04.29.08
Posted in Uncategorized at 5:12 pm by heaven
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.
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04.27.08
Posted in Uncategorized at 5:11 pm by heaven
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 to be acquired by GlaxoSmithKline:
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.
$720 Million Worth of Sirtuin Research:
Of course, Sirtris hasnt 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, thats a good bet for how itll do it. ... Once one of these drugs is approved, itll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, thats going to be something to watch. GSK is well aware of this - Im not saying that its 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 theyve thought beyond a replacement for Avandia. ...
Thats the truth, all right, and its 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, its 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? Whats your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizers recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasnt 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.
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04.25.08
Posted in Uncategorized at 5:10 pm by heaven
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 bodys 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 brains thermostat by producing heat nearby.
To do so, they created a mouse model that produced large quantities of uncoupling protein 2 in hypocretinneurons 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 didnt. 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?
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Posted in Uncategorized at 5:10 pm by heaven
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.
#35-Longevity Science-Setting the stage, the longevity dividend:
All you have to do is go into any bookstore in this country and go to the health section and youll 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 thats 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 Im talking about. Im 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.
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04.23.08
Posted in Uncategorized at 5:09 pm by heaven
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 Ive 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 PDFsThe 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.
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