Fight Aging! Newsletter, February 11th 2013

February 11th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!



- Planning to Live to 110
- Final Complexity is Less Relevant Than That of Root Causes
- Towards a Goal That Can Never Be Attained
- The Quest for Reversible Cryopreservation
- Discussion
- Latest Headlines from Fight Aging!
    - An Interview With Judith Campisi
    - Parkinson's Disease as Localized Garbage Catastrophe
    - An Actuarial Overview on Human Longevity and Mortality
    - A Popular Science Article on the Study of the Axolotl
    - Telomere Length as Biomarker of Somatic Redundancy
    - Being Overweight is Harmful at All Ages, In No Way Protective
    - Chromatin and Transposons in Senescent Cells
    - Gene Copy Number Variations Associated With Longevity
    - The Proximal Cause of Aging From the Point of View of the Programmed Aging Camp
    - The First Person to Live to 150 Has Already Been Born


I'll spare you a link to one of the talking heads of the "anti-aging" marketplace discussing her plans to live to 110, and how other folk might, hypothetically, follow along at home. You can find it easily enough via Google if so inclined. It puts me in mind of the following entirely made-up short exchange:

Quote:Me: I hear you are planning to live to 110?
Talking Head: Yes.
Me: So you must be donating handsomely to help fund the SENS research program, which aims to repair the causes of aging, right?
Talking Head: No.
Me: You're not planning this very well at all, then, are you?

People show up every now and again in public forums with talk of planning to live for a long time in good health using nothing more than supplements, diet, and exercise: make all the right lifestyle choices, eat a good diet, don't get fat, be calorie restricted, and so forth. There's even a billionaire who was talking a good game on the topic a couple of years back. Good health practices all raise the odds of living a healthier life, but with present day medical technology those odds don't see you making it to 90, let alone 100 or 110. Living as healthily as possible gives you slim odds - perhaps somewhere a little north of 25% - of celebrating your 90th birthday under present medical capabilities. The odds get worse if you let yourself go. The simple, unfortunate truth of the matter is this: if eating exceedingly well really could let people live to 100 and beyond with any reliability, then this would be well known, and the world population would include thousands upon thousands upon thousands of centenarians.

So plan away, planners. It won't help all that much in achieving any goal related to the number of candles on your cake, though it may well make your life much more pleasant along the way. Good health is a very underrated thing, usually by those who still have it. The only way the planner demographic will reliably hit their high-end life span targets is by benefiting from advances in medical technology, i.e. from the results of actions and initiatives that have absolutely nothing to do with their personal health practices. For the presently older demographic, those advances would have to be of the sort envisaged in the Strategies for Engineered Negligible Senescence (SENS): ways to actually create rejuvenation in the old by addressing the cellular and molecular damage that causes aging.

The bottom line here: if you're planning to live to 110, then you aren't planning very well if those plans don't largely revolve around helping to fund rejuvenation research of the sort pioneered by the SENS Research Foundation. Advances in medicine don't just happen: they require money, advocacy, and hard work. Which of those are you helping out with?


I think we can all agree that, separately, each of aging, cancer, and Alzheimer's disease is a complicated phenomenon. Is cancer more or less complicated than aging, however? Are the likely several different disease processes leading to a similar end presently lumped under the heading of Alzheimer's disease more or less complex than either cancer or aging? I think that arguments could be made for any ordering of the three, though not all of them are good arguments, and anything that fits in this short blog post is going to involve a fair amount of hand-waving. We could compare the funding and researcher man-years devoted to understanding each, for example, or papers published, or some other similar research metric. I suspect that cancer wins by those measures, if we airily assume that greater amounts of funding are led by the fact that there is much more to catalog at the level of genes, proteins, and cellular mechanisms. I don't think that this is a safe assumption.

If we look at the SENS vision of aging, or indeed any damage-based model of how and why we age, we might say that aging is more simple than Alzheimer's, or more simple than any age-related condition. Aging stems from simple root causes, which expand out into massively complex and varied failure modes as damage interacts with damage and systems flail and fail in any number of ways. To draw an analogy, the rust that eats iron structures is a very simple, homogenous thing - a trivial set of a few chemical reactions, easily described, easily prevented. Yet a structure can fail in countless ways due to rust, as the progression and damage caused is stochastic. Which girder or support will be eaten to breaking point first? Similar structures might fail in similar ways more often, perhaps because they allow moisture to linger in the same places.

But you get the point: from simple causes great complexity can arise. The more complex the structure, the greater the number of failure modes that simple forms of damage can cause. We humans are tremendous complex, vast, interlinked arrays of molecular machinery, and in most modern theories of aging the few rusts we are theorized to suffer (some with much more evidence than others) are pretty simple at root. Thus any age-related condition must be more complex than its cause, aging, by virtue of being an end result rather than the cause of that end result. That is one way of looking at it. Another is to view the end state of aging as a whole and measure that complexity - which is obviously also much more complex than the simple processes that gave rise to it.

Does the complexity of the end state of aging matter, however? Or for that matter, the end state of cancer or Alzheimer's disease? This is not an idle question, as it points to the consequences that result from different core philosophies or approaches in medicine and medical research. Do we fix a problem by working to understand its end states and then try to clean up after or block every branching failure mode, or do we aim to remove the root causes and then let our biology try to restore itself?

That is not a question with a correct answer for all times and places: sometimes it isn't enough just to remove a root cause, sometimes the root cause is unknown. It is clear, however, that when it comes to age-related conditions a great deal of modern medicine runs along the lines of being an ever more sophisticated means of sticking a finger into the rapidly eroding hole in the dam, rather than repairing the hole in a way that will last. Consider the widespread efforts to safely remove amyloid beta in Alzheimer's disease, for example: it seems likely that this is not a case of treating root causes, which remain poorly understood at this time, but rather cleaning up the most evident of the biological signatures.

The regulatory structure for medicine and medical research in the US and Europe biases researchers towards the goal of producing what are ultimately less effective treatments for end causes. The system is so set up that the path of least resistance is to research some part of the complex pathology of a late-stage disease, where there is more room to carve out something that can be patented, and then build what are essentially palliative medicines for people who are very sick, having long suffered their particular named condition. Prevention and root causes don't yet get anywhere near as much attention. When it comes to aging itself, it isn't even legal in the US to try to produce and commercialize a clinical therapy that might do some good.

But prevention and root causes are exactly where the attention should be when it comes to aging and age-related diseases. Root causes are simple, end stages are complex: that is reflected in the cost and time required to produce therapies. The way to harness the complexity of our self-repairing biology rather than fight against it is to look to removing causes rather than cleaning up after the spreading tree of secondary and tertiary consequences. This has long been understood by the public and researchers alike when it comes vaccination, poisons, and all sorts of other areas of medicine. Somehow it has gone a little astray in the matter of aging and age-related disease. That must change.


It is a polite fiction in some parts of the aging research community that the goal of the scientists' work is to improve health in the old without improving longevity. Like all the best polite fictions, it survives because many people have come to actually believe this line. It arose during the period when researchers couldn't talk openly about extending human life without risking their funding and their careers: proposing improvements to health in the old was the way to raise funds when you couldn't talk about extending healthy and overall life span. Sad to say, but the research and funding community was, up until comparatively recently, in the business of discouraging research and researchers who might head in that direction - or at the very least in the business of saying nothing about the matter in public. There is surprisingly little shame evident from those who engaged in those practices back in the day, now that things are somewhat different.

If we look at aging from the high level abstraction of reliability theory, it becomes clear that it should be impossible to improve health without also extending life. Aging is an accumulation of damage, and improving health involves fixing or preventing that damage. The statistics of the way in which any machinery - our bodies included - ages and fails, and the statistics of how long that failure will take to happen, depend on the level of unrepaired damage in the system's component parts. Arguing the opposite side of that position, that is is possible to fix damage without extending life expectancy, is a steep hill to climb: you have to come up with a convincing explanation as to why a human doesn't behave like any other physical system that undergoes limited self-repair - which starts to sound suspiciously like vitalism.

Nonetheless, we still see things like this, buried in the introduction to abstracts from one of last year's conferences: "the true goal of aging research is to increase the health of the elderly, not their longevity." I think it's a problem that a fair proportion of researchers in this field continue to either (a) put forward the proposition that you can improve long-term health without extending life as a matter of fact, or (b) conveniently omit any discussion of extended longevity as a possible goal or result of their work. This is to say nothing of the ethics of actually trying to avoid extending life span in a field where it is a possibility.


Much of the talk of low-temperature preservation of tissue here at Fight Aging! directly relates to the cryonics industry: the work of preserving the brains of those who age to death prior to the advent of rejuvenation biotechnology, so that they have some possible chance at a longer life in the future. There is a large mainstream cryobiology industry and research community that shares essentially the same goals when it comes to organs and tissues, although cryobiologists have historically been quite hostile towards cryonics groups. It's the same old story of the conformist mainstream pushing away anyone who is doing something out of the ordinary - yet all bold new technologies and approaches start exactly that way, with a small group moving the boundaries of the possible and the plausible.

In any case, back to the commonalities: both cryobiologists and cryonicists want to produce the means for reversible cryopreservation rather than the presently irreversible methods of vitrification used on the human patients stored at Alcor, the Cryonics Institute, KrioRus, and so forth. Presently irreversible is not forever irreversible, of course, but the cryoprotectant compounds used now are pretty toxic, which adds an additional level of difficulty to the task of restoring patients to life. A reasonable argument is that given that this task requires technologies such as swarms of medical nanorobots, and sufficient control over small-scale biology to be able to repair arrangements of macromolecules within cells, then sequestering toxic molecules along the way shouldn't be a big deal by comparison.

So the cryobiologists want to be able to store organs and other large tissue masses in the same way that we can presently store embryos - in the deep freeze, so that donated organs or organs grown to order can be stored until needed. The cryonics community includes some groups with expertise in this area, such as 21st Century Medicine, and the development of reversible cryopreservation would be one of the potential spin-off technologies that could draw greater funding and interest into cryonics. Follow the link above for more on the present state of work on cryopreservation that is not directly related to the cryonics industry.


The highlights and headlines from the past week follow below. Remember - if you like this newsletter, the chances are that your friends will find it useful too. Forward it on, or post a copy to your favorite online communities. Encourage the people you know to pitch in and make a difference to the future of health and longevity!



Friday, February 8, 2013
Scientific American interviews Judith Campisi, a member of the SENS Research Foundation's scientific advisory board and a noted figure in the aging research community. You'll note that her views are fairly conservative, much closer to the mainstream of longevity science than to SENS, however: "[SciAm]: Why is it so hard to figure out what causes aging? [Judith Campisi]: In many ways we already know what causes aging. We just don't know what causes aging in the kind of molecular detail that would allow us to intervene in large meaningful ways. It's not even clear that once we solve those mysteries we will be able to intervene in aging or dramatically extend longevity. I started my career studying cancer. Look at all the things we have learned since the 1970s about how cancers form in the body. And yet, still the best cures we have for most cancers are sledgehammers. Biology is complex - and this is a reality that the public has to come to grips with and our legislators have to come to grips with. I predict aging will follow the same trajectory as cancer research. Why is aging so difficult to figure out? It's because it's a really tough problem. I think it's tougher than cancer. The time has come to really wallow in the complexities. [SciAm]: What would you say is one of the biggest mysteries of aging research? [Judith Campisi]: Why do organisms with remarkable genetic similarity have sometimes remarkable differences in life span? We know that for the most part, many of the processes that go on in the human body also go on in yeast and mice. Yet, yeast live a few days, a mouse lives about three years, and people live for decades. We really do not know what evolution has done to take basically the same genes and produce different life spans. [SciAm]: Is that where the naked mole rat comes in? [Judith Campisi]: Yes. The mystery shows up even in species that are mouselike. The naked mole rat is more related to the mouse than to us - it looks like a mouse. And yet it lives for 30 years, or 10 times longer than a regular mouse. On top of all that, it has signs of oxidative damage that exceeds that of the mouse. Now there are three ideas that scientists have come up with to try to explain why naked mole rats live so long: Maybe oxidative damage doesn't cause aging. Maybe naked mole rats are evolutionary oddities. And then my personal favorite, maybe it's not oxidative damage that is the problem but how the cell responds to the damage. But that's all speculative."

Friday, February 8, 2013
Alpha-synuclein is associated with Parkinson's disease (PD), and is believed to play a central role in the mechanisms that cause the destruction of dopamine-generating neurons, and thus the pathology of the condition. Here, researchers dig deeper into the processes involved: "Overexpression of a protein called alpha-synuclein appears to disrupt vital recycling processes in neurons, starting with the terminal extensions of neurons and working its way back to the cells' center, with the potential consequence of progressive degeneration and eventual cell death. "This is an important new insight. I don't think anybody realized just how big a role alpha-synuclein played in managing the retrieval of worn-out proteins from synapses and the role of alterations in this process in development of PD." Using a variety of leading-edge imaging technologies, including a new fluorescent tagging technique developed for electron microscopy, [the] scientists created three-dimensional maps of alpha-synuclein distribution both in cultured neurons and in the neurons of mice engineered to over-express the human protein. They found that excess levels of alpha-synuclein accumulated in the presynaptic terminal - part of the junction where axons and dendrites of brain cells meet to exchange chemical signals. "The over-expression of alpha-synuclein caused hypertrophy in these terminals. The terminals were enlarged, filled with structures we normally don't see." [As] alpha-synuclein accumulates in the terminals, it appears to hinder normal degradation and recycling processes in neurons. This would progressively impair the release of neurotransmitters. In time, the neurons might simply stop functioning and die."

Thursday, February 7, 2013
When you look at the vast sums of money involved, one might argue that the actuarial community has a greater incentive to understand aging than the aging research establishment does - billions of dollars rest on the degree to which predictions of future human longevity match up to reality. Unfortunately for the actuaries (and the rest of us) that future is very uncertain. We stand at a cusp in biomedical research, an era of rapid progress in fundamental biotechnology, and one in which great leaps forward in application may or may not happen at any time. Producing true rejuvenation in laboratory mammals is a matter of a billion dollars and ten years or so at this point in time, and the vagaries of human organization that lead up to sufficient interest and funding to start on that goal are essentially random: perhaps we manage to talk the world around to it five years from now, perhaps fifteen, perhaps longer. Who knows - it's a people and persuasion issue, and those are hard to pin to a timeline. Here is an interesting PDF that tours some of the present thinking on human longevity by the actuarial community: "Longevity is an important issue: the implication of increasing longevity has far-reaching effects for our social programs; and for our financial security as we grow into old age. It is also a trend which actuaries are well suited to analyze: we have unique training and experience that allows us to distill large volumes of data into key elements that can inform predictions of future events. As we partner with other experts, we are helping to shape the discussion on the implications of increasing longevity. First, around the globe people are living longer. While there is evidence that the rate of improvement is different between men and women, and between people of different races, geographies and social statuses, the evidence remains that we are all living longer. Secondly, our understanding of what factors have a material effect on our expected lifetime is growing, but it is not complete. In particular, our understanding of older age mortality is limited, in part because the data at older ages is sparse and of varying quality. There are open questions related both to the rate of improvement and the ultimate age at which it is appropriate to assume a mortality table should end. Thirdly, in many regions, there is no broad consensus on the appropriate base mortality rates and improvement factors that should be used to value life-contingent liabilities, or on the models that should be used to forecast those rates into the future. This creates challenges for practitioners who must develop their own projections; inefficiencies as the use of different data, assumptions and models leads to different mortality forecasts; and inconsistencies across disciplines - for example, between the pension and insurance communities - as each develops its own independent view of future mortality. Having said this, the actuarial community has dealt with issues of this magnitude in the past: We need to begin to hone in on techniques that will allow us to become comfortable with the wide variances that can be produced by our projection models. As evidenced by the material presented in the body of this report, there are techniques - stress testing, scenario testing, risk heat maps, screening systems - that we can use to give us insight into what base mortality rates and improvement factors could be."

Thursday, February 7, 2013
From the Australian press, an example of one of a number of research groups that are studing the axolotl with an eye to mapping the mechanisms that drive their exceptional regenerative prowess: "They are masters at regenerating their own limbs, tails, jaws, retina and heart. They can recover from spinal chord and brain injury and can easily tolerate organ transplants. And to top things off, they don't get cancer. Meet the axolotl, otherwise known as the Mexican walking fish. ''This animal guards so many interesting biological secrets. Things that would leave humans in a wheelchair or dead they can just repair in no time at all.'' In Mexican walking fish, limbs can be removed and re-grown without so much as a scar and, amazingly, the heart can regenerate after having a third of it removed. Similarly, it can have sections of its spinal chord ''cut and pasted'' without killing it. Try doing that to a lab rat - let alone any other mammal. Some of the key genes that regulate spinal chord regeneration in axolotls have been established and compared with that of the mouse and rat. Chief among the questions surrounding the axolotl is whether a cure for cancer might lie beneath the translucent skin of the albino axolotl. Essentially, controlling cancer is about controlling cell growth. ''Cancer is like a wound that never heals and how the immune cells deal with this perpetuates cancer and allows rogue cells to proliferate and grow crazy. How axolotls can suppress cancer and activate regeneration is one of the things [we] would like to get to.''"

Wednesday, February 6, 2013
A paper of relevance to the reliability theory view of aging: "Biomarkers of aging are essential to predict mortality and aging related diseases. Paradoxically, age itself imposes a limitation on the use of known biomarkers of aging, because their associations with mortality generally diminish with age. How this pattern arises is however not understood. With meta-analysis we show that human leucocyte telomere length (TL) predicts mortality, and that this mortality association diminishes with age, as found for other biomarkers of aging. Subsequently, we demonstrate with simulation models that this observation cannot be reconciled with the popular hypothesis that TL is proportional to biological age. Using the reliability theory of aging we instead propose that TL is a biomarker of somatic redundancy, the body's capacity to absorb damage, which fits the observed pattern well. We discuss to what extent diminishing redundancy with age may also explain the observed diminishing mortality modulation with age of other biomarkers of aging. Considering diminishing somatic redundancy as the causal agent of aging may critically advance our understanding of the aging process, and improve predictions of life expectancy and vulnerability to aging-related diseases."

Wednesday, February 6, 2013
Researchers here argue that flawed data led to some scientists to conclude that being overweight is less harmful to long-term health than it in fact is: "Obesity kills, giving rise to a host of fatal diseases. This much is well known. But when it comes to seniors, a slew of prominent research has reported an "obesity paradox" that says, at age 65 and older, having an elevated BMI won't shorten your lifespan, and may even extend it. A new study takes another look at the numbers, finding the earlier research flawed. The paradox was a mirage: As obese Americans grow older, in fact, their risk of death climbs. The researchers argue that past studies of longevity and obesity were biased due to limitations of the National Health Interview Survey, or NHIS, which provides information on obesity. The survey excludes individuals who are institutionalized, such as in a hospital or nursing home - a group largely made up of seniors. Consequently, the data is overrepresented by older respondents who are healthy, including the relatively healthy obese. What's more, many obese individuals fail to make it to age 65 - and thus do not live long enough to participate in studies of older populations. "Obesity wreaks so much havoc on one's long-term survival capacity that obese adults either don't live long enough to be included in the survey or they are institutionalized and therefore also excluded. In that sense, the survey data doesn't capture the population we're most interested in.""

Tuesday, February 5, 2013
Senescent cells have removed themselves from normal operation and really should be destroyed, either by their own programmed cell death processes or by the immune system. Senescent cells accumulate with age, however, and while in place cause harm to surrounding tissues. Removing these unwanted and damaging senescent cells with targeted cell killing technologies is one of the necessary goals in longevity science; it has already been shown to provide benefits in gene-engineered mice, and several lines of research are presently leading towards the tools needed to build therapies to attain the same results for everyone else. Here is another example of the way in which senescent cells are not in good shape: "Parasitic strands of genetic material called transposable elements - transposons - lurk in our chromosomes, poised to wreak genomic havoc. Cells have evolved ways to defend themselves, but in a new study, [researchers] describe how cells lose this ability as they age, possibly resulting in a decline in their function and health. "The cell really is trying to keep these things quiet and keep these things repressed in its genome. We seem to be barely winning this high-stakes warfare, given that these molecular parasites make up over 40 percent of our genomes." Cells try to clamp down on transposons by winding and packing transposon-rich regions of the genome around little balls of protein called nucleosomes. This confining arrangement is called heterochromatin, and the DNA that is trapped in such a tight heterochromatin prison cannot be transcribed and expressed. What the research revealed, however, is that carefully maintaining a heterochromatin prison system is a younger cell's game. "It's very clear that chromatin changes profoundly with aging." Young and spry cells distinctly maintain open "euchromatin" formations in regions where essential genes are located and closed "heterochromatin" formations around areas with active transposable elements and few desirable genes. The distinction appeared to become worn in aging, or senescent, cells. In the observations, the chromatin that once was open tended to become more closed and the chromatin that was once closed, tended to become more open. Then the scientists compared the DNA that was coming from open or closed chromatin formations in the young and senescent cells. In their study not only did they find that the chromatin lockdown was breaking down, but also that the newly freed transposons were taking full advantage. What's not clear from the study is the relevance of the damage that the cells suffer from the transposable element jailbreak and resulting genetic crime spree. "Is the transposition really bad for the organism or is it something that happens so late that by that point the organism has already accumulated so much age-associated damage? Then maybe this extra insult of transposition is not going to make a lot of difference.""

Tuesday, February 5, 2013
One imagines that genetic copy number variations between individuals will prove to be much like other small differences in DNA, in that there are many tiny contributions to longevity, and it is hard to find consistent results in different study populations. "Copy number variations (CNVs) are rare losses and gains in DNA sequences that have been importantly implicated in the pathogenesis of various neurodevelopmental and psychiatric diseases. As opposed to SNP genotypes which have revealed common variants conferring modest relative risk to the individual with the variant, CNVs are often rare variants not observed or extremely rare in a normal control population and conferring high relative risk. SNP arrays have vastly improved the detection of CNVs across the human genome, [but] it remains to be determined if there are certain gene classes or networks of genes that are pathogenic or disease-causing in general, and if there are other gene networks that may be protective in the same manner. One way of testing this is to compare CNV states and frequencies between pediatric and geriatric subjects and determine if certain CNVs are lost in the older age group (i.e. suggesting pathogenic impact with shortened lifespan), and if other CNVs are enriched and considered protective. To test the hypothesis that rare variants could influence lifespan, we compared the rates of CNVs in healthy children (0-18 years of age) with individuals 67 years or older. CNVs at a significantly higher frequency in the pediatric cohort were considered risk variants impacting lifespan, while those enriched in the geriatric cohort were considered longevity protective variants. We performed a whole-genome CNV analysis on 7,313 children and 2,701 adults of European ancestry. [Positive] findings were evaluated in an independent cohort of 2,079 pediatric and 4,692 geriatric subjects. We detected 8 deletions and 10 duplications that were enriched in the pediatric group, while only one duplication was enriched in the geriatric cohort. Population stratification correction resulted in 5 deletions and 3 duplications remaining significant in the replication cohort. Evaluation of these genes for pathway enrichment demonstrated ~50% are involved in alternative splicing. We conclude that genetic variations disrupting RNA splicing could have long-term biological effects impacting lifespan."

Monday, February 4, 2013
I noted a review paper a few months back that considered the proximal cause of aging in terms of the evolution of cellular damage versus damage repair mechanisms. That aging is caused by an accumulation of certain forms of molecular and cellular damage is the dominant paradigm at present, though there is always debate over which forms of damage are primary, which secondary, and which important over a human life span. Of those researchers who aim to intervene in aging, most look to merely slow down the pace of damage by manipulating metabolism, while a minority follow the Strategies for Engineered Negligible Senescence (SENS) plan and aim to repair and reverse the damage without changing our metabolism. Meanwhile, off in left field there are those who theorize that aging is an evolved program, and therefore could be halted or reversed by suitable changes to metabolism or the genes governing it. To their eyes damage doesn't cause aging, it is a result of the program. This is something of a dangerous viewpoint, should it gather steam, even worse than the "slow aging by metabolic manipulation" camp for steering researchers away from the most effective course for treating aging - which is the SENS approach of repairing damage. But it is a sign of just how complex aging is as a phenomenon that we can still see such widely divergent interpretations of the existing data. Here is an open access consideration of the proximal cause of aging from one of the more prolific researchers in the programmed aging camp, by way of illustrating the points made above. You should probably read the whole thing, as the argument made is somewhat hard to excerpt and condense: "As discussed in detail previously, aging is of course not a program, but it is a quasi-program, a useless and unintentional continuation (or run on) of developmental programs. Similarly, cellular senescence is a continuation of cellular growth. In brief, over-stimulation leads to increased functions - [harmful hyperfunctions]. But what about the molecular damage? It was assumed that molecular damage contributes to aging because it accumulates with time. Well, over time you may accumulate money in your bank account. However, neither accumulation of molecular damage nor accumulation of money is a cause of your aging. Yes, molecular damage must accumulate. But although molecular damage accumulates, it does not necessarily limit lifespan, particularly if other causes limit life span. By analogy, if everyone died from accidents, starvation and infection early in life, then aging and age-related diseases (such as obesity and atherosclerosis) would not even be known. By the same token, "aging" due to molecular damage will not manifest itself, if aging due to hyperfunction invariably limits life span. For complex organisms like mammals the relationships between hyperfunctions (aging), diseases and damage (decline) are: 1. Hyperfunctions (increased cellular functions) including hypertrophy are primary. This is the essence of aging, which silently causes malfunctions and age-related diseases. 2. Decline of functions, malfunctions and atrophy are secondary. For example, hyper-stimulation of beta-cells by nutrients and mitogens can cause its apoptosis. Here is important to emphasize however that apoptosis can be also a form of hyperfunction, unneeded continuation primary function such as apoptosis during development of the immune system. 3. Damage is caused by aging, not the reverse. 4. Damage is not molecular. It is macro-damage (tissue, system and organ damage), like stroke, infarction, metastases, broken hip fracture and renal failure. Damage may take a form of sudden "catastrophe", even though hyperfunctional aging slowly generates diseases for decades. If a patient survives infarction (due to medical intervention), she can live for many years, reflecting the fact that catastrophe was not due to the burden of molecular damage."

Monday, February 4, 2013
Wagering on the proposition that the person who will first reach 150 years of age is already alive is no wager at all, really. It's a very safe bet that at some point in the next century the medical technologies needed for significant human rejuvenation will be developed. The risky bet is on whether it will happen soon enough for those of us in mid-life now - that will take much more advocacy, public enthusiasm, and rapid growth in research funding than has so far emerged. Here is an interview with Aubrey de Grey of the SENS Research Foundation at Forbes: "[Forbes]: Please comment on the myth of aging how how we need not accept it as "just part of getting old". [de Grey]: It's always been a mystery to me why this isn't totally obvious to everyone. Do we let cars fall apart when they get old? - yes in general, but not if we really want them not to - that's why we have 50 year old VW Beetles driving around, and even vintage cars. It's bizarre that people don't see that the exact same thing is true of the machine we call the human body, just that that machine is a lot more complicated so the development of sufficiently comprehensive preventative maintenance is a lot more challenging. [Forbes]: Could you briefly explain the nature of free radicals and the role in aging? [de Grey]: Free radicals come in a lot of flavours, and a number of them are created by the body. Some of them are good for us, but others are harmful, because they react with and damage molecules that we need for survival, such as our DNA. The body has a massive array of defences against these problems, which can be grouped into four categories - tricks to minimise the rate at which these toxic free radicals come into existence in the first place, enzymes and compounds that react harmlessly with them before they can react harmfully with something else, chemical tricks that make the harmful reactions happen less easily, and systems that repair the resulting damage after it's occurred - but those tricks are not completely comprehensive, so some damage still occurs and accumulates throughout life. We'd like to stop that happening, and we could theoretically do it by enhancing to perfection any one (or more) of those four types of defence. My view is that the last one, repairing damage post hoc, is the most practical. Eliminating free radical production would involve completely redesigning aspects of our metabolism, especially the way we use oxygen to extract energy from food. It would also have the problem that even the bad free radicals are also good in some ways, so we actually need them around somewhat; this is also the problem with perfecting the elimination of free radicals via harmless reactions. Ramifying our cells so that the reactions just don't occur is also tantamount to completely redesigning the body, So we're left with perfecting repair. [Forbes]: The digital health and quantified self movement are increasingly gaining steam. Do you see this an a critical step forward in the quest for longevity? [de Grey]: Not really, no. It's valuable, but only temporarily. That's because all personalised medicine is only valuable temporarily, while the treatments for such-and-such a condition are only modestly effective and can thereby be made more effective by being tuned to the specifics of the patient. We don't have personalised polio vaccines, because we don't need them - the same vaccine just works perfectly, on everyone. [Forbes]: Does the wait for "extensive data" and "controlled trials" adversely impact innovation in aging research? [de Grey]: Yes, but it adversely impacts innovation across all medical research. There's a huge need for greater creativity in the regulatory process, and that's coming: "adaptive licensing" is a big theme in that area right now."



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