging is now understood by evolutionary biologists to arise from a transient fall in age-specific adaptation, a fall that does not necessarily proceed toward ineluctable death.
This implies that SENS must be based on re-tuning adaptation, not repairing damage. As evolutionary manipulation of model organisms shows us how adaptation can be focused on engineering negligible senescence, there are thus both scientific and practical reasons for making SENS evolutionary; that is making SENSE.
It has to be said that I'm not on board with this way of looking at things; where it isn't a restating of the mainstream goal of re-engineering metabolism or genes to slow aging, it runs headlong and contrary into the reliability theory view of aging as damage to the machinery of the body. The various damage theories of aging are so elegant, so in sync with long-standing and proven work on the aging and breakdown of complex machinery, that postulating against them is a high wall to climb from where I stand.
Yes, you can extend life in animals through selective breeding, applying evolutionary pressure of your own. Rose has done just that in fruit flies. You can look at the biochemistry and genetics of your longer-lived animals, and plausibly reverse engineer out a longevity science from that - in much the same way as researchers are presently reverse engineering the longevity benefits of calorie restriction in mammals. But I think the critiques applied to the goal of developing metabolic manipulations to emulate calorie restriction benefits also apply to metabolic or genetic manipulation to emulate artificially selected longevity. Mainly:
- It's likely to be harder than learning to repair the metabolism we have
- It provides little or no benefit to those already old and age-damaged - it's not rejuvenation, only a slowing of existing processes
From EurekAlert!: "Inserting tiny scaffolding into the brain could dramatically reduce damage caused by strokes ... combining scaffold microparticles with neural stem cells (NSCs) could regenerate lost brain tissue. Strokes cause temporary loss of blood supply to the brain which results in areas of brain tissue dying - causing loss of bodily functions such as speech and movement. ... while NSC transplantation has been proven to improve functional outcomes in rats with stroke damage little reduction in lesion volume has been observed. ... Working with rats [researchers] are developing cell-scaffold combinations that could be injected into the brain to provide a framework inside the cavities caused by stroke so that the cells are held there until they can work their way to connect with surrounding healthy tissue. ... The ultimate aim is to establish if this approach can provide a more efficient and effective repair process in stroke."
Aging is a chain of additive processes, starting with damage at the level of molecules and cells caused by your metabolic processes, damage that accumulates like biochemical rust. Eventually there's enough rust to harm the working of critical systems at larger scales, such as small blood vessels, or the liver, or the muscles of the heart. Malfunctions and lost efficiency in those systems cause and accelerate problems in other organs, like the brain:
a third of the risk for dementia (33 percent) was associated with damage to the brain from small vessel disease. .. this small vessel damage is the cumulative effect of multiple small strokes caused by hypertension and diabetes, strokes so small that the person experiences no sensation or problems until the cumulative effect reaches a tipping point.
The rust that causes blood vessels to degrade in performance probably has to do with increasing oxidative damage, the accumulation of AGE compounds that interfere in cell signaling, and possibly the chemistry of chronic inflammation. Blood vessels are complex little machines that rely on their structure and a coordinated set of signaling mechanisms to do their job. As the damage of aging changes that structure, interferes with signaling, and degrades the effectiveness of our blood vessels, this in turn hurts the rest of our biochemical systems.
Progress continues in the components of prosthetic sight, with replacements for age-damaged retinas being the most advanced at this time. The latest versions are a few years from human trials, and the result is far from a full restoration of vision, but it's a great improvement over blindness. The technology will only get better with time: "The implant is based on a small chip that is surgically implanted behind the retina, at the back of the eyeball. An ultra-thin wire strengthens the damaged optic nerve; its purpose is to transmit light and images to the brain's vision system, where it is normally processed. Other than the implanted chip and wire, most of the device sits outside the eye. The users would need to wear special eye glasses containing a tiny battery-powered camera and a transmitter, which would send images to the chip implanted behind the retina. The new device is expected to be quite durable, since the chip is enclosed in a titanium casing, making it both water-proof and corrosion-proof. The researchers estimate that the device will last for at least 10 years inside the eye."
Large scale progress in research and clinical application of stem cell therapies requires an industry of cell provision. The MIT Technology Review profiles the efforts of BioTime to be a provider: "Stem cells hold great promise for medicine, both as a potential source of replacement cells for damaged organs and as a scientific resource to study disease and develop and test new drugs. But to realize that promise, scientists have to figure out how to make their products on an industrial scale. ... It's clear we'll need a much better strategy for reliably and reproducibly generating large numbers of specific cell types. Most studies until now have stopped short of doing this ... I could clearly see a customer base in scientists who simply see stem cells as a way of providing lots of cells for their use ... Currently, scientists prod stem cells to develop into specific cell types by exposing them to some of the same chemicals those cells would encounter during normal development. However, the process is often inefficient, yielding a small number of the desired cells that must then be purified from other cell types. ... BioTime is already gearing up commercial manufacturing, aiming to begin shipping cells in six to 12 months."
The more age-related disease and damage can be sourced to the ongoing accumulation in our cells of faulty mitochondria with damaged mitochondrial DNA, the better. We already know about the acceleration of free radical production central to the mitochondrial free radical theory of aging. In addition, we've seen suggestions that the advancing rate of nuclear DNA damage with age could have something to do with mitochondrial damage, as well as a potential link between telomere shortening and mitochondrial damage:
The discovery of more benefits from repairing mitochondria mean a greater likelihood of significant funding for medical technologies capable of achieving that end. The present state of science when it comes to wholesale replacement of damaged mitochondria or mitochondrial DNA is very promising, with the important exception of the money side of the research equation. It has been several years since protofection of new mitochondrial DNA was demonstrated to work in mice, and other groups have shown similar results since then via mechanisms discovered in tropical parasites, but the state of funding in no way matches the potential for this sort of research.
In short, we're all set with a brace of breakthroughs, but need a big flood of funding to support the development of these mitochondrial repair and replacement techniques in humans. From there, widespread application to reverse the damage of aging can hopefully follow. It seems likely, given the state of health of the average 30 year old, that a mitochondrial overhaul is something needed once every few decades at most - it takes a while for the damage to rise to the level that causes age-related disease.
If you head on over to ScienceNOW today, you'll find another good reason to fully develop mitochondrial repair and replacement technologies:
Cancer often strikes its final, fatal blow when a tumor spreads to other organs. A new study published online today in Science sheds light on this poorly understood process, called metastasis. The researchers report that mutations in mitochondrial DNA [mtDNA] can spur metastasis and that it can be reversed with drugs, at least in mice.
The precise mechanism isn't yet pinned down with certainty, although excess free radical production looks plausible, but the evidence pointing to damaged mitochondrial DNA as enablers of metstasis is pretty convincing. I hardly need to point out that the cancer research community is more or a less a flood of money in motion; if some of that weight of funding is directed to the repair of mitochondrial DNA, the resulting technologies will lead to far broader benefits.
Biotechnologies that allow targeting of very specific cell types are a powerful and versatile tool, as demonstrated in this application via Reuters: "Although human embryonic stem cells are a very powerful source to make differentiated cells, like heart cells, the problem is that you can have residual cells and there is a safety concern because they can form [a] mass of tumour cells ... So if you give a product that is 95 percent heart cells, but 5 percent embryonic stem cells, it may be a problem later on ... The researchers managed to generate antibodies in mice after injecting human embryonic stem cells into the animals. The antibodies were then harvested and added to cultured embryonic stem cells that had been newly differentiated on laboratory dishes. ... [the antibody] specifically eliminated undifferentiated cells within 30 minutes but left differentiated cells untouched." So here, tools developed in cancer research are turned to making a foundation for regenerative medicine more practical.
As reported at EurekAlert!, researchers are testing induced pluripotency (IPS) in areas in which stem cell therapies have already shown potential. Can the more readily engineered IPS cells do the job? "Neurons derived from reprogrammed adult skin cells successfully integrated into fetal mouse brains and reduced symptoms in a Parkinson's disease rat model ... This is the first demonstration that reprogrammed cells can integrate into the neural system or positively affect neurodegenerative disease ... For the neural experiments Wernig used induced pluripotent stem cells (IPS cells), which were created by reprogramming adult skin cells using retroviruses to express four genes (Oct4, Sox2, c-Myc and Klf4) into the cells' DNA. The IPS cells were then differentiated into neural precursor cells and dopamine neurons using techniques originally developed in embryonic stem cells. ... Wernig saw that transplanted cells formed clusters where they had been injected and then migrated extensively into the surrounding brain tissues. ... the neural precursor cells that migrated had differentiated into several subtypes of neural cells, including neurons and glia, and had functionally integrated into the brain."
When I talk about stem cell science, it's usually in the context of goals in tissue engineering and regenerative medicine, especially as they apply to repairing the damage of aging. Organ regrowth, scalable production of large numbers of tailored cells, autologous cell therapies, and so forth.
There's a whole other side to stem cell research, however: making it easier and less costly to both understand disease mechanisms and test therapies in the laboratory. If researchers can reliably use therapeutic cloning - or other methods - to produce pluripotent cells from adult cells, then limits placed on the study of disease mechanisms due to scarity of cell samples vanish. This would be a great step forward:
Scientists have taken skin cells from patients with eight different diseases and turned them into stem cells. ... The stem cells were created by taking biopsies from patients with diseases such as Huntington's and muscular dystrophy.
By taking skin cells from diseased patients, returning them to their embryonic form before redirecting them to becoming heart cells, a greater understanding of how heart disease develops can be gained ... They can also be used to test drugs - potentially paving the way for more effective treatments.
The technology in this case is induced pluripotency rather than therapeutic cloning, the use of recently discovered genetic switches to reprogram cells into a stem-cell-like state. Diversity of competing methodologies is a good sign for future progress in any field.
All too many efforts aimed at treating age-related disease are nothing more than brief patches for the problem - treat the symptoms but not the cause for a small gain. Regenerative medicine sometimes falls into this category: researchers "have discovered that dopamine cells that have been transplanted into the brain of patients with Parkinson disease [PD] develop pathologic changes characteristic of [PD] and do not appear to function normally ... Dopamine cells are transplanted into the brain of PD patients in the hope that they can replace those that degenerate and thereby improve symptoms of the disease. This study shows that implanted cells can become affected by the disease process and thereby limits the long-term utility of this approach. ... In the study, the patient improved initially but then deteriorated. ... these findings suggest that the disease process is ongoing and can damage newly implanted cells." When all you can do is patch, you patch, but we're moving into a more capable era now. We should aim higher, at eliminating root causes.
You can now preview Ending Aging at Google Books: "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. ... 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."
A logical extension of the metabolic engineering school of longevity science - researchers who seek to slow aging by changing human metabolism - is to find out how extremely long-lived animals manage to be extremely long-lived. Is there something we can learn from their biochemistry that can then be back-ported into the human model via drugs, gene engineering, or other methodologies?
Setting aside my thoughts on the practicality of changing human metabolism to slow aging (hard, complex, worthless for those already old) versus repairing the metabolism we have to reverse aging (less challenging, useful for those already old), I think that the answer is yes, there is much of worth in the varied biochemistries of the animal kingdom:
- Let's Sequence the Exceptionally Long-Lived Mammals
- Naked Mole-Rats and Negligible Senescence
- Ageless Animals, the Lobster Edition
How is it that a whale can resist cancer effectively enough to live for two centuries in the wild, bearing in mind a whale has so many, many more cells than we humans that might become cancerous. How does the construction of naked mole-rat cellular membranes allow them to shrug off oxidative damage and live nine times longer than similar rodent species? Why do lobsters - and possibly some species of clam - seem not to age at all?
A thousand other questions exist. Chris Patil at Ouroboros is thinking along these lines today:
Some species appear not to age, in the sense that they become no more likely to die as time passes - take, for example, Arctic quahogs, the longest-lived animals on record. How does such negligible senescence evolve?
The first step in understanding the cellular and molecular basis of negligible senescence is to look at factors that are known to influence lifespan in other organisms - oxidized proteins, antioxidant defense systems, heat shock proteins - and see whether any of them show unusual patterns in long-lived animals. Ivanina et al. did just that with the mollusks, looking at aging-related molecular pathways in one clam and one oyster species. Unfortunately, shaking down the "usual suspects" didn't reveal any hints
Another possibility is that molluscs are different enough from the more traditional (though less delicious) model organisms of biogerontology that our list of usual suspects won’t be useful - we might need a whole different lineup. Certainly, something is different about particular species of clams, trees, insects and possibly even rodents - it’s up to us to figure out what. The difference between "conventionally" aging species and negligibly senescent ones is one of quality rather than degree, and it may be that the mechanisms explaining (theoretically) infinite lifespans are wholly unrelated to those explaining finite ones. In order to reveal them, we may have to venture outside the warm glow of the lamppost.
A fairly clear description of the way aggregates like lipofuscin, which your body cannot break down but nonetheless accumulate through the normal operation of your metabolism, harm your cells: "The most striking morphological change in neurons during normal aging is the accumulation of autophagic vacuoles filled with lipofuscin or neuromelanin pigments. These organelles are similar to those containing the [lipofuscin] associated with neurological disorders, particularly in diseases caused by lysosomal dysfunction. [Lipofuscin and pigments] arise from incompletely degraded proteins and lipids principally derived from the breakdown of mitochondria, or products of oxidized catecholamines. Pigmented autophagic vacuoles may eventually occupy a major portion of the neuronal cell body volume, due to resistance of the pigments to lysosomal degradation and/or inadequate fusion of the vacuoles with lysosomes." As long-lived cells are bloated by vacuoles containing material they can't get rid of, they cease to behave correctly, leading to degeneration and disease. Repairing and preventing this state of affairs requires research like the LysoSENS program, aiming for ways to safely break down lipofuscin and other damaging materials.
A recent paper suggests that resistance to climatic variablity might be one reason why increased longevity can win out in an evolutionary battle with short lived species that reproduce more rapidly: "We analyzed multiyear demographic data for 36 plant and animal species with a broad range of life histories and types of environment to ask how sensitive their long-term stochastic population growth rates are likely to be to changes in the means and standard deviations of vital rates (survival, reproduction, growth) in response to changing climate. ... Short-lived species (insects and annual plants and algae) are predicted to be more strongly (and negatively) affected by increasing vital rate variability relative to longer-lived species (perennial plants, birds, ungulates). ... Our results highlight the potential vulnerability of short-lived species to an increasingly variable climate." You might also recall other work suggesting that crowding effects can lead to runaway evolution of extreme longevity.
As you might recall, it wasn't so long ago that researchers discovered the source of progeria in lamin A defects, which also occur - far less dramatically - in the course of normal aging. Lamin proteins, you might recall, help to form the important structural shell of the cell nucleus. Things start to go wrong when cells are improperly formed:
Malformed lamin A proteins lie at the root of the accelerated aging condition progeria. ... In cells taken from the elderly, the nuclei tend to be wrinkled up, the DNA accumulates damage, and the levels of some proteins that package up DNA go askew ... This mirrors the same changes that they previously observed in cells from [Hutchinson-Gilford progeria syndrome (HGPS)] children. ... The team suggests that healthy cells always make a trace amount of an aberrant form of lamin A protein, but that young cells can sense and eliminate it. Elderly cells, it seems, cannot. Critically, blocking production of this deviant protein corrected all the problems with the nucleus. ... You can take these old cells and make them young again."
Recently, it has come to light that lamin (also known as progerin) protein defects, and the resulting mishaped and stucturally deficient cell nucleui, also damage stem cell capacity. It might be this stem cell deterioration that largely causes the accelerated aging of progeria - and, by extension, contributes to age-related degeneration in the rest of us too:
researchers postulate that the biochemical root of HPGS, or progeria, causes accelerated aging by affecting stem cell populations: "The cause of HGPS, a mutated protein called progerin, was identified in 2003. However, the mechanism by which progerin causes the widespread clinical effects of HGPS has been unclear. ... [researchers have now] found that progerin activates genes involved in the Notch signaling pathway, a major regulator of stem cell differentiation - the process by which stem cells give rise to the mature cells that make up different tissues. ... Their experiments revealed that progerin profoundly affects the fate of these stem cells, greatly skewing the rate at which they mature into different tissues. ... Progerin is present at low levels in the cells of healthy people. One could envision a scenario in which progerin's effects on the Notch pathway and, by extension, on adult stem cells could, over time, lead to many of the tissue changes we commonly associate with the aging process
I bumped into a couple of papers today that expand on the mechanisms linking defective lamin proteins, poorly formed cell nuclei and stem cell dysfunction.
Specific mutations in the human gene encoding lamin A or in the lamin A-processing enzyme, Zmpste24, cause premature aging. New data on mice and humans suggest that these mutations affect adult stem cells by interfering with the Notch and Wnt signaling pathways.
Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments.
To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24-null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region.
We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24(-/-) mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.
It seems unclear as to where this will all lead for those of us fortunately enough not to suffer from progeria. Some calibration of the degree to which normal levels of lamina damage contibute to aging would be a good first step - it is by no means clear that this mode of age-related change is as important as the others we are presented with.
You might recall a 2006 technology demonstration in which comparatively simple nanoparticles were used to deliver the toxin fumagillin to sites of errant blood vessel formation, and thus disrupt atherosclerotic plaques without otherwise damaging the patient. Here, ScienceDaily reports on the same approach directed to attack cancer: "The nanoparticles are extremely tiny beads of an inert, oily compound that can be coated with a wide variety of active substances. ... the researchers describe a significant reduction of tumor growth in rabbits that were treated with nanoparticles coated with a fungal toxin called fumagillin. ... In addition to fumagillin, the nanoparticles' surfaces held molecules designed to stick to proteins found primarily on the cells of growing blood vessels. So the nanoparticles latched on to sites of blood vessel proliferation and released their fumagillin load into blood vessel cells. Fumagillin blocks multiplication of blood vessel cells, so it inhibited tumors from expanding their blood supply and slowed their growth." Precisely targeted chemotherapy is being demonstrated to be a more effective chemotherapy, lacking in unpleasant side-effects. This sort of technology is a foundation for highly effective, painless cancer therapies.
Regenerative medicine and tissue engineering require the ability to create cells to order, and researchers are presently working to produce that infrastructure. Illustrative work to that end via EurekAlert!: "a major stumbling block to developing new treatments has been the difficulty scientists have faced ensuring the stem cells turn into the type of cell required for any particular condition - in the case of diabetes, pancreatic cells. ... Unprompted, the majority of stem cells turn into simple nerve cells called neurons. Less than one per cent of embryonic stem cells would normally become insulin-producing pancreatic cells, so the challenge has been to find a way of producing much greater quantities of these cells. ... The team found that the transcription factor PAX4 encouraged high numbers of embryonic stem cells - about 20% - to become pancreatic beta cells with the potential to produce insulin when transplanted into the body. Furthermore, the scientists for the first time were able to separate the new beta cells from other types of cell produced using a technique called 'fluorescent-activated cell sorting' which uses a special dye to colour the pancreatic cells green."
Over at Sentient Developments you'll find a rendition of what might be termed the core points of healthy life extension. I myself have a long-standing version up at the Longevity Meme, and another back in the Fight Aging! archives. Simply put, cutting out the frills and lumping cryonics into longevity research in general:
I would go so far as to say that there are only three things that you can do today to be as sure as present science allows that you have increased your remaining healthy life expectancy. The gold standard for weight of scientific evidence is a narrow platform at present:
- responsibly practice calorie restriction
- exercise regularly
- support the most proactive, plausible longevity research
None of this should really be a surprise. I'd add a fourth item for modest supplementation, but any discussion of the scientific support there gets bogged down very quickly - it's an enormously broad and complex topic, beset by a noisy band of marketeers ready to tell you anything that will make you shell out for whatever it is they're selling today.
George Dvorsky's version at Sentient Developments is more detailed and helpful in the most part, but he falls into the deep pit that yawns for so many in the healthy life extension community: an overly great focus on the minutiae of diet and supplementation, and taking as gospel things that don't actually have a great deal of scientific support.
Look at how much of his post rests on blueberries and antioxidants versus Strategies for Engineered Negligible Senescence research - that blueberry or no blueberry choice might be right under your nose three times a day, but it's inconsequential in comparison to the pace and direction of scientific research. It's also inconsequential in comparison to whether or not you practice calorie restriction.
As a general rule, you should view studies on diet with great suspicion, especially those claiming long term health benefits from a single type of food X or food Y. The same goes for supplements. All too few of those studies properly control for differences in calorie intake, or other meaningful correlations. In cases where a good weight of evidence backs some form of benefit, that benefit is invariably dwarfed by the benefit supplied by exercise and calorie restriction. Why do people spend so much time and energy on clawing back 0.1% of the 10% of life span they're dinging themselves by overeating and not exercising? It's a mystery.
It is reasonable to state, bluntly, that you or I can reliably engineer no greater chance of improving our natural long-term health than by simply eating sensibly, practicing calorie restriction (which pretty much forces eating sensibly on you), exercising regularly, and taking a sane multivitamin. Anything more than that, and you have to accept that you're tinkering with no real way of knowing whether you're gaining any benefit. Not that there's anything wrong with that as a hobby, but don't delude yourself into thinking that you can eat as much as you like and top it off with blueberries to at least make something better.
For example, let's look at antioxidants. It is becoming clear that ingesting antioxidants has very little - and possibly a minor negative - effect on healthy longevity. On the other hand, Targeting antioxidants to mitochondria by gene therapy or clever chemical engineering slows aging in mice by 30%. Needless to say, the antioxidants you swallow are going nowhere near your mitochondria, and so are doing more or less nothing of any good on that front.
We won't even talk about things like alkaline water and so forth. That veers off into the land of magical thinking and the noisy "anti-aging" marketplace that so loves to take the money of the gullible.
Now that I've savaged items #1 and #2 in Dvorsky's post, I can say that the rest of it is good advice that you should read, especially on supporting the future of longevity research. Nothing other than major advances in medical science will reliably let you live to see 100 years of age - so best we all get working on that, right?
Many cancers are driven by cancer stem cells, and these errant stem cell populations have characteristic differences that can be exploited. From the Telegraph: "A new way to fight a common form of skin cancer has resulted from the discovery of how the uncontrollable growth of the tumour is driven by rogue cells. ... a protein known as beta-catenin is crucial for sustaining these cancer stem cells - in genetically engineered animals without this protein, the tumours shrink because there is no longer a signal to tell the cells to keep renewing themselves. The team's discovery may open up a possible route to treating this type of skin cancer in humans by blocking this protein because they found that squamous cell carcinomas - the human equivalent of the mouse tumours - also rely on beta-catenin. As the stem cells responsible for renewing normal skin do not depend on beta-catenin, targeting this molecule could help wipe out the cancer stem cells in a malignant tumour."
Researchers continue to work on methods of nerve regeneration. Here's one via ScienceDaily: "spinal cord injury often leads to permanent paralysis and loss of sensation below the site of the injury because the damaged nerve fibers can't regenerate. The nerve fibers or axons have the capacity to grow again, but don't because they're blocked by scar tissue that develops around the injury. ... researchers have shown that a new nano-engineered gel inhibits the formation of scar tissue at the injury site and enables the severed spinal cord fibers to regenerate and grow. The gel is injected as a liquid into the spinal cord and self-assembles into a scaffold that supports the new nerve fibers as they grow up and down the spinal cord, penetrating the site of the injury. When the gel was injected into mice with a spinal cord injury, after six weeks the animals had a greatly enhanced ability to use their hind legs and walk."
Biochemical changes initiated by calorie restriction appear quite rapidly at the cellular level. The value to your health is in keeping that going over the long-term, but it is interesting to see the speed with which the controlling systems of metabolism react to dietary changes. Recent research into calorie restriction as an adjunct to chemotherapy illustrates the point:
Fasting before chemotherapy makes the toxic treatments less dangerous and more effective - a clever hack that could let doctors deliver drugs straight to cancer cells without actually targeting them.
Caloric restriction activates cell-rejuvenating genes and could explain why tumor-ridden mice starved for two days were able to handle chemotherapy doses that killed half of a control group and left the other half devastated.
Critically, while healthy cells were protected, cancer cells remained vulnerable to the treatment. Longo effectively sent drugs straight into the tumors - a much-anticipated technique that's so far eluded cancer researchers.
Though Longo duplicated the effect in human cells, it needs to be stressed that this is a very early finding. Nonetheless, scientists are enthusiastic: if healthy cells are exempted, chemotherapy doses could be upped and side effects lowered.
The paper can be found at PNAS for those who like to read the scientific literature.
I point this out largely out of interest value for most of us. I'd like to think that there won't be much bulk, untargeted chemotherapy taking place in the world two decades from now - a reasonable expectation given current trends and progress in cancer research. The replacement for chemotherapy will be engineered and targeted vector therapies, using new knowledge of the molecules and cell structures that mark cancer cells as different, destroying only those cancer cells while leaving the patient otherwise perfectly healthy and unharmed.
The practice of calorie restriction for health is still a smart idea, even an age of nanomedical cancer killers, of course. Why be more unhealthy than you have to be? Every extra year you can live in good health without the intervention of medical science is another year for that medical science to advance and improve for the time when you do need it.
Learn more about vitrification in the cryonics industry at Depressed Metabolism: "A major public misperception is that cryonics involves the freezing of dead people. The objective of cryonics is not to preserve dead people with the hope of future revival but to place critically ill patients in a state of biostasis until a time when more advanced medical technologies might be available to treat and cure them. Currently, all major cryonics organizations induce metabolic arrest of the brain by attempting vitrification rather than freezing. Unless a patient has suffered a long period of circulatory arrest, after which perfusion of the body or brain is no longer possible, metabolic arrest is induced by cooling down the patient to cryogenic temperatures. Vitrification can be defined as 'the process of converting a material into a glass-like amorphous solid that is free from any crystalline structure.' Because vitrification of pure water would require extremely rapid cooling rates, vitrification in cryonics is achieved by substituting the water of patients with a highly concentrated cryoprotectant agent before cooling."
Researchers are already moving beyond complex nanoparticles and into the realm of the first simple medical nanomachines. Via EurekAlert!: "Known as a 'nanoimpeller,' the device is the first light-powered nanomachine that operates inside a living cell, a development that has strong implications for cancer treatment. ... Nanomaterials suitable for this type of operation must consist of both an appropriate container and a photo-activated moving component. ... researchers used mesoporous silica nanoparticles and coated the interiors of the pores with azobenzene, a chemical that can oscillate between two different conformations upon light exposure. Operation of the nanoimpeller was demonstrated using a variety of human cancer cells, including colon and pancreatic cancer cells. The nanoparticles were given to human cancer cells in vitro and taken up in the dark. When light was directed at the particles, the nanoimpeller mechanism took effect and released the contents. The pores of the particles can be loaded with cargo molecules, such as dyes or anticancer drugs. In response to light exposure, a wagging motion occurs, causing the cargo molecules to escape from the pores and attack the cell. ... impeller operation can be regulated precisely by the intensity of the light, the excitation time and the specific wavelength."