The latest two podcasts at SAGE Crossroads look at either side of views on compression of morbidity:

Fries' hypothesis is that the burden of lifetime illness may be compressed into a shorter period before the time of death, if the age of onset of the first chronic infirmity can be postponed before the age of death. In order to confirm this hypothesis, the evidence must show that it is possible to delay the onset of infirmity, and that corresponding increases in longevity will be modest.

On the one side:

Longevity will continue to increase under hopeful scenarios for the human future, and morbidity will continue to decrease. The question is the relative rate of those, and I’m just telling you and anybody else who would make such an argument that in fact the data is in. The mortality rates are going down 1 percent a year. That’s a substantial decline in mortality rates. That’s been continuing for a century, that’s almost a straight line, at 1 percent a year. The morbidity rates are going down 2 percent a year. It’s the story.

And on the other side:

KYLE JENSEN: Now do you feel that the compression of morbidity theory should be the focus of biomedical gerontology?

AUBREY DE GREY: No, not really I don’t. It’s important first of all to remember that the original description of compression of morbidity by Jim Fries in 1990 did not even propose this. What he proposed was that actually it would be easier to implement changes in lifestyle that would postpone the onset of morbidity than it would be to develop medical technologies to postpone death. In other words, he felt that by changes of lifestyle we could compress the period between the two, but he never suggested that we would actually compress morbidity by intervening in the biology of aging. Indeed, he felt that intervening in the biology of aging was essentially impossible. What we are actually seeing is failure to implement those changes of lifestyle that Jim Fries suggested. We are seeing increase in lifespan and also [delay in] onset of morbidity. Not much change in the rates of those two so the interval between the two [remains the same]. There is not progress being made in compressing morbidity. There is a bit of variation. In some statistics we see a little bit of compression in some people; in some places we see a little bit of expansion. By in large what we are seeing is exactly what you would expect from postponing aging. In other words, you postpone the onset of morbidity and you also postpone death by about the same amount.

As they say, you can do all sorts of things with statistics and definitions, and I'm far from qualified to put forward any sort of firm opinion as to whether present statistics better support one side or another. Compression of morbidity is something of the declared goal of those in the mainstream of aging research who don't want to talk about extending life span, however, which makes it a little more than a matter of statistical interpretation. When a researcher talks about compression of morbity, that is something of a cipher, an identifying mark as to where he stands on the topic of engineered longevity: possibly in favor, but not willing to risk offending conservative funding organizations, possibly against. Either case has much the same result - a researcher who isn't working as freely as he might to extend human longevity.

From my reductionist viewpoint, I find it hard to reconcile an existence of compression of morbidity with the performance of reliability theory as applied to aging, amongst other things. Theories of aging based upon accumulation of biochemical damage and incremental system failure are very convincing, and have a great deal of experimental support, but don't predict that compression of morbidity is possible to any great degree. The only way to push out health life span is to prevent or repair damage, and that will also push out overall life span.

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I noticed a mortality study that illustrates some of the common wisdom regarding the common diseases of aging:

The remaining lifetime risk of cancer at age 40 was 45.1% and at age 90 was 9.6%. The remaining lifetime risk of major cardiovascular disease at age 40 was 34.8% and at age 90 was 16.7%.

...

The remaining lifetime risk of both diseases approached a plateau in the 10th decade. This may be due to decreased detection of disease and reporting of symptoms and increased resistance to disease in those who survive to old age.

The older a person becomes - or rather, the more capable a person is of achieving longevity - the less likely he or she is to suffer from the major diseases of aging. As the authors point out, however, it's a challenge to build reliable data:

The measurement and interpretation of the incidence of disease in advanced age is complex. Lower incidence in late life may reflect decreased screening and medical surveillance rather than decreased risk. ... This cohort of health conscious doctors has several advantages for studying the incidence of disease in men of advanced age, as it has a large proportion of participants surviving to age 90 and beyond, as well as a higher level of screening for disease and diagnosis than in a general population.

This and other collections of data on mortality risk consistantly show that incidence of cancer and cardiovascular disease is lower for those who live longer. Other research shows that living longer within the present state of medical science is a matter of making consistently sensible choices in life for most of us - not a matter of good genes to any great degree. Join the dots: all that exercise and good diet really does make a difference in the long term.

Now if you have a good few decades left before getting to the point at which you have to start worrying in earnest about your heart and runaway cells killing you from the inside, it's probably the case that the future trajectory of your life will be far more determined by progress in medical science than living well. Absent progress, your life will look much like that of your parents. With exceptional progress, the sky is the limit - aging itself might be defeated before you reach the point at which it will kill you. So while you're on the execise machine, or pondering a good diet, spare some thought for how you can support the future of medical research as well. There is where the real difference lies.

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We can never know absolutely and for sure whether doing the "right things" for our health will make a significant difference to our own healthy longevity. You have to wait and see, one chance to get it right, no going back to fix things up. We do, however, have a wealth of evidence that actions long commonly regarded as the "right things" for good health will indeed be good for our future healthy longevity. This evidence is quite separate from the comparatively recent investigations of medical science into the biochemical roots of good health and longevity.

What is this evidence? That wealthier, higher IQ people tend to live longer and suffer less age-related illness. For example:

Lower scores on measures of IQ at two time points were associated with [cardiovascular disease] and, particularly, total mortality, at a level of magnitude greater than several other established risk factors.

I don't think that it's ever been a grand mystery that regular exercise, a good physician relationship, and eating sanely are going to be good for you; the common wisdom for good health long predated the scientific studies showing that it was the case. The grand mystery is why so few people keep up with those efforts in their own lives, and suffer because of that negligence. I've been inclined to interpret results like the research above to mean that more intelligent people tend to get wealthier but also tend to do more of the right things for their health - you can be as rich as you like, but if you weren't exercising all that time you were making money, you're still going be at a higher risk for suffering cardiovascular disease at the end of the day.

Smarter people have a greater tendency to keep up with common sense health practices and gain a benefit by doing so. That's my thesis. As to why that is the case - well, that gets back to what IQ actually measures, whether time preference is very different between individuals, and so forth.

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Inflammaging is a term coined to describe one way in which the immune system runs awry with age. Like a malfunctioning thermostat, the level of inflammatory response is consistantly too high, leading to damage to aged tissue:

Inflammation is necessary to cope with damaging agents and is crucial for survival, particularly to cope with acute inflammation during our reproductive years. But chronic exposure to a variety of antigens, especially to some viruses such as cytomegalovirus, for a period much longer than that predicted by evolution, induces a chronic low-grade inflammatory status that contributes to age-associated morbidity and mortality. This condition carries the proposed name "inflammaging".

I noticed a paper today which contains an interesting take on how inflammation leads to damage. It's not just the inflammatory response, per this theory, but also the anti-inflammatory systems evolved to shut off an inflammatory response after it has served its purpose. If inflammation is constantly jammed on, then so is the anti-inflammatory system - based on the hormone cortisol - that is trying to shut it down. So you have at once all the downsides of both a constantly active immune system, and an immune system that is constantly damped down: damage from constant activity yet poor immune response when you do need it to fight off disease:

"Inflamm-aging" denotes the up-regulation of certain pro-inflammatory cytokines at older ages, and associated chronic diseases. It is well known that blood levels of cortisol also increase with age, an increase commonly considered to be due to activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis by many non-specific stressors.

On the contrary, herein I describe how the activation of Hypothalamus-Pituitary-Adrenal (HPA), far from being unspecific, constitutes: a) the main specific response and counterbalance to "Inflammaging" ('anti-inflammaging'), b) an explanation for the well known paradox of immune-senescence: i.e. the coexistence of inflammation and immunodeficiency, as well as c) a complex mechanism of remodelling elicited by inflammaging, explaining the long and winding pathophysiological road that goes from robustness to frailty.

Indeed, the phenomenon of anti-inflammaging, mainly exerted by cortisol, with the passage of time becomes the cause of a marked decline of immunological functions, and its coexistence with the increased levels of pro-inflammatory cytokines of inflammaging, ultimately have negative impacts on metabolism, bone density, strength, exercise tolerance, the vascular system, cognitive function, and mood. Thus inflammaging and anti-inflammaging together determine many of the progressive pathophysiological changes that characterize the "aged-phenotype", and the struggle to maintain robustness finally results in frailty.

The author points to cortisol, and if you look at the Wikipedia entry you will see touches upon a wide range of vital systems in the body. If inflammation is always on, then excess cortisol is constantly trying to turn it off, causing harm along the way.

Fortunately solutions to prevent the immune system from getting into this state in the first place are within sight. If the medical research community makes a sane shift from a philosophy of futile attempts to patch up the end results of aging to preventing and reversing specific degenerations earlier in life, then I imagine we'll see a range of ways to restore a damaged immune system in the clinic by 2030. Have a look back in the Fight Aging! archives for some pointers:

• When and How Does the Decay of Your Immune System Start?
• Striking Back at Cytomegalovirus
• Steps Towards Rebuilding the Aged Immune System
• The Aging Immune System, Thymic Involution, and Wnt4

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An item of interest on an otherwise slow day:

In this podcast, you’ll hear Dr. Platika review the accomplishments of the Pittsburgh Life Sciences Greenhouse, and he’ll talk about his new job: helping to get funding to study the world's oldest people.

Dr. Platika is the chairman of the Supercentenarian Research Foundation, a new organization designed to raise funding for studies of supercentenarians, or people who have lived more than 110 years. Dr. Platika wants to know: Why have the very aged survived as long as they have? Are they less susceptible to the common diseases that slow down the rest of us? Ultimately, Dr. Platika hopes the foundation will contribute to the discovery of products that help people fight degenerative and other conditions associated with aging and maintain their mobility and quality of life.

The SRF has fairly close ties to the Methuselah Foundation, as I recall. Certainly, amyloidosis is a condition that interests both parties: a buildup of different types of clumping biochemicals in different tissues that leads to loss of function and eventually death. It is thought to be an important cause of death in supercentenarians who have evaded all the other common killers.

"The superseniors deviate from the norm not just in how long they live but in how they die," says Coles, who arranges autopsies of the oldest old as part of his work with the recently established Supercentenarian Research Foundation. Only nine Supercentenarians have undergone postmortems - Calment, for example, never agreed to one - and Coles and colleagues have performed six of these procedures, including one earlier this year in Cali, Colombia, on a man who died at age 111.

Coles argues, based on these autopsies, that supers aren't perishing from the typical scourges of old age, such as cancer, heart disease, stroke, and Alzheimer's Disease. What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

The Methuselah Foundation is funding development of biomedical remediation as a technology platform to safely remove amyloid and other forms of aggregate from tissues, which should prevent that process from contributing to degenerative aging.

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When compared to a random selection of folk in their middle ages and younger, centenarians have biochemistries that seem better adapted to long term survival. That makes sense, given that few of those random folk would make it to 100 under the same life circumstances as the centenarians. Hopefully researchers can use the identified differences to make faster progress in longevity science. Here is an example:

OBJECTIVES: To analyze several functions and antioxidant parameters of peripheral blood neutrophils from healthy centenarians (men and women) and compare them with those of healthy young (aged 25-35) and middle-aged (aged 65-75) men and women.

...

PARTICIPANTS: Twenty-one healthy centenarians (8 men), 30 young adults (15 men), and 30 middle-aged adults (15 men).

...

RESULTS: Neutrophil functions of the middle-aged group were worse than those of young adults and centenarians ... The neutrophil functions of the centenarians were closer to those of the young adults. ... With normal aging, total glutathione levels decrease, but the centenarians in this study showed levels similar to those of young adults. Centenarians showed the highest catalase activity of the three groups.

CONCLUSION: Progressive impairment of the immune system accompanies aging. The better preservation of function and antioxidant systems in the neutrophils of centenarians could play a key role in the longevity of these subjects.

The catalase data is interesting, given the work of Rabinovitch showing that increased catalase expression in mice - if targeted to the mitochondria - extends healthy life. It seems that there might be a fair degree of difference within the human species as to how genetically resistant people are to aging. For more on why catalase - an antioxidant - likely works to extend life when introduced to the mitochondria, you might look back into the Fight Aging! archives.

The catalase soaks up some portion of free radicals before they can attack your vulnerable mitochondrial DNA. Damage to this [DNA] leads to an unfortunate chain of events that causes entire cells to rabidly produce damaging free radicals and export them throughout the body. But stop a fraction of the original mitochondrial free radicals from attacking their birthplace, and you have slowed the rate at which one cause of aging happens - you have slowed down aging, and extended healthy life.

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Not to sound like a broken record, but the state of the mitochondria inside your cells is very important. The level of damaged suffered by these mitochondria is a determinant of your future health and longevity because of the further damaging processes set in motion by faulty mitochondria. Furthermore, we can point to some known ways to extend longevity - such as calorie restriction - and show that they cause changes in biochemical processes that act to eliminate damaged mitochondria before they cause significant harm or prevent that damage from occuring in the first place. As this recent abstract points out for one small facet of aging:

The mechanisms by which caloric restriction preserves skeletal muscle health with aging continue to be explored; however, mounting evidence points toward a convergence of effects at the level of the mitochondrion. Specifically, caloric restriction reduces mitochondrial reactive oxygen species production and promotes mitochondrial renewal via enhanced drive on mitochondrial biogenesis and autophagy.

The mitochondrial free radical theory of aging describes in detail how it is proposed that increasing numbers of damaged mitochondria lead to the slow breakdown of systems within the body. A crucial point here is that each of your cells contains thousands of mitochondria, a population constantly in flux with members being broken down when damaged and replaced through binary fission of remaining mitochondria, dividing in two like bacteria. Mitochondria have their own internal DNA, separate from nuclear DNA in your cells, and when that mitochondrial DNA gets damaged then every future generation of mitochondria carry the damage with them.

The core of the mitochondrial free radical theory of aging is an explanation as to how certain forms of mitochondrial DNA damage, such as large deletions, can subvert the normal processes that check for damaged mitochondria to recycle. These damaged mitochondria will be recycled more slowly than their pristine counterparts and will thus soon replicate unchecked to take over the entire mitochondrial population of a cell. Things start to go downhill for that cell and all other nearby cells soon thereafter as the mechanisms of metabolism run awry. Here is a paper providing solid evidence for that concept:

Age-dependent accumulation of partially-deleted mitochondrial DNA (DeltamtDNA) has been suggested to contribute to aging and the development of age-associated diseases including Parkinson's disease. However, the molecular mechanisms underlying the generation and accumulation of DeltamtDNA have not been addressed in vivo.

In this study [we] obtained in vivo evidence that DeltamtDNAs with larger deletions accumulate faster than those with smaller deletions, implying a replicative advantage of smaller mtDNAs. These findings identify DSB, DNA repair systems and replicative advantage as likely mechanisms underlying the generation and age-associated accumulation of DeltamtDNA.

More damage means more replication of damaged mitochondria. This isn't all idle research, of course: having identified damage to mitochondrial DNA as a significant contributer to degenerative aging, there are a wealth of potential ways to reverse or eliminate it through medical science, some already demonstrated in laboratory animals. Look back in the Fight Aging! archives to see some of them:

• Targeting Mitochondria
• Eating Mitochondria
• Can Damaged Mitochondria Repair Their DNA?
• SENS 2 Report: Moving Mitochondria
• Slightly Insider Info: Mitochondrial Protofection Works

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Fairness and equality, much like communism, are concepts that pull at the hardwired nature of we humans. For reasons no doubt much to do with the evolutionary success of our ancestors, we instinctively seek to tear down those who have more than we do. Fairness and equality, again much like communism, turn into a race for the bottom when put into practice:

Creating "equality" by taking from the successful ruins the creation of wealth - very much a non-zero sum game - for all. It takes away the vital incentives and rewards for success. At the end of the process, as demonstrated by all that transpired in the Soviet Union, you are left with the same old inequalities, but now taking place amongst ruins, starvation and disease.

I noticed an exploration of one manifestation of this human urge today:

The fair innings argument maintains that for healthcare resources to be distributed fairly every person should receive sufficient healthcare to provide them with the opportunity to live in good health for a normal span of years. What constitutes a normal span of years is often defined as life expectancy at birth, but this criterion fails to provide adequate grounds for the equal distribution of healthcare across and between generations. A more suitable criterion for the normal life span is the idea that the human life span is biologically limited. Many current gerontological theories argue that the biological limit to human life spans is related to the ageing process. If technological advances in medicine can retard the ageing process by treating and preventing the diseases and disorders associated with it, human longevity will be limited only by the developments in and the successful application of medicine. In consequence, the fair innings argument will no longer be able to justify denying people healthcare resources because they have lived longer than the normal life span.

The very existence of the fair innings argument - the term coming from cricket, I imagine, refering to a decent time spent at bat, a good life lived, time to get out of the pool - is a terrible end manifestation of the urge to equality. That people talk about denying medical care to those who need it the most, and that they establish an idea of what length of life should be in defense of that aim, demonstrates that any attempt to impose equality is also a retreat from compassion and a refutation of progress.

An older paper runs along much the same lines and is open access: the basics of the fair innings argument haven't changed.

The fair innings argument (FIA) is frequently put forward as a justification for denying elderly patients treatment when they are in competition with younger patients and resources are scarce. In this paper I will examine some arguments that are used to support the FIA. My conclusion will be that they do not stand up to scrutiny and therefore, the FIA should not be used to justify the denial of treatment to elderly patients, or to support rationing of health care by age.

The whole debate has to be put in context, however. This is related to the operation of the universal health care system in the UK, a system that has long been in the doleful steady state of all such socialist, centralized systems: waste, terrible services, and - most importantly - rationing. Every taxpayer involuntarily funding this behemoth feels that they own a piece of it, and everyone has that tug on their human nature urging them to make sure that no-one gets more than they do. It's ugly, and it's why socialism fails. Along the way to failure, however, it produces dangerous ideas, such as "human beings have a fixed length of life, after which they should be cut off and left to die."

I much prefer the vanishing alternate path for health provision: a free market of competing service providers, and people taxed less, free to save and plan for their own medical needs. In that environment progress and longevity are welcome, and increased need for medicine is a market opportunity to excel in providing services.

I say if this were a privatized system, we would all say “gee it’s wonderful. All these people want more health care, this industry is thriving”. Let me put one other analogy. Suppose we made cars a government entitlement. Instead of cheering when auto production went up, we’d say, "Oh my God, we can’t afford this!". How you finance it may greatly affect the psychology and actually the freedom of the economy to take advantage of these new opportunities.

Sadly, freedom in medical choice is not the zeitgeist of this age. Worse looks more likely than better for the years immediately ahead.

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You'll recall that experiments restricting intake of the dietary amino acid methionine - without restricting calories - demonstrate some of the same beneficial health effects as calorie restriction. This suggests that the level of methionine ingested is primarily what cues our biochemistry to produce the benefits it does under a low calorie diet that still supplies the right levels of micronutrients. See, for example:

• Methionine Restriction and Longevity
• The Metabolic Basis of Longevity
• On Methionine Restriction, Suppression of Mitochondrial Dysfunction and Aging

Now here's a reversal of these experiments, in which researchers restrict all the other dietary amino acids except methionine, and come to much the same conclusion:

Previous studies have shown that the decrease in mitochondrial reactive oxygen species (mitROS) generation and oxidative damage to mitochondrial DNA (mtDNA) that occurs during life extending dietary restriction also occurs during protein or methionine restriction, whereas it does not take place during carbohydrate or lipid restriction.

In order to study the possible effects of other amino acids, in this investigation all the dietary amino acids, except methionine, were restricted by 40% in male Wistar rats (RESTAAS group). After 6-7 weeks, experimental parameters were measured in the liver.

...

[The] results, together with previous ones, strongly suggest that the decrease in mitROS generation and oxidative damage to mtDNA that occurs during dietary restriction is due to restriction of a single amino acid: methionine. They also show for the first time that restriction of dietary amino acids different from methionine decreases mitochondrial protein oxidative modification [and] increases SIRT1, in rat liver.

Meaning that while methionine restriction accounts for much of calorie restriction, it doesn't account for all of it. There may be multiple parallel mechanisms operating, which in turn suggests that building calorie restriction mimetic drugs that capture anywhere near the entire effect of actual calorie restriction will be challenging. Meanwhile, while research groups are spending hundreds of millions to billions of dollars on research an development, you can obtain the whole benefit of calorie restriction for just about free. Just start eating less, sensibly, while ensuring that your intake of micronutrients remains optimal.

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Regular readers will know that advanced glycation endproducts (AGEs) are not a good thing; they're one of the types of biochemical gunk that accumulate in our tissues to degrade function and cause follow-on issues relating to that lost functionality.

Problems caused - or not helped - by AGE buildup include kidney disease, and the many variations of blood pressure and heart conditions caused by a lack of elasticity in the tissues of heart and blood vessels. Diabetics in particular suffer due to more rapid accumulation of AGEs based on their metabolic biochemistry (e.g. high blood sugar, inflammation, free radicals).

You might also recall some of my posts on RAGE, the receptor for AGEs and how that fits in to the way in which AGEs damage the workings of your biochemistry.

At least some of the degenerations brought on by AGE buildup can be laid at the feet of the interaction with RAGE, and the resulting actions then taken by your cells. Cell receptors are like keyboards or buttons - hit them with the right sort of molecules and you're instructing the cell to take action.

There is, however, some debate over the role of AGEs ingested with food - cooked meat is comparatively high in AGEs, for example, and pretty much anything else that involves the Malliard reaction. Do these AGEs contribute to damage in the same way as those generated inside the body as a side effect of the operation of human metabolism? Here's a recent paper on the topic:

Effects of high-AGE beverage on RAGE and VEGF expressions in the liver and kidneys

BACKGROUND: The formation and accumulation of advanced glycation end products (AGEs) increase in some lifestyle-related diseases as well as in aging; however, little is known about the relationship between food-derived AGEs and the pathology of such diseases.

AIM OF THE STUDY AND METHODS: To explore whether food items containing high levels of AGEs are involved in the development of lifestyle-related diseases, rats were orally administered a commercial high-AGE beverage (LB-A) ... With a particular focus on angiogenesis-associated diseases, the gene expressions of vascular endothelial growth factor (VEGF) and the receptor for AGEs (RAGE) were examined in the liver and kidneys using real-time reverse transcription-polymerase chain reaction. Moreover, AGE deposition was immunohistochemically investigated in these tissues.

RESULTS AND CONCLUSIONS: Hepatic VEGF expression was significantly increased in rats administered LB-A ... Furthermore, immunohistochemical analysis detected glucose-derived AGE-positive cells in the liver from the LB-A group. These results suggest that AGE-rich beverages increase hepatic VEGF expression and AGE accumulation, bringing about early events associated with lifestyle-related diseases.

Fair evidence to suggest that reducing your AGE intake in addition to reducing your overall calorie intake might be a good idea over the long term.

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I'm pleased to note that the volunteer folders-at-home who gather at the Immortality Institute forum have pushed the Longevity Meme Folding@Home team into the top 100 list - it's sitting right at rank 100 as I type this. I'd love to say I helped, but the steady climb through the ranks and increasing donation of computational resources is really all due to the hard work of those who organizated, encouraged, and recruited to grow the team to its present size. Well done all. There is a celebratory discussion thread underway over at the Immortality Institute.

Feel free to set off some fireworks or eat some cake or something to mark the occasion.

When the team hit rank 200 at the start of this year, I donated a small chunk of change to the Methuselah Foundation as an incentive for the folders. The team has sprinted ahead to rank 100 faster than I had anticipated given the competition - and so has caught me without a plan as to what to do to mark the occasion. Since you can't go far wrong by offering money, I think I'll donate a further $2000 to the Methuselah Foundation this year in support of Strategies for Engineered Negligible Senescence research.

Keep up the good work!

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The mailing list of the Gerontology Research Group is something of a watering hole for many of the interesting folk in the pro-longevity gerontology community and related supporters of medical intervention to extend healthy life. Members include the Supercentenarian Research Foundation board, Methuselah Foundation volunteers, calorie restriction researchers, transhumanist writers, and so forth. L. Stephen Coles of the GRG recently penned a short editorial on the limits of longevity which closes with:

We should appreciate that the really-important parameters of longevity operate at the molecular level, such as the accumulation of sticky amyloid compounds which relentlessly infiltrate all our organs, the mechanism for which we have yet to decipher. When we do figure it out (science) and when we learn what to do about it (medicine), "all bets (on life-insurance-policy planning) will be off." We will be on the road to a real revolution in the human condition.

It being that time of year, I should note that the Supercentenarian Research Foundation is soliciting donations:

We seek to further scientific research into to why Supercentenarians live as long as they do? (And, conversely, why they don't live longer still?) We are incorporated and have held many meetings of our Board of Directors. We have received approval for our 501(c)(3) non profit, tax-exempt status from the US Internal Revenue Service. Nevertheless, we are urgently in need of "seed money" to fund the formation of an international team of physicians and investigators who could travel to visit each of our living Supercentenarians around the world in person before they are no longer with us. Obviously, the data that we plan to obtain is a precious resource that could disappear from our radar screens unless we get started soon.

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Biotechnology and life science research is forging ahead despite the steadily worsening situation in bringing medical advances to market - stifling regulation that seems to do little but get worse year after year, and now an ongoing economic collapse that looks set to continue for some time. Here are a couple of examples from the field of regenerative medicine in the past few days:

Single Adult Stem Cell Can Self Renew, Repair Tissue Damage In Live Mammal

The transplanted adult stem cell and its differentiated descendants restored lost function to mice with hind limb muscle tissue damage. ... Unlike tumor cells, the transplanted stem cells achieved homeostasis, growing to a stable, constant level and ceasing replication. After demonstrating that the transplanted stem cells proliferated and fully restored the animal's lost function, Sacco and Blau recovered new stem cells from the transplant with full stem cell potency, meeting the final "gold standard" test for adult multipotent stem cells.

Single virus used to convert adult cells to embryonic stem cell-like cells

Researchers have greatly simplified the creation of so-called induced pluripotent stem (iPS) cells, cutting the number of viruses used in the reprogramming process from four to one. Scientists hope that these embryonic stem-cell-like cells could eventually be used to treat such ailments as Parkinson's disease and diabetes.

New Way To More Rapidly Generate Bone Tissue Developed

Using stem cell lines not typically combined, researchers [have] designed a new way to "grow" bone and other tissues.

...

The inability to foster angiogenesis - a physiological process involving the growth of new blood vessels from pre-existing vessels - has been a major roadblock in tissue regeneration. Previous approaches have included the use of angiogenic growth factors and the fabrication of artificial blood vessels. However, there are problems associated with these approaches. Among these problems: artificially fabricated blood vessels do not readily branch out and network with host blood vessels, and blood vessels induced by angiogenic growth factors tend to be immature and "leaky."

To overcome these obstacles, a team of Columbia researchers has co-transplanted hematopoietic and mesenchymal stem/progenitor cells to promote the regeneration of vascularized tissues. What they found was that the tissue regenerated in bone more rapidly than when either type of stem cell was used alone.

It is encouraging to have seen a steady stream of improvements to new techniques this past year. Researchers are moving rapidly to build a sound basis for the near-future construction of replacement organs and directed regrowth of damaged tissue inside the body.

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Here's an open access paper for those of you interested in bioinformatics: using network theory and existing data on genes and proteins to predict new longevity genes and targets for further investigation. This is an example of the modern nuts and bolts of efforts to fully understand longevity from a reductionist point of view - a long road ahead there.

Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders.

...

We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein-protein interaction dataset in order to construct a shortest-path longevity network.

...

we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction.

I happen to think that the best near-term result - over the next decade, say - to come out of efforts aimed at complete understanding of our biochemistry will be a speeding of medical engineering for increased longevity. Engineering comes before science, and is improved by increased understanding provided by science, but you don't have to wait for full understanding to make progress. Bridge building was a fine art long before architectural and materials science became mature fields, and so too could longevity therapies be developed well in advance of a full understanding of metabolism. Medicine is, after all, a branch of engineering.

For an more detailed explanation as to why this is so, you might read up on the Strategies for Engineered Negligible Senescence. We already know more than enough to work at repairing our age-damaged biochemistry through medical science, as we can identify the precise ways in which old biochemistry differs from young biochemistry. Further understanding why these differerences exist will make the task of repairing them easier, but is not strictly necessary to progress. You don't need to know the chemistry of rust in order to perform the maintenance work of removing it from machinery - you just need to know how to remove rust.

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Autophagy is the process by which cells break down damaged components and replace them with newly created ones. The quality and degree of ongoing autophagy - and most importantly autophagy of damaged mitochondria in your cells - appears to be important for longevity. See past posts here at Fight Aging! for example:

• On Autophagy
• Autophagy Required For Calorie Restriction Benefits?
• The Prospects for Enhancing Autophagy to Combat Age-Related Degeneration
• All Roads Lead to Autophagy?
• More Evidence For Autophagy as a Good Thing

Autophagy researchers are amassing a heavy weight of evidence pointing to autophagy as a key process that boosts healthy longevity, most likely by cycling out damaged mitochondria before those damaged mitochondria can replicate to wreck havoc in your tissues.

Scientists generally concur that accumulated damage throughout the body due to free radicals is one important root cause of age-related degeneration - but the devil is in the details. The vast, overwhelming majority of those free radicals are generated by your [mitochondria] as an unavoidable byproduct. The rate of free radical generation increases greatly with age as the [mitochondria] are themselves damaged by the free radicals they created.

Continuing in this vein, a great post over at Ouroboros analyzes research that provides more and better confirmation of the role of autophagy in extending healthy life span through calorie restriction:

Mitochondria are central to many theories of aging because they produce damaging reactive oxygen species (ROS) as a by-product of normal function. Over time, ROS can degrade mitochondrial DNA (mtDNA), interfering with cellular energy production. The cell’s strategy for dealing with this damage is to recycle its mitochondria on a regular basis.

...

The main result of this paper is that calorie restriction makes mitochondria turn over a substantial 35% faster, at least in mouse liver. This provides another explanation for the recent finding that [calorie restriction] protects mtDNA from age-related damage.

It's worth a few moments to stop and think about the deep biochemical damage your body is accumulating because of the extra calories you consume.

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Scientific progress goes through cyclic periods of fragmentation followed by synthesis. During fragmentation, many different groups toil away at their own little pieces of the great unknown. Each group generates data that, at first, appears to have little to do with other efforts. As the data piles higher, correlations start to appear - and so do the efforts at synthesis. Gradually, the focus in a field shifts from finding new information to making sense of what is known, pulling it all together such that links, correlations, and chained mechanisms are understood. Then they next great unknown beckons and the process of fragmentation starts once more.

At present the grand study of human biochemistry is moving from fragmentation to synthesis. It is still the case that some different specialties know little of one another's work. Researchers look at the same mechanisms and compounds, giving them different names and assuming different dominant roles in biochemical processes, all the while missing out on the enlightenment that a complete picture can bring. But that state of affairs is generally on the way out, helped by modern information technology. The cost of knowledge is dropping precipitously, and so the process of synthesis becomes easier and starts earlier:

In past years, I was fond of comparing biogerontology to the tale of the blind men and the elephant: everyone was approaching the problem from different directions, unable to see the big picture - and reaching conclusions that had more to do with the direction of approach (i.e., initial biases) than the fundamental importance of any given observation.

But this analogy is becoming increasingly less apt, and we may be on the verge of the era of unifying theories in the biology of aging.

What causes aging? The various subfields of biogerontology answer this question in very different ways. To vastly oversimplify: In one corner we have metabolism, including the related stories of sirtuins and calorie restriction; in another corner, we have DNA damage and stochasticity of gene expression. (Already we're seeing the unifying tendency of recent findings: a few years ago I might have put those four items in four separate corners, but on the basis of recent reports I feel comfortable starting to bin them together. There are those, however, who would argue I'm being premature if not outright inaccurate in so doing.) In both corners, one could make a legitimate claim that the phenomenon in question has serious explanatory power regarding a fundamental mechanism of aging or longevity assurance - but is there a connection between the two?

This is a view within the mainstream focus on metabolism, DNA damage and the like - quite different from the Strategies for Engineered Negligible Senescence approach to aging science - but you should read the rest; it's very interesting.

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I noticed a press article on cryonics and the Alcor Life Extension Foundation today:

With medical advances, many put faith in freezing

Leis studies geosciences at the University of Arizona and works in the school's Lunar and Planetary Laboratory, helping study high-resolution images of Mars. Meanwhile, he's paying $22 a month into a life insurance policy that would provide $250,000 if he dies young.

That's enough freeze his body at minus 196 degrees Celsius and store it indefinitely at the Alcor Life Extension Foundation here, waiting for medical advances that could bring him back to life.

...

Leis, the University of Arizona student, said he's happy to have the option to be preserved until someone figures out how to revive and cure him.

"The technological breakthroughs in cryopreservation suggest that we at least have the ability to preserve biological matter relatively well for a longer period of time," he said. "Whether or not we will be able to do anything with that biological matter down the road remains unseen."

Alcor uses vitrification these days, a process that is very different from freezing and which causes far less damage to tissue.

There's the standard humbug from a bioethicist in the middle of the piece, sticking with the party line of pulling nonsense objections from thin air in response to every endeavor in medicine. If they couldn't at least make the pretense of finding fault, they wouldn't have a job, after all. It's just a pity that bioethicists aren't engaged in more useful work, such as actually getting something accomplished:

Arthur Caplan, a professor of bioethics at the University of Pennsylvania, said those considering being frozen should think about what it would be like to come back. For example, a person revived in the future wouldn't have any relationships or ties to that time.

"Who we are isn't just defined by what's in our heads; it's also by our relationships,"

...

Rafal said he disagrees with Caplan's concerns about a revived person fitting into a future culture. "A reasonable person would find a place in society and have a new life with no difficulty," he said.

Which is exactly the case. You can go through life making up dumb reasons not to forge ahead, or you can forge ahead. I know which approach I prefer.

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I don't think it's any great secret that failing to exercise regularly and accumulating visceral fat around the organs are both bad for your long term health - but I suspect that most people don't realise just how bad it is. Either that or it's the way in which we are hardwired to discount the future and cause harm to the person we will one day be - time preference at work. In any case, here is a reminder from the scientific community:

Adiposity and Alzheimer's disease

Alzheimer's disease is the most common form of dementia. There are no known preventive or curative measures. There is increasing evidence for the role of total adiposity, usually measured clinically as BMI, and central adiposity [or visceral abdominal fat], in Alzheimer's disease.

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Salient publications in 2007 and 2008 showed that (a) central adiposity in middle age predicts dementia in old age; (b) the relation between high adiposity and dementia is attenuated with older age; (c) waist circumference in old age, a measure of central adiposity, may be a better predictor of dementia than BMI; (d) lower BMI predicts dementia in elderly people; and (e) weight loss may precede dementia diagnosis by decades, which may explain seemingly paradoxical findings.

All a long way of saying if you get fat and stay fat, your biochemistry is more likely to destroy the structure and function of your mind. And those thinner old people who are suffering as well? Their developing dementia - partially caused by earlier excess fat - led them to lose weight during their decline. There are easier ways through life than this, and unlike many of the slings and arrows we suffer, for the vast majority of us our level of body fat is a choice.

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Sierra Sciences is one of a number of small companies working on telomeres and telomerase with an eye to engineering therapies for age related disease or perhaps even rejuvenation of some form.

Sierra Sciences, LLC. (Sierra) is a biotech research company located in Reno, Nevada. Our mission is to discover a medicine to prevent and/or reverse cellular senescence (the phenomenon where cells lose the ability to divide).

We believe that cellular senescence is an underlying cause of many conditions in cells which are related to the diseases of human aging, including aging itself.

Senescent cells are almost certainly not good: they build up with age, and secrete unwanted biochemicals that contribute to cancer risk in surrounding tissue, amongst other bad behavior. I've written about Sierra Sciences before, back when I wasn't so sold on the efficacy of this line of research.

The past few years have not been kind to the telomere theory of aging as it originally stood - that telomere shortening alone causes aging. The contribution of shortened telomeres to the plot is more complex and not yet well understood; a great deal is yet to be learned about the underlying biochemistry and genetics. Scientists are still obtaining apparently contradictory results in telomere and telomerase research, which indicates that the fundamentals are not yet clear.

Fortunately, the possibilities of science are not bounded by my opinions and things have a way of coming back into focus. Recently research strongly suggests that telomeres and telomerase are very connected to the age-related decline of mitochondria, and that progress in understanding how and why this is so may ultimately lead to longevity-enhancing interventions on that front.

In any case, you'll find an presentation by Laura Briggs of Sierra Sciences over at Future Current, given at the Understanding Aging conference earlier this year. It's an eye opener for those folk who are under the impression that there's any such thing as "simple science":

In cells, in cell culture anyway, preventing telomere shortening will extend the healthspan and lifespan of those cells. Unfortunately, we do not know if that is going to apply to humans. Can we extrapolate what we know about cell cultures to humans? That is a question that has not been answered yet. That is the fundamental question that Sierra Sciences is attempting to answer. We would love to get to this point and answer this question.

...

There are a number of diseases that could be helped by the prevention of telomere shortening. With that I will start with what I came here to talk about, which are some of the tools that we are using in the struggle to keep our telomeres long. Sierra Sciences has been in existence for about nine years. We have worked really hard trying to figure out all we can about telomerase. ... We now have a 300,000 compound library and are searching for compounds that will turn on telomerase.

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One ideal end result of stem cell research would be the ability to provoke cells within the body into controlled regeneration, replicating the world they did during early development to repair any cell loss suffered by the body. Easier said than done, but technology demonstrations over the past few years have shown that the potential is there: controlling signals exist to direct cellular behavior. They are very complex, and still poorly understood, but progress is being made. This report is an example of the sort of work presently taking place:

mammals can be stimulated to regrow inner nerve cells in their damaged retinas. Located in the back of the eye, the retina's role in vision is to convert light into nerve impulses to the brain.

...

Other scientists have shown before that certain retina nerve cells from mice can proliferate in a laboratory dish. This new report gives evidence that retina cells can be encouraged to regenerate in living mice.

This is a demonstration only, as the regenerated cells are created after artificial biochemical signals are issued into the bodies of mice, but don't last long. It's not enough to just create new cells: they must be created in such a way as to integrate with their functional systems they are to support.

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My attention was directed today to the list of research publications from scientists awarded grants by the California Institute for Regenerative Medicine. Regardless of your views on the heavy-handed entry of government into research funding, it provides a interesting snapshot of the state of stem cell research; scientists making progress in reverse engineering the ways the body builds and repairs itself. Take a look:

Researchers at UC, Los Angeles have created cells that go on to form normal T cells out of human embryonic stem cells.

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Researchers at UC, Irvine identified the true location of adult stem cells in the brain.

...

Researchers at UC, Berkeley identified a signaling molecule that interferes with the ability of older skeletal muscle to regenerate. After injury, adult skeletal muscle regenerates by activating muscle stem cells that fuse with the existing muscle cells to repair the damage. This ability to regenerate diminishes with age, not because of a decline in the number of resident stem cells, but because stem cells in the older muscle don’t respond when damage occurs. It turns out that older muscles release molecules that actively inhibit the resident stem cells. In this study, the team identified one of those molecules and showed that interfering with that molecule’s function restores the ability of muscle in older mice to regenerate after injury.

...

Researchers at UC, Los Angeles discovered a series of mutations that can convert normal blood stem cells into cancer stem cells. It is believed that many types of cancer result from cancer stem cells created by such mutations. ... The team hopes that by studying these pathways they will find ways to block them with small molecule drugs and cure the often fatal disease.

Our stem cells are complex machinery; in between the scientific successes that have immediate application, much of present research is the biochemical equivalent of tracing wires and dismantling clockwork to understand how it works. The pace of basic research is fast, however, and the field is comparatively well funded. Ten years from now, I would not be at all surprised to see the research community to possess a fairly complete picture of the biochemistry of stem cells: how they work, and what signals and genes control each step of the processes that take place inside our bodies. From there on in, it's all application of that knowledge.

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We should all thank Jeriaska of Future Current for providing such a fine service in writing up and publishing presentations, interviews, and lectures from conferences of interest to the transhumanist and healthy life extension communities. Two of the latest are from the Understanding Aging conference hosted earlier this year by the Methuselah Foundation:

Natural Cancer Resistance in Mice and in Humans

The main concept for this project is very simple. This idea, that we may have natural resistance to cancer present in our body at all times, is not a new idea. It has been proposed for over a hundred years. In other words, the reason that we are sitting here cancer-free is not because we’re lucky, it is because we may have an innate system in our body to protect us - in other words, to get rid of cancer cells. As we get older, this protection may get weaker. That balance between the generation of cancer cells on a continuous basis can overtake the ability of your body to get rid of them

If you are already familiar with Zheng Cui's work, this presentation provides some very interesting additional data. If not, you might want to read the excellent introduction posted at the Methuselah Foundation blog.

Unfocused Pulsed Lasers Selectively Destroy Lipofuscin

The idea is lipofuscin is this aggregate of oxidized lipids and proteins that accumulates in autophagosomes or lysosomes. Lipofuscin itself we think is the problem. We think lipofuscin is sufficient to knock down autophagy as it accumulates. Eventually you get cells that are loaded with lipofuscin and the lysosomes cannot do their job of rejuvenating the cell. We think many aspects of aging are the result. If that is true, this is where the whole idea of "removing the garbage" comes in. We think the garbage itself is the problem, and if you can get rid of it we can make some serious inroads into conquering aging.

If you found these items interesting, then I recommend you look over the online videos from the Understanding Aging conference.

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It used to be the common wisdom that adult brains never generated new neurons - that you had what you started with, and it was irreversibly downhill from there. Fortunately this turned out to be far from the case. The thinking now is that since mechanisms exist to generate new neurons, we should find out whether these mechanisms be enhanced and manipulated to regenerate at least some of the damage of aging - exactly the same model that drives stem cell researchers focused on other organs. But this is all some years behind other branches of regenerative medicine, and likely a much more challenging goal than repair of a heart or a liver. Researchers are still mapping out the basics with the new tools of modern biotechnology:

One of the most remarkable, and unexpected, discoveries in brain science over the past two decades was that, contrary to a century of neuroscience dogma, the brain can generate new neurons throughout adulthood. Not only can, but does, and prolifically: thousands of new neurons are created each day in several regions of the brain.

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But it is not enough for such neurons merely to be formed. To play their part in memory storage, they must send out processes - dendrites to receive information, and axons to pass it along - to other brain regions, and become integrated into pre-existing neuronal circuitry. A new study by Sebastian Jessberger et al. shows that a protein called cdk5 plays a pivotal role in this integration.

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Whatever the precise mechanism, the discovery of cdk5's role in guiding new neurons to their proper place improves the understanding of neurogenesis in the adult hippocampus, a process that is believed to be aberrant in cognitive aging, Alzheimer disease, and some forms of epilepsy and depression. In addition, it may suggest ways to improve prospects for neural transplantation for neurodegenerative diseases such as Parkinson disease.

The clinical benefits of experimental transplants have been inconsistent and largely disappointing to date, with most transplanted neurons unable to integrate into existing brain circuits. A better understanding of what neurons need to find their way and fit into their new surroundings may increase the chances of success for this treatment.

Progess continues, slow and steady.

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