Vote For Longevity Science in the Chase Community Giving Initiative

Over the past year or two, the grassroots community of longevity science supporters and advocates have been getting a lot of practice in networking and persuasion. There is a growing trend amongst large organizations to crowdsource some of their charitable contributions: it's great publicity and seems to generate much more goodwill and awareness for the recipient causes than a straight donation. So everyone wins. In this, we can see the effects of competition at work; initiatives generally involve voting or some other form of popularity contest that can be won by through grassroots social networking and organization.

Longevity science supporters have won some and lost some over the past year, seeking to direct funds to the SENS Foundation or Methuselah Foundation. It's all good experience and exposure even when the prize goes to another charity - or as happened in the Amex contest, where the organizers themselves veto any support for longevity science, no matter how the vote goes. Social networking in a community is like a muscle: use it or lose it, and grow stronger with practice. But for an engineered longevity research community to grow in the long term, advocates must be able to convincingly explain why reversing the damage of aging is just as worthy a cause as homeless shelters, children's cancer research, environmentalism, and other, similarly broadly supported endeavors. Participating in these crowdsourced contests for charitable donations helps the community to figure out how to do this.

The latest event of interest is the Chase Community Giving initiative on Facebook. Over the next couple of weeks, votes will be accepted to establish a list of the top 100 charities. Each will receive $25,000, and then a second phase of voting and organizer selection will determine larger grants. I encourage you all to go and plug in your list of favored charities with the SENS Foundation and Methuselah Foundation at the top. But first, you might want to swing by the Immortality Institute forums to read the thread they have there, since the Institute volunteers have worked to save you time forming a list of charities. You'll find a good list in a post on the second page, with each item linked to the relevant place in the Chase Community Giving section of Facebook. That list is reproduced below:

Facebook members can vote for up to 20 charities. ... The stiffest competition will likely come from relatively smaller charities like the winners of America's Giving Challenge charity contest.


In order to avoid voting fatigue and make sure that voter at least vote for the most important charities, the charity list could be divided into the following sections:

Recommended charities

These charities are the most important ones to vote for as they have a more direct impact on life extension research.

  1. Immortality Institute
  2. Methuselah Foundation
  3. Supercentenarian Research Foundation
  4. Vitae Institute

Suggested charities

These charities fund mainstream research related to aging, Alzheimer's disease, stem cells, and Parkinson's disease.

  1. Alliance For Aging Research
  2. Genetics Policy Institute
  3. American Aging Association
  4. Campaign for Aging Research (might be shifting focus from aging research to the study of aging in society)
  5. Alzheimers And Aging Research Center
  6. Institute For Advanced Studies In Aging & Geriatric Medicine
  7. Fisher Center for Alzheimer's Research Foundation
  8. Cure Alzheimer's Fund
  9. Sabrina Cohen Foundation for Stem Cell Research
  10. International Society For Stem Cell Research
  11. Michael Stern Parkinsons Research Foundation
  12. Parkinson's Action Network
  13. Paul Ruby Foundation for Parkinson's Research
  14. Parkinsons Disease Research Society
  15. Foundation For Parkinsons And Neurological Research
  16. Louies Run For The Mass General Hospital Parkinsons Research

Other charities

These charities have political or educational goals related to stem cell research.

  1. Texans For Stem Cell Research
  2. Michigan Citizens for Stem Cell Research & Cures
  3. World Stem Cell Foundation
  4. Stem Cell Net Foundation

So go forth and vote for longevity science - and encourage your friends to do likewise. The more that the community strives to win this sort of contest, the better the results will be. We won the last one, after all.

Aptamers as Cancer Targeting Mechanism

The future of cancer therapies lies in increasingly precise methods of targeting only cancer cells for destruction or reprogramming. Here is another of the many techniques presently under development: "Aptamers are small pieces of RNA that bind to a specific target molecule, usually a protein. They offer ease of use because they can be easily regenerated and modified and therefore have increased stability over some other agents, such as protein-based antibodies. Notably, they have a very low chance of immune-system interference, making them great candidates for tumor diagnosis and therapy. ... Most importantly, it's not necessary to have detailed knowledge of protein changes in the disease before the selection process. This greatly simplifies the process of molecular probe development. The selected aptamers can be used to discover proteins not previously linked with the disease in question, which could speed up the search for effective therapies. ... researchers used a large pool of RNA strands and applied them to a rodent with a liver tumor, the type of metastatic tumor that often results from a colon cancer tumor. ... We hypothesized that the RNA molecules that bind to normal cellular elements would be filtered out, and this happened. In this way, we found the RNA molecules that went specifically to the tumor."


Interest in the Naked Mole-Rat

A popular science article on rising interest amongst researchers in naked-mole rat biochemistry: "Able to live up to 30 years, these 3 to 4 inch East African critters are being used to study everything from strokes to cancer to aging in hopes that scientists might find new insights into human health complications. ... At the University of Texas Health Science Center in San Antonio, researcher Rochelle Buffenstein is responsible for tending a 1,500-member-strong mole rat colony that makes its abode in series of large clear tanks connected by long transparent tubes. Though the San Antonio colony is by far the largest in the U.S., a number of other universities around the country have begun founding their own mole rat communities for research purposes. Despite significant levels of inbreeding within their colonies - a phenomenon that usually tends to weaken genetic integrity and thus decrease longevity - naked mole rats can live to be 30 years old, or more than 15 times longer than the average lab mouse. ... perhaps most the most significant and intriguing oddity displayed by these rodents is their complete resistance to cancer. ... researchers speculated that their immunity to cancer may be attributed to a particular gene known as p16 which prevents cells from growing together in crowded clusters."


Reminder: Aubrey de Grey Live on on November 30th

By way of a reminder, biomedical gerontologist and well known advocate for radical life extension Aubrey de Grey will be participating in a live webcast on on November 30th - this coming Monday. The open invitation from CNN runs much as follows:

Vital Signs host and CNN Chief Medical Correspondent, Dr. Sanjay Gupta will be joined by best-selling author Dan Buettner who has done extensive studies on the areas in the world people live the longest, healthiest lives, known as Blue Zones, and shares their formula for a long life. The other panelist is geneticist Dr. Aubrey de Grey, best-selling author of "Ending Aging: The Rejuvenation Breakthroughs That Could Reverse Human Aging in Our Lifetime." He believes regenerative medicine could, in a matter of decades, extend life expectancy to 1000 years.

This special edition of Vital Signs: The Clinic will be broadcast LIVE on and we want you to take part in the conversation. You can do that by using the [comments box at the CNN article], post on or e-mail You can also send questions via Twitter. What would you ask the experts? Do you want to learn how to live until 100 and beyond? Or find out which diets or exercise to follow for living longer? Do you have concerns about how an aging population might impact on resources?

This seems to be more of a European-oriented event, given that it's being held at 12:00 GMT - i.e. four in the morning on the West Coast of the US. A little early even for the early birds amongst us. Still, this is another good opportunity to raise awareness of the present potential of longevity science, and congratulations to the SENS Foundation folk for making it happen.

Exercise and Leucine Versus Sarcopenia

There is good reason to believe that increased leucine in the diet and exercise can counteract some of the muscle loss characteristic to aging: "Loss of muscle mass is an unfavourable consequence of aging and many chronic diseases. The debilitating effects of muscle loss include declines in physical function and quality of life and increases in morbidity and mortality. Loss of muscle mass is the result of a decrease in muscle protein synthesis, an increase in muscle protein degradation, or a combination of both. Much research on muscle wasting has tended to focus on preventing muscle protein breakdown, and less attention has been paid to providing adequate stimulation to increase muscle protein synthesis. In this review, we present evidence to suggest that interventions aimed at increasing muscle protein synthesis represent the most effective countermeasure for preventing, delaying, or reversing the loss of skeletal muscle mass experienced in various muscle wasting conditions. Based on results from acute and chronic studies in humans in a wide variety of wasting conditions, we propose that resistance exercise training combined with appropriately timed protein (likely leucine-rich) ingestion represents a highly effective means."


mTOR and Age-Related Stem Cell Decline

The protein mTOR is one of many flagged as important to longevity by studies of calorie restriction biochemistry. Here it is implicated in the decline in stem cell function with age: "Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These [included] a relative decrease in lymphopoiesis [and] impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly."


The Latest Rejuvenation Research: Volume 12, Number 5

The latest issue of Rejuvenation Research, the journal chaired by biomedical gerontologist Aubrey de Grey, is available online. In this issue, Michael Fossel lays out the case for a focus on telomere biology:

In 1990, telomere length was shown to correlate with cellular senescence; this discovery was followed by a series of papers affirming a causal relationship between telomere length and cell senescence. Further work demonstrated that telomere elongation reverses cellular senescnce in both cells and reconstituted human tissues. Since telomerase, the enzyme that elongates telomeres, is absent (or only transiently active) in normal human somatic cells, the result is a gradual decrease in telomere length with age in most human tissues. The implied potential for in vivo human telomere enlongation raises two critical clinical issues: (a) Does telomere shortening play a key role in human diseases and, if so, (2) is telomere enlongation an effective clinical intervention.

You'll find a fair amount of material on telomere research back in the archives:

Another paper in this Rejuvenation Research issue touches on the question of what the public at large thinks about engineered longevity and the prospects for living longer - which should inform our expectations for future fundraising initiatives. I'm inclined to think that money raised for research is a somewhat better metric than surveys for gaining an idea of the level of support that presently exists, but analysis of public sentiment isn't an area in which clear cut and useful answers tend to emerge. It is true, however, that fundraising for longevity science is enjoying far greater success than it has in past decades, even though we are still talking about tiny amounts in comparison to any established field.

Despite speculations about likely public attitudes toward life extension, to date there have been few attempts to empirically examine the public's perspective of these issues. Using open-ended survey questions via telephone interviews, this study explored the attitudes of 605 members of the Australian public toward the implications of life extension. Participants were asked to briefly describe in their own words what they believed would be the beneficial, as well as negative, implications arising from life extension (if there were any), both for themselves personally and for society as a whole. Participants were also asked to describe any ethical concerns they had about life extension, if they had any at all. ... A considerable number of participants envisioned at least some beneficial as well as negative implications for themselves and for society, and many claimed to have at least some ethical concerns.

Embryonic Stem Cells in Regenerative Medicine

The New Scientist surveys current efforts to build regenerative therapies based on the pluripotency of embryonic stem cells: "Tissue grown from human embryonic stem cells, the most prized, and most controversial, cells ever grown in a lab, could at last make it into the human body. After a decade of scientific and political wrangling, several therapies are now edging towards human trials. Which will be first? ... The first human embryonic stem cells (hESCs) to make it into the human body could be ones that save sight. Last week, Advanced Cell Technology (ACT) of Worcester, Massachusetts, applied for permission to inject stem-cell derived retinal pigment epithelial cells (RPEs) into the eyes of 12 patients with Stargardt's macular dystrophy, a rare inherited condition which leads to blindness in middle age. ... Last week came the first report of human skin made from hESCs. Although the cells have so far only been tested on mice, the idea is to use skin grown from these stem cells as temporary grafts for people with burns, while they wait for a permanent graft to be grown from their own tissue."


A Promising Cancer Vaccine Strategy

Via EurekAlert!: "A cancer vaccine carried into the body on a carefully engineered, fingernail-sized implant is the first to successfully eliminate tumors in mammals ... The new approach [uses] plastic disks impregnated with tumor-specific antigens and implanted under the skin to reprogram the mammalian immune system to attack tumors. The new paper describes the use of such implants to eradicate melanoma tumors in mice. ... [This approach] redirects the immune system to target tumors, and appears both more effective and less cumbersome than other cancer vaccines ... Conventional cancer vaccinations remove immune cells from the body, reprogram them to attack malignant tissues, and return them to the body. However, more than 90 percent of reinjected cells have died before having any effect in experiments. ... The [implants] are 8.5 millimeters in diameter and made of [a] biodegradable polymer. Ninety percent air, the disks are highly permeable to immune cells and release cytokines, powerful recruiters of immune-system messengers called dendritic cells. These cells enter an implant's pores, where they are exposed to antigens specific to the type of tumor being targeted. The dendritic cells then report to nearby lymph nodes, where they direct the immune system's T cells to hunt down and kill tumor cells."


Thoughts on Synthesis in Aging Research

I stumbled across some thoughts from the field of neuroscience earlier today, and thought I'd share. Scientific journals publish more than just research findings, after all. You'll also find the occasional deep editorial, opinion piece, or words of wisdom:

The brain is responsible for providing everything from the basic involuntary physiological events that allow one to breathe and live, to the conscious actions and thoughts that dictate the very essence of mankind. As such, the preservation of brain function as individuals age is not only crucial to support the ability to live but also the ability to maintain their individuality. Aging is an inevitable process that everyone faces and one that has captivated people's minds since the beginning of our existence. Promises of life extension and immortality have been marketed from alchemists to charlatans and continue to flood popular media even today. The apparent desire to beat the ravages of age often outweighs rigorous thought, and that very popular obsession has sometimes diluted the seriousness of the field. That said, understanding the aging nervous system is a field that has attracted some of the brightest and best clinicians as well as basic scientists whose intellectual ideas and scholarly research bear on the field in an effort to reach an understanding of the fundamental mechanistic events underlying aging.


Over time, numerous theories on aging have been proposed. However, the fundamental link that unites these theories toward a cohesive understanding of aging is still lacking. The dissection of genetics versus environment and the way in which the genetics and the environment interact to affect development and maturation and demise is a pending subject for the research community. Pressing questions that need to be addressed are those concerning mechanisms associated with brain aging vulnerability, and the way in which selective neuronal populations become susceptible to disease as people age. Also, what makes certain individuals maintain incredible mental vitality and lucidity throughout life, and why others lose the essence of their individuality is key to understanding the fundamental layout of not only aging, but also the brain itself.


To date, aging neurosciences research is divided across disciplines. The study of age-related molecular switches driving cellular processes from stem cells to mature neurons is, to some extent, studied separately from how the switches are genetically determined, or the process in which environmental factors such as stress, sex-specific events such as menopause, nutrition or even climate affect the blueprints. In addition, the functional manifestations of aging encompassing cognitive, motor, and emotional age-related changes are often studied as separate entities. The challenge, therefore, is to unite the fields into closer approximation to allow a constructive input and open synergetic dialogue between these closely related research entities.

As I might have mentioned once or twice in the recent past, we're due a decade or so of synthesis in the life sciences. Of fields merging, of threads woven from disparate and unconnected parts of the research community, of things suddenly making sense when many different viewpoints are summed together. Biology is so ridiculously complex that any one research group is often as not enmeshed in their own tiny thicket of the vast forest, toiling away at a hard problem and generating data that might one day become a small part of a therapy or medical breakthrough. Progress towards the practical application of life science research is beginning to depend as much upon synthesists - scientists who work to link together the output of many different groups - as it does upon those mining the great unknown to generate new knowledge.

ResearchBlogging.orgSmith, M. (2009). Walking toward a convergence in aging research Frontiers in Neuroscience, 3 (1) DOI: 10.3389/neuro.01.012.2009

If HDL is Good, Why Not Make More Of It?

Here is an intriguing line of thinking: if we can identify unambiguously beneficial components of our metabolism, why not make artificial replicas and flood the body with them? "The particles that ferry cholesterol through the bloodstream are popularly known as 'bad' or 'good': bad if they deposit cholesterol on vessel walls, potentially clogging them; good if they carry the cholesterol on to the liver for excretion. Now scientists have created tiny particles in the laboratory that mimic those good carriers, scooping up the cholesterol before it can grow into dangerous deposits of plaque. The surfaces of these new particles are coated with fats and proteins so they can bind tightly with the sticky cholesterol to transport it through the bloodstream. ... Researchers have endowed these artificial particles with the same properties as natural particles that circulate in the blood, [called] high-density lipoproteins, or HDL ... The artificial carriers can clean up sites where plaques can otherwise rupture, leading to strokes and heart attacks."


Another Approach Versus Metastasis

The real killer in cancer is its spread within the body: metastasis. A reliable method of eliminating metastasis would go a long way to making cancer just a bad, treatable condition rather than the end of life for a quarter of us. Here is one approach: researchers have "found a way to capture tumor cells in the bloodstream that could dramatically improve earlier cancer diagnosis and prevent deadly metastasis. ... researchers can inject a cocktail of magnetic and gold nanoparticles with a special biological coating into the bloodstream to target circulating tumor cells. A magnet attached to the skin above peripheral blood vessels can then capture the cells. ... By magnetically collecting most of the tumor cells from blood circulating in vessels throughout the whole body, this new method can potentially increase specificity and sensitivity up to 1,000 times compared to existing technology ... Once the tumor cells are targeted and captured by the magnet, they can either be microsurgically removed from vessels for further genetic analysis or can be noninvasively eradicated directly in blood vessels by laser irradiation through the skin that is still safe for normal blood cells."


Overpopulation: Too Many Damned Malthusians

This world of ours is not overpopulated. There is no overpopulation. A great many aspects and consequences of human society and human nature are wrong, unpleasant, and downright malign - but a lack of resources or space is not on that list. Where there is suffering, hunger, and inhumanity to others, you will inevitably find it taking place amidst the squandered potential for plenty: resources left untapped; poverty run rampant thanks to political kleptocracies; meaningless war and destruction instead of trade to benefit all sides.

But the iconic Malthusian looks at the mess made of some parts of the world and doesn't see mismanagement. Instead he sees nothing more than too many people - which means that his proposed "solutions" are varying degrees of useless, counterproductive, and outright evil. Unfortunately, iconic Malthusians are everywhere. Malthusian thinking suffuses modern environmentalism. An entire generation of Western civilization is taught overpopulation as an uncritical fact.

By far and away the most common reason I see given these days in opposition to engineered longevity is fear of overpopulation. Environmentalism has become almost a religion in its own right now, and many strands of that religion are essentially death cults: loose networks of like-thinking people who fervently believe, for whatever reasons, that the world is dying, that humans already live too long, and that people should be forced to relinquish technology and return to a simpler era. Extreme fringe variants of the environmentalist death cult really do stand for the complete destruction of humanity, but even supposedly reasonable, middle of the road people are influenced by deathist environmentalism to the point at which it is seen as reasonable to say that (a) too many people exist, and therefore (b) the unending horror, pain, and suffering of death by aging is necessary.

A sterling article at Spiked Online hits all the right points:

In the year 200 AD, there were approximately 180 million human beings on the planet Earth. And at that time a Christian philosopher called Tertullian argued: 'We are burdensome to the world, the resources are scarcely adequate for us… already nature does not sustain us.' In other words, there were too many people for the planet to cope with and we were bleeding Mother Nature dry.


In the early 1800s, there were approximately 980 million human beings on the planet Earth. One of them was the population scaremonger Thomas Malthus, who argued that if too many more people were born then 'premature death would visit mankind' - there would be food shortages, 'epidemics, pestilence and plagues', which would ‘sweep off tens of thousands [of people]’.


In 1971 there were approximately 3.6billion human beings on the planet Earth. And at that time Paul Ehrlich, a patron of the Optimum Population Trust and author of a book called The Population Bomb ... He said India couldn’t possibly feed all its people and would experience some kind of collapse around 1980.


What this potted history of population scaremongering ought to demonstrate is this: Malthusians are always wrong about everything.

Malthusianism is, in essence, yet another facet of some peoples' inability to see change in the world around them. Some folk see only what is, refusing to acknowledge what will be. Which is a strange state to be in given the rampant pace of technological advancement at present. New and better resources to meet any level of demand will be developed, and thanks to the operation of markets, entrepreneurs, and competition, will be developed well in advance of need. That is what we humans excel at accomplishing. More people in the world means more demand for resources, more rewards for those who find new and better ways to satisfy those demands, more opportunity for development, more minds working on science and technology, more new and improved resources developed to replace old ones.

This is the way the world has always worked, all through those centuries of Malthusian cries that the sky is falling. The Malthusians have always been absolutely, completely wrong. This is the way the world works now - and the living Malthusians are just as wrong as all their ideological ancestors.

Complicating Alzheimer's

Much of the Alzheimer's research community is focused on removing the characteristic buildup of amyloid-beta from the brain. Amyloid and Alzheimer's are linked, so remove the amyloid. As the tools of biotechnology improve, however, matters begin to look more complicated. For example: "recent research demonstrates that amyloid-beta is also necessary to maintain proper brain functioning. ... Without amyloid-beta, a normal product of cellular metabolism, one's ability to learn and remember could be profoundly damaged, so drugs currently in development to eliminate amyloid-beta could be rendered obsolete. ... By studying synapses in brain slices of healthy mice and in neuronal networks growing in vitro, [researchers] determined that there is an optimal amount of amyloid-beta needed to keep the neurons working well. ... if this precise balance is even slightly disturbed, the effectiveness of information transfer between neurons is greatly impaired. ... amyloid-beta peptide, believed to be toxic, regulates the type of information that neurons transfer."


Fat and Dementia Risk

Yet another study showing the risk you run by letting your body amass fat unchecked in middle age: "Women who store fat on their waist in middle age are more than twice as likely to develop dementia when they get older ... Anyone carrying a lot of fat around the middle is at greater risk of dying prematurely due to a heart attack or stroke. If they nevertheless manage to live beyond 70, they run a greater risk of dementia. ... The research is based on the Prospective Population Study of Women in Gothenburg, which was started at the end of the 1960s when almost 1,500 women between the ages of 38 and 60 underwent comprehensive examinations and answered questions about their health and lifestyle. A follow-up 32 years later showed that 161 women had developed dementia, with the average age of diagnosis being 75. This study shows that women who were broader around the waist than the hips in middle age ran slightly more than twice the risk of developing dementia when they got old. However, the researchers could find no link to a high body mass index (BMI). ... Other studies have shown that a high BMI is also linked to dementia, but this was not the case in ours. This may be because obesity and overweight were relatively unusual among the women who took part in the Prospective Population Study."


Fear of Aging is Absolutely Rational

Are you afraid of getting older? You should be. Degenerative aging isn't pretty. That said, we live in an era characterized by a fascination with youth; aging and the old are put to one side, and the ugly details of the way in which the body and mind break down are glossed over or shoved under the carpet. Move on a step from that and you'll see the bevy of folk trying to sell you the message that aging into frailty and death before you're ready is just fine - that you shouldn't worry about it, that you should just relax into your life being taken from you, one piece at a time.

But those talking heads are spouting nonsense. You should absolutely be afraid of aging.

Wouldn't you be somewhat scared by an implacable man coming to steal your kidney, half your liver, and feed you poison that will waste way your muscles? Of course you would. The end result of the damage of aging is just as intimidating. Apologism for and acceptance of degenerative aging is a sort of Stockholm syndrome, if you ask me. Invisible forces hold you hostage, threatening you with a future of pain, suffering, and frailty - and based on what you've seen happen to others, the situation looks like ending badly for you. Under these circumstances, human psychology tilts in favor of (a) assigning imaginary faces and personalities to impersonal processes, and (b) trying to stay on the jailer's good side.

So you have people trying to accommodate aging; play a game of give and take, and strive to accept what happens as their physiology decays. Which is madness. The relationship between humanity and aging should better fit a war story, not a tale of slavery and acceptance. How are we going to dig ourselves out of this pit if all we do is pretend that things will be fine - or if not fine, at least acceptable?

Aging is a horror, but it isn't supernatural. It is the result of physical processes operating on the biological systems of our bodies. Physics, chemistry, biology. These are biological systems that can be repaired, replaced, and restored: medicine, therapies, biotechnology. But we need to develop the means to achieve that end: technologies capable of repairing and reversing aging are foreseen, proposed, and carefully described - just not yet researched and developed.

If we all sit back and accept the suffering that lies ahead, then medicines to fight aging will never be developed. It seems an easy choice to me, but I still hear those talking heads telling us that aging is just fine, and we should give in to it. So not all of us are sane and well informed, it seems.

On Investment in the Longevity Trend

That investment advisors are discussing the prospects for engineered longevity at all is more of an indicator than what they actually say. Nonetheless, these are words of wisdom: "I was at dinner with some friends and the conversation turned to the topic of undiscovered investment opportunities. One of my nominations for undiscovered investment theme was life extension technology. ... The natural winner in life extension is the biotechnology industry. But not so fast! The real winners may not be available for investment. Here is a case in point. Back in 1979-80, I correctly identified the microcomputer (they were called microcomputers back then as IBM didn't introduce the PC until August 1981), would be the growth industry of the future. I told anyone who listened that the microcomputer would be as common as the office photocopier in five years. I was wrong, it was more common than the photocopier as there were multiple PCs in most offices. Who were the major publicly listed players in the microcomputer then? They were Commodore, Tandy (Radio Shack) and Atari, which was a division of Warner Communications. Apple hadn't gone public yet and hadn't gotten into the business at the time. Microsoft was just a small private concern. This story shows that it is possible to identify a long-term trend, but the winners may not be available to the ordinary investor for quite some time."


Roots of Age-Related Hearing Loss

From ScienceDaily: "Age-related hearing loss is a very common symptom of aging in humans, and also is universal among mammal species, and it's one of the earliest detectable sensory changes in aging. ... In mice, the new study shows that the damage starts with free radicals, which are key suspects in many harmful changes of aging. Free radicals trigger a process called apoptosis, or programmed cell death, by which damaged cells 'commit suicide.' Apoptosis is often beneficial, as it eliminates cells that may be destined for cancer. Before the study, it was already clear [that] aging was associated with a major loss of hair cells and ganglion cells, so it was plausible that programmed cell death was playing a role in hearing loss. We also thought that oxidative stress - the presence of free radicals - contributes to age-related hearing loss, so we put two and two together and showed that oxidative stress does indeed induce age-related hearing loss. ... [Researchers] found that the suicide program was operating in hair cells and spiral ganglion neurons, and that the suicide program relied on activity in a suicide gene called bak. Activity of the bak gene [is] required for the development of age-related hearing loss. The strongest evidence for this was the fact that a strain of mice that did not have the bak gene did not show the expected hearing loss at 15 months of age."


A Little Intermittent Fasting Research

The dominant topic for this past week of posts was the beneficial biochemistry of eating less; changes to gene expression and metabolism, enhanced health and extended longevity. That wasn't an intentional choice - it just worked out that way as various items caught my eye. All the same, why not round it off with an paper on intermittent fasting research, noticed by the folk who keep stocked.

Intermittent fasting and calorie restriction are two ways of reducing your calorie intake to obtain health benefits. Intermittant fasting might be accomplished by eating every other day, for example, while calorie restriction means eating every day, but eating less. In both cases, you have to make sure your intake of micronutrients is optimal, and your physician agrees, as for any sane dietary choice.

The paper is a demonstration that intermittent fasting quickly hits one of the same biochemical triggers as calorie restriction: TOR, or target of rapamycin, which in turn boosts the process of autophagy:

In many organisms, dietary restriction appears to extend lifespan, at least in part, by down-regulating the nutrient-sensor TOR (Target Of Rapamycin). TOR inhibition elicits autophagy, the large-scale recycling of cytoplasmic macromolecules and organelles.

More autophagy is a good thing; more aggressively cleaning out damaged cellular components should extend functional life span by lowering the rate at which further damage accumulates, and there is a fair weight of scientific evidence behind that viewpoint. In any case, here is the intermittent fasting study; notice that some changes in metabolic operation show up very quickly in response to changing dietary intake:

Intermittent fasting (IF) was shown to increase whole-body insulin sensitivity, but it is uncertain whether IF selectively influences intermediary metabolism. ... Glucose, glycerol, and valine fluxes were measured after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers ... Phosphorylation of mTOR was significantly lower after IF than after the SD.

The cost of running small, quick studies of this sort in humans is fairly low - certainly far lower than your average study of metabolism and aging in mice and rats. This cost will only fall as the tools of biotechnology become better and cheaper. Given that, I'd expect to see many more studies over the next few years that carefully compare the initial metabolic response of various mammals - humans included - to a lower calorie intake. In theory that should lead to a better handle on how the long-term effects of calorie restriction or intermittent fasting will play out in humans.

An Interview on CR With Luigi Fontana

Here's a calorie restriction (CR) article I missed from earlier this month: "If anyone is in a position to assess the risks and benefits of CR, it is Dr. Luigi Fontana, research associate professor of medicine at Washington University. He is overseeing a group of 50 patients involved in an 11-year study of calorie restriction. The study is part of CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a large clinical trial being funded by the National Institute on Aging ... Why is CR controversial in the United States? Dietitians seem opposed to this. ... First of all, probably most dietitians don't have knowledge about calorie restriction. These are pretty new data. Before they were only on mice and rats. So they say, 'OK, mice and rats, who cares about mice and rats?' And so this is a pretty new phenomenon, and any time there is a new phenomenon, there are a lot of people who say, 'No, no, no, no, no!' It's a typical reaction to something that is new. ... All the metabolic, hormonal and cellular adaptations so far we have seen in mice and rats, we know they are living longer, not only healthier but longer. We know that is also happening in monkeys and in humans."


Building Skin From Stem Cells

Researchers have succeeded in tissue engineering fully functional and complete skin patches from stem cells: the scientists recreated "a whole epidermis from human embryonic stem cells. The goal is to one day be able to propose this unlimited resource of cells as an alternative treatment in particular for victims of third degree burns and patients with genetic diseases affecting the skin. ... Human embryonic stem cells (hES) have two fundamental characteristics: a capacity for unlimited proliferation and pluripotency i.e. the capacity to differentiate into all the cell types in the human body. The first objective of the team was to obtain skin stem cells (keratinocytes) similar to those naturally present in the human epidermis from hES cells. Keratinocytes, permit the constant renewal of the skin. Once this stage was achieved, the second objective of the researchers consisted in finalising strategies to isolate keratinocyte stem cells in order to test their capacity to reconstitute a functional epidermis firstly in vitro -- then in vivo. ... Twelve weeks after transplantation, the mice presented localized areas of completely normal and functional adult human epidermis containing all the skin cell types."


Another Candidate for Lynchpin Gene Controlling Calorie Restriction

One of the better research outcomes a biologist can hope for is to find that a particular mechanism, disease, or benefit has a single point of control somewhere in its web of interlinked genes and feedback loops. A single gene or protein that acts as a switch or a dial, and has no or few entanglements with other biological systems. That lack of entanglements is important - a switch that turns one thing off and three other things on isn't of much use, at least for those of us who like our medicine without potentially lethal side-effects, but human biochemistry contains far more multi-switches than examples of any simpler construction. Evolution is based upon the promiscuous reuse of components, and almost any protein of note involved in regulating metabolism has more than one duty to perform.

In any case, researchers engaged in picking apart the mechanisms underlying calorie restriction might still manage to uncover a simple switch somewhere in amidst the all complexity and chains of genes and proteins turning one another on and off. They've been hacking away the brush for some years now, but there's no shortage of undergrowth yet to be cleared. You might see hints of a possible simple switch in the fact that autophagy is required for the longevity benefits of calorie restriction - disable autophagy and you disable calorie restriction. But autophagy is a complex process in and of itself. More brush to clear.

Here is a recent paper that looks at another potential candidate protein that might be manipulated to induce some the biochemical benefits of calorie restriction without the dietary change. (Though given that some of those benefits stem from a lack of visceral fat tissue caused by eating less, it seems unlikely that a manipulation of this sort would capture all the benefits of actually practicing CR). You might look at the open access original at PLoS Biology, or this more carefully explained piece in the popular science press:

Dietary restriction induces a transcription factor called CREB-binding protein (CBP), which controls the activity of genes that regulate cellular function. By developing drugs that mimic the protective effects of CBP - those usually caused by dietary restriction - scientists may be able to extend lifespan and reduce vulnerability to age-related illnesses.

"We discovered that CBP predicts lifespan and accounts for 80 percent of lifespan variation in mammals," said Dr. Mobbs.


We showed that dietary restriction activates CBP in a roundworm model, and when we blocked this activation, we blocked all the protective effects of dietary restriction,"


Dr. Mobbs hypothesizes that dietary restriction induces CBP by blocking glucose metabolism, which produces oxidative stress, a cellular process that leads to tissue damage and also promotes cancer cell growth. Interestingly, dietary restriction triggers CBP for as long as the restriction is maintained, suggesting that the protective effects may wear off if higher dietary intake resumes. CBP responds to changes in glucose within hours, indicating genetic communications respond quickly to fluctuations in dietary intake.

That last part matches with other work that shows the changes in biochemistry and metabolism accompanying calorie restriction take effect quite rapidly. The real benefits - the enhanced health and increased longevity observed in laboratory animals - stem from maintaining that metabolic state over time.

ResearchBlogging.orgZhang, M., Poplawski, M., Yen, K., Cheng, H., Bloss, E., Zhu, X., Patel, H., & Mobbs, C. (2009). Role of CBP and SATB-1 in Aging, Dietary Restriction, and Insulin-Like Signaling PLoS Biology, 7 (11) DOI: 10.1371/journal.pbio.1000245

ACT Aiming for Human Stem Cell Trials

Advanced Cell Technology (ACT), one of the oldest companies formed specifically to develop regenerative medicine, is setting up for another round of human trials based on its work: "it has asked for approval to test human embryonic stem cells in treating a rare cause of blindness. The company said it filed an IND, an investigational new drug application, with the U.S. Food and Drug Administration to use the stem cells to treat patients with Stargardt's macular dystrophy. If approved, it would be the second U.S. approval to test human embryonic stem cells in human patients. ... ACT has previously reported it used human embryonic stem cells to make retinal cells. They have reversed blindness in rats. ... The treatment for eye disease uses stem cells to re-create a type of cell in the retina that supports the photoreceptors needed for vision. These cells, called retinal pigment epithelium (RPE), are often the first to die off in Stargardt's macular dystrophy. ... It has been over a decade since human embryonic stem cells were first discovered. The field desperately needs a big clinical success. After years of research and political debate, we're finally on the verge of showing the potential clinical value of embryonic stem cells. Our research clearly shows that stem cell-derived retinal cells can rescue visual function in animals that otherwise would have gone blind. We are hopeful that the cells will be similarly efficacious in patients."


Aubrey de Grey on, November 30th

From CNN: "This special edition of Vital Signs: The Clinic will be broadcast LIVE on [on November 30th] and we want you to take part in the conversation. ... Vital Signs host and CNN Chief Medical Correspondent, Dr. Sanjay Gupta will be joined by best-selling author Dan Buettner who has done extensive studies on the areas in the world people live the longest, healthiest lives, known as Blue Zones, and shares their formula for a long life.
The other panelist is geneticist Dr. Aubrey de Grey, who believes regenerative medicine could, in a matter of decades, extend life expectancy to 1000 years. What would you ask the experts? Do you want to learn how to live until 100 and beyond? Or find out which diets or exercise to follow for living longer?" These are good examples of the two very opposite ends of the respectable pro-longevity community. The Blue Zones material is (to be charitable) just a branding of what is known of the relationship between good health practices in diet and exercise and human longevity. Aubrey de Grey's Strategies for Engineered Negligible Senescence, on the other hand, are a serious examination of how to greatly extend healthy human life span through near-future research and development.


The Benefits of Increased PGC-1alpha Expression

A short introduction to the gene PGC-1alpha: this is one of a number of genes of interest involved in the biochemical changes, resistance to age-related disease, and extended healthy life span brought about by calorie restriction (CR). It favorably changes the operation of mitochondria, and based on the effects of other genes and proteins involved in these mechanisms, I would expect enhanced expression of PCG-1alpha to have at least some modest beneficial effect on life span. That said, I'm not aware of any life span studies involving PCG-1alpha manipulation, but there is a fair amount of published research out there on its more immediate effects.

For a longer introduction, including some explanation as to why mitochondria are so important to aging and longevity, you might look back in the archives. Every gene and protein in the regulatory networks surrounding mitochondrial operation potentially determines some portion of the rate at which an individual ages:

Our understanding of the complexity of signalling pathways to and from the mitochondria is increasing, describing a network through which mitochondria may communicate functional status to the nucleus to impact cellular function. Metabolic reprogramming by CR may be central to the mechanism of lifespan extension, where changes in mitochondrial function confer an energetic shift that is conducive to increased cellular fitness, resulting in the promotion of longevity.

Here's a recent paper demonstrating increased PGC-1alpha expression in mice to share a few more of the established benefits of calorie restriction:

Aging is a major risk factor for metabolic disease and loss of skeletal muscle mass and strength, a condition known as sarcopenia. Both conditions present a major health burden to the elderly population. Here, we analyzed the effect of mildly increased PGC-1alpha expression in skeletal muscle during aging. We found that transgenic MCK-PGC-1alpha animals had preserved mitochondrial function, neuromuscular junctions, and muscle integrity during aging. Increased PGC-1alpha levels in skeletal muscle prevented muscle wasting by reducing apoptosis, autophagy, and proteasome degradation.

The preservation of muscle integrity and function in MCK-PGC-1alpha animals resulted in significantly improved whole-body health; both the loss of bone mineral density and the increase of systemic chronic inflammation, observed during normal aging, were prevented. Importantly, MCK-PGC-1alpha animals also showed improved metabolic responses as evident by increased insulin sensitivity and insulin signaling in aged mice.

Our results highlight the importance of intact muscle function and metabolism for whole-body homeostasis and indicate that modulation of PGC-1alpha levels in skeletal muscle presents an avenue for the prevention and treatment of a group of age-related disorders.

I'm not so sure about that claim of reduced autophagy, given the importance of autophagy to mitochondrial function and the benefits of calorie restriction. The rest of it all fits into place with the changes observed in the metabolism of calorie restricted - and consequently longer-lived - mammals, however.

ResearchBlogging.orgWenz T, Rossi SG, Rotundo RL, Spiegelman BM, & Moraes CT (2009). Increased muscle PGC-1{alpha} expression protects from sarcopenia and metabolic disease during aging. Proceedings of the National Academy of Sciences of the United States of America PMID: 19918075

A Presentation on Supercentenarians

From the Age Management Medicine Group, a diagram-rich article based on a presentation given by one of the folk from the Supercentenarian Research Foundation: "A Supercentenarian is anyone age 110 years or older. ... While the number of centenarians has been rising exponentially, the number of supercentenarians has remained flat. ... The most likely cause of death of Supercentenarians is called Senile Cardiac TTR-Amyloidosis ... SRF (Supercentenarian Research Foundation) has performed eight autopsies [of supercentenarians so far and six] of the eight cases have TTR-Amyloidosis as their common cause of death. This is the invisible barrier. ... Why do Supercentenarians live as long as they do? (How do they escape from chronic diseases, such as Heart Disease, Cancer, Stroke, Diabetes, and Alzheimer's Disease, which are the top diagnoses written today on Death Certificates in the US and limit the average life expectancy of older Americans?) Why don't they live longer than they do? (TTR Amyloidosis could be the Grim Reaper waiting in the wings for everyone, unless we figure out what to do about it first)."


Evaluating Autologous Stem Cell Heart Therapies

Even comparatively crude autologous stem cell transplants provide benefits for heart disease patients: "The largest national stem cell study for heart disease showed the first evidence that transplanting a potent form of adult stem cells into the heart muscle of subjects with severe angina results in less pain and an improved ability to walk. The transplant subjects also experienced fewer deaths than those who didn't receive stem cells. In the 12-month Phase II, double-blind trial, subjects' own purified stem cells, called CD34+ cells, were injected into their hearts in an effort to spur the growth of small blood vessels that make up the microcirculation of the heart muscle. Researchers believe the loss of these blood vessels contributes to the pain of chronic, severe angina. ... The stem cell transplant is the first therapy to produce an improvement in severe angina subjects' ability to walk on a treadmill. Twelve months after the procedure, the transplant subjects were able to double their improvement on a treadmill compared to the placebo group."


Ronald Bailey Reports on the Manhattan Beach Project

Ronald Bailey, who has long covered conferences organized by the transhumanist and engineered longevity communities, has an article in Reason Magazine on the recent Manhattan Beach Project longevity summit.

Our first scientific anti-aging conference was held in Manhattan Beach, California over nine years ago. This was no ordinary conference. Rather, it was a high-powered brainstorm session to figure out how to reverse aging. Twelve researchers from around the world combined their genius and their levels of expertise in their specific specialties, and they laid the groundwork for what eventually evolved into a scientific roadmap for full age reversal.


a Longevity Summit under the Manhattan Beach Project umbrella is scheduled for what looks to be [mid-November]. The Summit agenda lists a mix of well known names from the longevity advocacy and aging research communities, speaking on a range of interesting topics.

You should head on over and take a look:

If you’re under age 30, it is likely that you will be able to live as long as you want. That is, barring accidents and wars, you have centuries of healthy life ahead of you. So the participants in the Longevity Summit convened in Manhattan Beach, California, contend. Over the weekend Maximum Life Foundation president David Kekich gathered a group of scientists, entrepreneurs, and visionaries to meet for three days with the goal of developing a scientific and business strategy to make extreme human life extension a real possibility within a couple of decades. Kekich dubbed the effort the Manhattan Beach Project.


Anti-aging research is a rich and varied territory right now. Researchers are finally beginning to get a handle on the actual causes of aging. With this increased scientific understanding, some researchers now believe they are on the way to figuring out how to stop it, and - eventually - how to reverse it.

But read the whole thing; it goes into more detail as to the presenting scientists and their messages. You're also unlikely to find this line elsewhere: "Theoretical biogerontologist, Aubrey de Grey, [is] the energizer bunny of anti-aging scientific research and advocacy." Quite so. You'll find many of the summit presenters mentioned in the context of their research back in the Fight Aging! archives if you care to go digging.

Near to the end of the article there is some speculation and discussion of topics rarely mentioned in the press, but often discussed by the pro-longevity community: why is there so little support for engineered longevity and aging research? To what degree is the scam-ridden, scum-infested "anti-aging" marketplace to blame for public suspicion and disinterest? Why are there so few wealthy people openly funding longevity and aging research, given the potentially great rewards and firm scientific support? And so forth. The community of advocates, entrepreneurs, and researchers interested in the development and application of longevity science lack good answers to these questions. Myself included. But good answers are needed, as they would lead to strategies for fundraising and persuasion that work far more effectively than those used over the past decade or two.

Trial of a Viral Cancer Therapy

One class of the new generation of cancer therapies presently under development uses targeted viruses to kill cancer cells. Here is an example of the type: "BioVex Inc, a company developing new generation biologics for the treatment and prevention of cancer and infectious disease, announced today that the data from its completed Phase 2 clinical study ... [the therapy] is a first-in-class oncolytic, or cancer destroying virus, that works by replicating and spreading within solid tumors (leaving healthy cells unaffected), thereby causing cancer cell death and stimulating the immune system to destroy un-injected metastatic deposits. Both modes of action have been clearly validated in the clinic, where multiple patients with metastatic disease progressing at enrollment have been declared disease free. ... Previous clinical trials have enrolled patients with breast cancer, melanoma, head and neck cancer and pancreatic cancer, with indications of clinical activity being observed in each. The Company recently commenced a Phase 3 study in metastatic melanoma." Therapies with few side effects and even low rates of success against metastatic cancer are a big deal. The success rate will only improve with time, and is already far greater than that of any presently widespread treatment option.


Cryonics and Wealth Preservation

A piece at h+ Magazine briefly examines the efforts of members of the cryonics community to set up legal frameworks that stand a good chance of preserving wealth across decades of being considered legally dead. In the long term, you can't take it with you: any undefended resource will eventually be stolen one way or another, no matter what laws and contracts say. But in the shorter term, and for small groups of people, this legal approach is a fair strategy: "The laws are complicated, and not stacked in your favor, but if done carefully it's possible to leave a huge death benefit payoff from your life insurance policy to your cryonically-preserved self. And since life insurance can also be used to finance your cryopreservation, you need not wait until you are rich to sign up. Most in the middle class, if they seriously want it, can afford it now. So by taking the right steps, you can look forward to waking up one bright future morning from cryopreservation the proud owner of a bank account brimming with money. Don't get me wrong. Leaving money to your future self is complicated. The courts have decided that cryopreserved people are not suspended or preserved. Rather, they are irrevocably dead, and by being dead have no legal right of ownership or inheritance. These laws may change if the first cryopreserved people are resuscitated and sue for some new kind of civil rights, but that could be decades away. In the meantime, those who are not yet being preserved have spent years pondering and discussing possible methods of self-inheritance. They call it Cryonics Estate Planning and there are now at least three ways to achieve the goal."


Human Calorie Restriction Studies Continue Apace

Studies of the biochemistry of calorie restriction (CR) in humans are being held in a number of research institutes in the US. So far, as expected, the beneficial biochemical changes caused by CR in humans look very much like the biochemical changes observed in mice, rats, and rhesus monkeys. That bodes well for a gain in human life span as a result of this practice, though at the present level of available biotechnology there is little option but to wait and see what the results will be on that count. The consensus amongst biogerontologists appears to be that CR will extend human life span by a handful of percentage points, but practitioners of calorie restriction would be expected to evade or resist all of the common age-related diseases.

Biologist Michael Rose, known for his work on aging in flies, is a calorie restriction (CR) skeptic, it would seem. He and John Phelan have developed a mathematical model that predicts a "lifetime of low-calorie dieting would only extend human life span by about 7 percent, unlike smaller animals, whose life spans are affected more by the effects of starvation. ... Longevity is not a trait that exists in isolation; it evolves as part of a complex life history, with a wide range of underpinning physiological mechanisms involving, among other things, chronic disease processes."

Bear in mind that estimates for the expected difference in human life span between people who exercise regularly and people who do not exercise regularly are in the range of 10 years, give or take a few years. There is no medical technology available today that can achieve anywhere near these sorts of results.

In any case, you might look at this recent paper which examines CR in healthy, thin people:

Calorie restriction (CR) slows aging and is thought to improve insulin sensitivity in laboratory animals. In contrast, decreased insulin signaling and/or mild insulin resistance paradoxically extends maximal lifespan in various genetic animal models of longevity. Nothing is known regarding the long-term effects of CR on glucose tolerance and insulin action in lean healthy humans.

In this study we evaluated body composition, glucose, and insulin responses to an oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had been eating a CR diet for an average of 6.9 +/- 5.5 years, (mean age 53.0 +/- 11 years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28 age- and sex-matched sedentary controls eating Western diets (WD).

We found that the CR and EX volunteers were significantly leaner than the WD volunteers. Insulin sensitivity [was] significantly higher in the CR and EX groups than in the WD group (P = 0.001). Nonetheless, despite high serum adiponectin and low inflammation, approximately 40% of CR individuals exhibited an exaggerated hyperglycemic response to a glucose load. This impaired glucose tolerance is associated with lower circulating levels of IGF-1, total testosterone, and triiodothyronine, which are typical adaptations to life-extending CR in rodents.

As for other human studies of CR, it shows that the CR metabolism is better set up for long term health and avoidance of age-related disease.

ResearchBlogging.orgFontana L, Klein S, & Holloszy JO (2009). Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokine production. Age (Dordrecht, Netherlands) PMID: 19904628

Thoughts on Regenerative Medicine

From the Times: "Over the past decade increasing understanding of both adult and embryonic stem cells has opened a new frontier for science through regenerative medicine. As research has revealed how the body's master cells can be coaxed to form new tissue, it has raised the prospect of producing new organs to replace those that have been damaged. Growing new cells with specialised functions, however, is only the first hurdle that has to be cleared before regenerative medicine can help patients. A clump of cells is rarely, by itself, much use to anybody. They also need to be properly plumbed into blood vessels, to be protected from the body's immune system and to be structured in a shape that allows them to perform. This means that regenerative medicine is not reliant only on the cell biologists who can coax stem cells to make the right sort of tissue. It also needs engineers and immunologists. It is by its nature an interdisciplinary field. ... As fast as this technology is advancing, however, there is still a long way to go before scientists can re-create more complex organs. Professor Hollander said: 'The early successes have involved organs without moving parts or complicated biology.' The creation of new breasts, windpipes and bladders is an amazing step forward for medicine, but it remains a different challenge to grow new hearts or livers."


Tissue Engineering the Breast

From the BBC: "Researchers in Australia plan to test a medical 'scaffold' designed to stimulate natural breast tissue to regrow following surgery. Doctors [will] test the technique next year in a trial involving six patients. The team say that the permanent fat found in breasts can be grown inside this contoured scaffold. They claim to have successfully tested the device in pigs. ... when the 'empty chamber' is implanted, fat tissue will naturally fill it to form a new breast. This chamber will also contain a gel made using the patients' muscle cells to 'induce fat tissue production'. ... the attractions of this approach were its simplicity and the fact that the tissue growth occurred inside the body. ... At the time of implanting the cells the surgeon redirects the vasculature of the body which keeps a good blood supply to the implant. That is in itself nothing new, but combining it with a cell implant is an interesting step. ... the technological advance was the use of a biomaterial cage used to trap the cells in the right place. In future, the team plan to make this cage biodegradable so it does not have to be removed."


Methuselah Foundation PSA Videos

I'm slipping behind the times here, it seems; the recently produced batch of Methuselah Foundation public service announcement video slots were mentioned by the deathist authors at Futurisms before that topic made it to the head of my "yet to post" list. Those folk write well, actually; it is a pity that they feel, like Leon Kass, that the spirit and purpose of their conservatism is to stand in support of present suffering and barbarism against a bright future of cures, change, and progress. History will judge them unkindly, if it recalls them at all.

In any case, here are some of the videos that the Methuselah Foundation volunteers have been working on of late. See what you think:

The Manhattan Beach Project

I see that David Kekich's Manhattan Beach Project meeting this month is getting some local press attention. He's an ambitious fellow, looking for ways to persuade enough money into the right projects to achieve SENS-like timelines for rejuvenation science: "David Kekich plans to end aging by the year 2029. Sound far-fetched? 'It know it sounds fictional,' the businessman said, 'but it's all based on hard, solid science. It will happen, it's just a matter of when.' He and more than a dozen scientists and researchers from the across the country will gather this weekend in Manhattan Beach for a three-day summit to design a plan for raising the necessary capital - 'only a few billion dollars,' he predicts - and the technology to lengthen human life spans within the next two decades. Dubbed the 'Manhattan Beach Project' after the secret atomic-bomb-building Manhattan Project of the 1940s, Kekich and his crew will 'collaborate on a battle plan to seek out and conquer anything that stands in the way of increased human life span,' according to press materials. ... human life span will continue to rise. ... For that reason alone, Kekich says this is a wise business investment - demand for services that extend life will be in huge demand, he predicts. ... We lose about 100,000 people to aging every day. We lose their talents, their relationships, their ability to solve problems. People are really at their peak in terms of talent at this age.'"


Can Memory Fill Up?

That human memory can "fill up" has long been a staple of science fiction involving radical life extension. It seems like a reasonable projection - we only have so many brain cells - but that doesn't mean it happens in reality. For example, old memories might be consistently erased to make space. But here is an example of research in support of short term memory storage effectively becoming full due to changes that occur with age: "new neurons sprouted in the hippocampus cause the decay of short-term fear memories in that brain region, without an overall memory loss. ... the birth of new neurons promotes the gradual loss of memory traces from the hippocampus as those memories are transferred elsewhere in the brain for permanent storage. Although they examined this process only in the context of fear memory, [researchers say that] all memories that are initially stored in the hippocampus are influenced by this process. ... In effect, the new results suggest that failure of neurogenesis [such as happens with advancing age] will lead to problems because the brain's short-term memory is literally full. ... we may perhaps experience difficulties in acquiring new information because the storage capacity of the hippocampus is 'occupied by un-erased old memories.' ... voluntary exercise, which causes a rise in the birth of new neurons, sped up the decay rate of hippocampus-dependency of memory, without any memory loss."


Myostatin, Muscle Loss, and Patching the Symptoms

Most of the potential applications of new knowledge of human biochemistry aimed at treating age-related degeneration are really just patches. They don't aim to address the underlying causes of degeneration, but rather try to paint over the symptoms. If that was all that was possible, then so be it - but research and development in this age of advancing biotechnology has far greater potential.

Needless to say, there is no clear line separating "patch" from "addresses root causes." Causes cascade, and it's not always fully understood why a particular age-related degeneration exists. A good illustration of this sort of uncertainty can be found in the development of therapies to suppress myostatin and so spur muscle growth, work with potential for treating sarcopenia, or age-related muscle loss. From a recent article:

The researchers tried to use one protein called follistatin to impede the action of another, myostatin, that’s known to inhibit muscle growth. They injected the gene for follistatin into the right legs of six healthy monkeys and after eight weeks, their right legs had grown and were larger than their left legs.

"We created a stronger muscle," said Brian Kaspar, the principal investigator for Nationwide’s research institute. "We also showed that the muscle generated more force."

To deliver the gene, the researchers loaded it onto a so- called adeno-associated virus and injected it into the monkeys. This type of virus is designed to be harmless and is commonly used as a delivery vehicle in gene therapy procedures.

Given that natural human myostatin mutants exist, this sort of thing shows promise. More muscle in the old is better than less muscle, but is this just a patch? Will additional muscle fibers in the old be just as damaged and lacking in strength as those grown without the influence of myostatin? Interestingly, this isn't a straightforward question, as myostatin appears to work through regulation of satellite cells:

In young mice, lack of myostatin resulted in increased satellite cell number and activation compared to wild-type, suggesting a greater propensity to undergo myogenesis, a difference maintained in the aged mice. ... In conclusion, a lack of myostatin appears to reduce age-related sarcopenia and loss of muscle regenerative capacity.

Satellite cells are progenitor cells that build muscle when activated, and their activity declines with age. There is an ongoing debate as to whether this decline - and resulting loss of muscle mass and strength - is due to a reduction in the size of the satellite cell population, or whether the population is still large and capable of action, but other age-related changes in biochemistry block the activation of these progenitor cells. Or both. If the latter situation is largely the case, then manipulation of myostatin starts to look a little less like a patch, and a little more like aiming at root causes - boosting the activity of a cell population that is being recalcitrant. But this doesn't address the layer of causes below that; why age-related changes in our biochemistry cause stem cells to stop working.

The path to the future I'd like to see result from modern biotechnology is a passage from the strategy of patching symptoms to the strategy of addressing root causes. This is a move from present-day inefficiency - and therapies that only postpone the inevitable age-related breakdown of our biochemistry - towards efficiency and the ability to completely prevent age-related degeneration.

More Telomerase in Centenarians

From LiveScience: "The new study, which focused on Ashkenazi Jews, finds those who lived the longest had inherited a hyperactive version of an enzyme called telomerase that rebuilds telomeres. In effect, centenarians tend to have a top-notch body mechanic at work 24/7 repairing the hardware that runs the body, versus a normal person whose body's cellular control center is left to wear out with time. ... Humans of exceptional longevity are better able to maintain the length of their telomeres. And we found that they owe their longevity, at least in part, to advantageous variants of genes involved in telomere maintenance ... [Researchers] studied Ashkenazi Jews, a homogeneous population whose genetics are well-studied. Three groups were part of the research: A very old (average age 97) but healthy group of 86 people; 175 of their offspring; and a control group of 93 offspring of parents who lived a normal lifespan. ... Our research was meant to answer two questions. Do people who live long lives tend to have long telomeres? And if so, could variations in their genes that code for telomerase account for their long telomeres?... 'Yes' on both accounts, the scientists conclude."


The Trouble With Flies

Calorie restriction has such a strong effect on health and longevity in laboratory animals that any study failing to account for it - which is pretty much everything run prior to the mid 1990s - is potentially tainted. You think your treatment is providing benefits? No, it just makes the mice feel unwell, and so they eat less. Similarly, within the realm of deliberate calorie restriction studies, those that fail to correctly control feeding are probably producing incorrect results. No-one said that science was easy, and fly studies - where liquid foods are used - are particularly troublesome: "Recent studies have indicated that flies respond to dilute food solutions by compensatory feeding. The existence of compensation mechanisms calls for a reconsideration of the relationships between diet, feeding behaviour and longevity. This study shows that flies fed on liquid diets, sense sucrose and yeast nutrients and adapt to changes in the quantity and presentation of the two nutrients. ... Compensatory feeding suppresses the beneficial action of dietary restriction on longevity when flies are fed on liquid diets supplemented with yeast extracts. Flies which are given the choice to feed on separate yeast and sucrose food sources were longer lived than flies fed on nutrient mixtures. We conclude [that] food presentation is a major factor which determines the sensitivity of flies to dietary restriction."


Digging Deeper Into p66Shc and Enhanced Longevity

Mitochondria, you will recall, are the power plants of our cells, churning out stored energy in the form of ATP molecules, and pollution in the form of damaging free radicals or reactive oxygen species (ROS). Mitochondria have their own DNA, separate from the DNA in the nucleus of our cells, a legacy of their origin as free-roaming bacteria. Free radicals are very reactive, which means that they can tear apart the biochemical machinery of cells by reacting with crucial components. This free radical pollution is at the heart of the mitochondrial free radical theory of aging, which presents a large component of the aging process as essentially a runaway feedback loop: mitochondria damage themselves via their own free radicals, making them produce even more free radicals. This in turn leads to cells overtaken by that pollution, and which throw free radicals out into the body to cause widespread harm as the years pass.

Thus mitochondria are considered to be important: changes in genes that alter the operation of mitochondria can cause dramatic shifts in life span in mice. Differences in mitochondrial biochemistry are correlated with differences in life span between similar species. Mitochondria are involved with cellular programmed death mechanisms, and mitochondrial damage is possibly a cause of the telomere shortening that happens with age. Everywhere you look in the metabolism of aging, there are roads that lead to the thousands of mitochondria that flock within each of your cells.

If you look back into the 2007 Fight Aging! archives, you'll find an introductory post on p66Shc, a mitochondrial longevity mutation in mice that has been known for a decade or so. This might be viewed as a lever with which researchers can pry open the secrets of mitochondrial operation and its relationship to life span - and pry they have. It's slow work, however:

If you look back in the literature available online, you'll see going on for ten years of work on the topic of p66Shc; scientists picking away at the knot, inch by inch. It's a complex subject. But the discussions are not that much further along now - the general outline is much the same - and I don't hold out a great deal of hope that they'll be significantly and materially advanced in 2017 either. There are only so many scientists, and a great deal of biochemistry to cover. In many ways, the tools of modern biotechnology have already greatly exceeded the management capacity of the scientific community - we can collect far more data per unit time than can be usefully turned into knowledge at this time.

In that post, I go on to make my usual point: that this is a good illustration of the nature of metabolic manipulation as a way to enhanced human longevity. It's hard, and it's a very, very long road. A better road exists - meaning the Strategies for Engineered Negligible Senescence and similar work that focuses on reversing known biochemical changes of aging rather than trying to re-engineer our genes and metabolism to merely slow the rate at which those changes occur.

But in any case, if you haven't bought into that point of view by now, one more repetition isn't going to do it. Let me instead return to p66Shc, and a recent open access paper (with a PDF version) in which researchers peel away another layer of the onion:

A decrease in Reactive Oxygen Species (ROS) production has been associated with extended lifespan in animal models of longevity. Mice deficient in the p66Shc gene are long-lived, and their cells are both resistant to oxidative stress and produce less ROS.


Thus, p66Shc deficiency causes a defect in activation of the PHOX complex that results in decreased superoxide production. p66Shc-deficient mice have recently been observed to be resistant to atherosclerosis, and oxidant injury in kidney and brain. Since phagocyte-derived superoxide is often a component of oxidant injury and inflammation, we suggest that the decreased superoxide production by PHOX in p66Shc-deficient mice could contribute significantly to their relative protection from oxidant injury, and consequent longevity.

Superoxide is, as they point out, sufficiently reactive and dangerous to biochemical constructs to be used as a kill mechanism by the immune system. The proposed longevity-inducing mechanism in the paper above adds to two other proposed mechanisms in the archive post I pointed out - everything in the biochemistry of our cells is connected to multiple processes and structures, and removing p66Shc does more than just lower superoxide production. Nothing is simple in biology!

ResearchBlogging.orgTomilov, A., Bicocca, V., Schoenfeld, R., Giorgio, M., Migliaccio, E., Ramsey, J., Hagopian, K., Pelicci, P., & Cortopassi, G. (2009). Decreased superoxide production in macrophages of long-lived p66Shc-knockout mice Journal of Biological Chemistry DOI: 10.1074/jbc.M109.017491

Fuel for the Debate Over DNA Damage and Aging

While the general consensus in biogerontology circles appears to be that nuclear DNA damage contributes to degenerative aging, this is far from a settled claim. Here is a correlation that should add fuel to the fire: "The identification of the cellular mechanisms responsible for the wide differences in species lifespan remains one of the major unsolved problems of the biology of aging. We measured the capacity of nuclear protein to recognize DNA double strand breaks (DSB) and telomere length of skin fibroblasts derived from mammalian species that exhibit wide differences in longevity. Our results indicate DNA DSB recognition increases exponentially with longevity. Further, an analysis of the level of Ku80 protein [involved in DSB repair] in human, cow, and mouse suggests that Ku levels vary dramatically between species and these levels are strongly correlated with longevity. In contrast mean telomere length appears to decrease with increasing longevity of the species, although not significantly. These findings suggest that an enhanced ability to bind to DNA-ends [such as via the action of Ku80] may be important for longevity." In other words a better ability to repair double strand breaks in DNA correlates with species longevity. If you head over to the Fight Aging! archives for 2004 you'll find discussion of a theory of aging based on double strand breaks.


An Alternative to p53 For Shutting Down Cancers

News from the cancer research community: "more than half of all human cancers have mutations that disable a protein called p53. As a critical anti-cancer watchdog, p53 masterminds several cancer-fighting operations within cells. When cells lose p53, tumors grow aggressively and often cannot be treated. ... [Researchers] have succeeded in shutting off the growth of tumors in which p53 is missing by turning up the production of TAp63 proteins, which make up one class of proteins produced by the p63 gene. TAp63 completely blocked tumor initiation, the team found, by inducing senescence, a state of growth arrest in which tumor cells are still metabolically alive but fail to divide. More importantly, turning up the levels of TAp63 in cells that did not have p53 blocked the progression of established tumors in mice. ... Tumor growth continued in the placebo group, with the tumors becoming five times larger within a week. In contrast, the tumors in the mice [producing TAp63] were abruptly shut down, and the tumors even shrank in size. Mills speculates that the tumor cells disappear because the newly senescent cells might attract the attention of the immune system, which have the ability to destroy them."


The Prospects for Engineering Enhanced Memory

As researchers uncover the mechanisms by which memories are formed and the structures within which they are stored, the day on which memory can be artificially enhanced grows nearer. Just as important as increasing the ability to remember in healthy, young people, however, is the ability to halt and reverse the decline of memory in the old and the frail. Some earlier posts from this year's archive illustrate the sort of investigations and theorizing presently taking place:

For my money, some of the most interesting results turning up these days involve the identification of single genes - and the proteins produced from their blueprint - that are crucial to the formation of memory. The expression of these genes might plausibly be adjusted to enhance memory, but the first item of business is to find them. As is usual in this sort of research, the importance of these proteins is confirmed by removing them and observing the results:

The ability to convert new sensory impressions into lasting memories in the brain is the basis for all learning. Much is known about the first steps of this process, those that lead to memories lasting a few hours, whereby altered signalling between neurons causes a series of chemical changes in the connections between nerve fibers, called synapses. However, less is understood about how the chemical changes in the synapses are converted into lasting memories stored in the cerebral cortex. A research team at Karolinska Institutet has now discovered that signalling via a receptor molecule called nogo receptor 1 (NgR1) in the nerve membrane plays a key part in this process.


Medicines designed to target the NgR1 receptor system would be able to improve the brain's ability to form long-term memories.

Complete understanding of the formation of memories - still many years away - will be an enormous step forward, the foundation of entire industries we have yet to imagine. It will open the door to engineering away the loss of capacity in the processes of human memory that occur with age. But even incremental advances along the way have the potential to bring great benefits to humanity.

More on Zebrafish Biochemistry

From ScienceDaily: "The search for the holy grail of regenerative medicine - the ability to 'grow back' a perfect body part when one is lost to injury or disease - has been under way for years, yet the steps involved in this seemingly magic process are still poorly understood. Now researchers [have] identified an essential cellular pathway in zebrafish that paves the way for limb regeneration by unlocking gene expression patterns last seen during embryonic development. They found that a process known as histone demethylation switches cells at the amputation site from an inactive to an active state, which turns on the genes required to build a copy of the lost limb. ... This is the first real molecular insight into what is happening during limb regeneration. Until now, how amputation is translated into gene activation has been like magic. Finally we have a handle on a process we can actually follow. ... This finding will help us to ask more specific questions about mammalian limb regeneration: Are the same genes involved when we amputate a mammalian limb? If not, what would happen if we turned them on? And if we can affect these methylation marks in an amputated limb, what effect would that have?"



If the end goal is to be able to grow replacement tissue for all parts of the body, sooner or later you will arrive at the engineering of male genitals. In fact sooner, it seems, which isn't much of a surprise given human nature. Via EurekAlert!: "In an advance that could one day enable surgeons to reconstruct and restore function to damaged or diseased penile tissue in humans, researchers have used tissue engineering techniques to completely replace penile erectile tissue in animals. ... After implantation with the replacement tissue, the rabbits had normal sexual function and produced offspring. ... Further studies are required, of course, but our results are encouraging ... Reconstructing damaged or diseased penile erectile tissue has traditionally been a challenge because of the tissue's unique structure and complex function. There is no replacement for this tissue that allows for normal sexual function. ... The scientists first harvested smooth muscle cells and endothelial cells, the same type of cells that line blood vessels, from the animals' erectile tissue. These cells were multiplied in the laboratory. Using a two-step process, the cells were injected into a three-dimensional scaffold that provided support while the cells developed. As early as one month after implanting the scaffold in the animal's penis, organized tissue with vessel structures began to form."


Keeping Track of Laser Ablation Research

You'll recall that a few months ago the Immortality Institute community raised the funds needed for a proof of concept laser ablation of lipofuscin. The biochemicals making up lipofuscin build up in long-lived cell populations with age, degrading their ability to function. This is one of the root causes of age-related degeneration. The funded study aims to show that pulsed laser light can break down these unwanted chemical byproducts without damaging the cells that contain them. The end result of this research will hopefully be a demonstration that nematode worms treated in this way live longer, thanks to the removal of lipofuscin. The researcher, Nason Schooler, is blogging his progress, and updates also appear on the Immortality Institute page for the research project: "My leveling feet for the breadboards finally came in yesterday. I was waiting on them before doing my real optics setup, because I had to tear down all the optics in order to install them. Now the boards with feet are all set up and leveled, and I have the laser installed in a vise - which is a huge stability improvement over the wooden platform I had before. I'll try to get some pix up this weekend. As soon as the optics are setup, experiments will begin. I've got fresh batches of worms all ready to go."


Cryonics in the UK

The Guardian looks at a non-profit cryonics initiative in the UK: "In a bungalow in Peacehaven, by the east Sussex seaside, a 72-year-old man and his 62-year-old wife are planning their future. There's no discussion of anything morbid, like death, because, as far as they are concerned there is no such thing as death. When they stop breathing, they will pass into a state of suspended animation. They will be frozen in a giant flask of liquid nitrogen at almost -200C, which will preserve their brains and organs in as fresh a state as possible until technology has advanced to the stage where they can be revived. ... I was aware from a very young age that life is very short. It occurred to me that no matter what you've got, you're still going to die. I remember thinking, 'I enjoy things: why does anybody want to die?' ... Alan now runs Cryonics UK, and every month he holds meetings with fellow cryonicists and potential converts to discuss the practicalities and potential problems of their suspension - of which there are many. First, upon so-called 'death', a team of experts must rush to their sides, pump out their blood and fill them with antifreeze. ... Second, there are no storage facilities in Britain, so patients will have to be transferred to the US or Russia. Third, science has some way to go before we can bring people back to life." This is much how the established cryonics organizations in the US started back in the day.


Livly and Granulocyte Therapies to Kill Cancer

For any given human cancer there is, somewhere, a person who possesses immune cells that can kill it efficiently and rapidly. That, at least, is the theory - and the evidence backing it up is good. Some people have granulocyte immune cells that are immensely effective at destroying cancer, and those cells and their cancer-killing properties can be safely transferred to other people. You might recall that the work of Zheng Cui, presented at SENS3, provided an impressive demonstration of this strategy for dealing with cancer:

Dr. Cui tested the ability of these cells to fight off cancer by transfusing them into normal mice with cancers. Surprisingly, the simple transfusion of the cancer-fighting immune cells from the resistant mice effectively transfered the same remarkable protection to the normal mice. And even more excitingly, the treatment didn't just prevent cancers from forming, but actually fought off existing cancer: when researchers transfused the anti-cancer white blood cells into normal mice with existing skin tumors, the tumors regressed completely in a matter of weeks. Moreover, a single dose of the cancer-fighting immune cells gave the normal animals a cancer immunity that often lasted for the rest of their lives.

At SENS3, Dr. Cui presented the next logical step in his research: work demonstrating the existence of, and characterizing, high-potency cancer-killing granulocytes in humans.

Dr. Cui's team first went looking for the existence of potent cancer-killing granulocytes in a group of healthy volunteers. This was done by testing the volunteers' granulocytes' ability to destroy cancer cells in a petrie dish. They found that, unlike in mice (who seem to have an all-or-nothing effect), there appears to be a classical bell-shaped distribution of cancer-killing ability in the granulocytes of people in the population: a few people have white blood cells extremely weak cancer-killing activity, the great majority have an 'average' competence, and a very small group of outliers have the kind of overwhelming search-and-destroy activity (at least in a test tube!) that is seen in the SR/CR mice.

Since then interest in granulocyte transplant therapies has been growing. A clinical trial is underway in Florida, for example. What I wanted to draw your attention to today, however, is the non-profit Livly. A number of familiar faces are involved, such as John Schloendorn who has worked on bioremediation research for the SENS Foundation's lysoSENS project. The folk at Livly are presently involved in advancing the state of the art in granulocyte therapies:

Currently, Livly's work is focused on using the innate immune system to combat cancer. This idea was popular in the 80s, but had been abandoned in favor of adaptive immunity (the now fashionable "cancer vaccines"). Recently, Dr. Zheng Cui of Wake Forest University received much popular press for reviving this idea.


Livly's story began when John’s friend Chris Heward, President of Kronos Science Labs in Phoenix, AZ, was diagnosed with terminal esophageal cancer in the fall of 2008. Doctors gave him no chance of surviving the year, even with the best available standard of care. So he decided to forego the so-called "palliative" chemotherapy treatment and give this leukocyte transfer idea a shot. Kronos worked with Wake Forest to begins screening a large number of healthy individuals for innate cancer-killing activity. However, the cancer progressed far too rapidly. Chris died in early 2009, before the group was able to have a leukocyte transfusion ready.

Eri and John founded Livly in order to take a more direct role in fighting cancer. After determining that thier work would contribute to the field, they could not turn their backs on this mission while only waiting, watching and hoping that other loved ones would not also be victims of cancer.

The next phase of cell transplant therapies is to do away with the need for a foreign source of cells by understanding how and why such a transplant achieves its goal. In this case, a plausible future involves altering some of the patient's own immune cells to have the cancer-killing ability found in only a few people, then culturing a large quantity of them, and returning them to the body. Another option is some form of drug that alters the behavior of the patient's existing granulocytes, thus removing the need for any transplant.

The Search For Genetic Polymorphisms of Human Longevity

Some people have better genes than other people; such is the luck of the draw. The effects of most genetic differences on human longevity appear to be small in comparison to the effects produced by lifestyle choices, however. You are still the master of your own destiny in that regard. Time wasted in wishing you had a better variant of FOXO3A would be better spent exercising.

A great deal of modern life science research is focused on deciphering the operation of our genes and metabolism. Along the way, researchers are digging up many statistical associations between human life span and specific genetic polymorphisms, such as different alleles of a single gene. This is happening rapidly enough that individual results are no longer newsworthy; this is a data gathering phase in the broader research community, and the data is rolling in. Relentless gains in the cost effectiveness of genetic biotechnologies mean that databases of these associations will grow far faster than they are mined for potential applications and cross-references in the years ahead.

By way of illustration, here are a couple of recent examples of the sort of investigative work into human genetics and longevity that is presently taking place.

The IRS2 Gly1057Asp Variant Is Associated With Human Longevity

Reduced insulin and insulin-like growth factor-1 (IGF-1) signaling extends the life span of invertebrate and mammals. Recently, reduced insulin receptor substrate-2 (IRS2) signaling was found associated with increased longevity in mice. The aim of our study was to evaluate whether a common polymorphism (Gly1057Asp) in human IRS2 gene is associated with human longevity.


Six hundred seventy-seven participants (289 males and 388 females) between 16 and 104 years of age, categorized as long lived (LL; >85 years old) or controls (C; <85 years old), were genotyped for Gly1057Asp-IRS2 locus variability (rs1805097). ... Categorizing participants into percentiles by age, IRS2Asp/Asp participants were more likely to reach extreme old age.

Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians

Human phagocyte-specific chitotriosidase (CHIT-1) is a chitinolytic enzyme associated with several diseases involving macrophage activation. Previous studies have demonstrated that a high activity of Chit could have widespread effects on atherosclerosis, cardiovascular disease and dementia. The 24-bp duplication in the CHIT-1 gene is associated with a deficiency in enzymatic activity. In this study, we attempted to assess whether CHIT-1 could be a plausible candidate gene responsible for human longevity. Therefore, we compared the distribution of the CHIT-1 polymorphism genotype in three different populations of the Mediterranean area (Italian, Greek and Tunisian) aged over 90 years. As a control group for each nonagenarian and centenarian, a 60-70-year-old subject was genotyped.

We found that the heterozygote frequency for the 24-bp duplication in the CHIT-1 gene was not significantly different among the oldest old subjects of Mediterranean populations, whereas it was significantly different between oldest old subjects and control subjects, being highest among the oldest old subjects and lowest among control groups. In the oldest old group, no subject was observed to be homozygous for CHIT-1 deficiency. Moreover, the mean enzymatic activity in heterozygous oldest subjects was lower than that in the control group. These data indicate that the heterozygosis for a 24-bp duplication in the CHIT-1 gene could have a protective effect in human longevity.

These are fairly typical of the type of associations being uncovered: fairly robust from a statistical perspective, with the putative benefit being small, or specific to narrow aspects of age-related disease or metabolism. That second item, the CHIT-1 gene, is unusual in its uniformity in the oldest subjects of the study. So: yes, some people have better genes than others. But go running or take up calorie restriction rather than dwell upon that fact. You'll end up ahead of the genetically superior couch potatoes of this world by taking that high road.

ResearchBlogging.orgMalaguarnera L, Ohazuruike LN, Tsianaka C, Antic T, Di Rosa M, & Malaguarnera M (2009). Human chitotriosidase polymorphism is associated with human longevity in Mediterranean nonagenarians and centenarians. Journal of human genetics PMID: 19881466

Illustrating the Potency of Hormesis

Researchers are occasionally surprised when a genetic modification expected to reduce life span in fact extends it. In this example, a defense against lipid peroxidation is disabled in mice. (You might recall that lipid peroxidation is one of the ways in which oxidative damage originating in the mitochondria spreads throughout the body). Rather than reducing the life span of these mice due to greater damage, this actually has the effect of galvanizing further defensive mechanisms to greater activity. So in fact, such a mouse winds up with more effective repair and protection mechanisms over the long term. This is an example of hormesis - regular application of a little damage provokes an ongoing and massive response from the body's repair mechanisms, which leads to a longer healthy life span. From the paper: "The lipid peroxidation product 4-hydroxynonenal (4-HNE) forms as a consequence of oxidative stress. ... A major route of 4-HNE disposal is via glutathione conjugation, in the mouse catalyzed primarily by glutathione transferase mGSTA4-4. Unexpectedly, mGsta4-null mice, in which 4-HNE detoxification is impaired, have an extended life span. This finding could be explained by the observed activation of the transcription factor Nrf2 in the knockout mice, which in turn leads to an induction of [a] detoxification mechanism that contributes to enhanced longevity."


Theorizing on the Role of Longevity Genes

It isn't completely clear exactly how many longevity genes affect our biochemistry. For example: "The researchers studied a family of transcription factors called FoxO known to be involved in proliferation, differentiation and programmed cell death. FoxO genes are required for the extreme longevity seen in some strains of laboratory roundworms, and a single mutation in the FoxO3 gene has recently been associated with long life in Japanese, German, American and Italian populations. ... We wanted to know if FoxO3 could be involved in regulating the pool of neural stem cells ... researchers examined laboratory mice in which the FoxO3 gene was knocked out. ... the few stem cells found in the adult mice without FoxO3 more rapidly churned out neural cell precursors - those cells destined to become new neurons - than did the mice with normal FoxO3 levels. In fact, the brains of the mice that lacked FoxO3 were heavier than the control group, perhaps because they were burning through their pool of neural stem cells by making too many new nerve cells. ... It's intriguing to think that genes that regulate life span in invertebrates may have evolved to control stem cell pools in mammals. ... [researchers] are working on creating a mouse in which FoxO3 levels are artificially elevated. If their theory about the function of the protein in the brain is correct, it's possible that the neural stem cell pools of these mice will be protected from the ravages of time. ... We're very interested in understanding how everything unravels during the aging process."


Replacing Skin Grafts With Autologous Stem Cells

From the MIT Technology Review: "Traditionally, treatment for severe second-degree burns consists of adding insult to injury: cutting a swath of skin from another site on the same patient in order to graft it over the burn. The process works, but causes more pain for the burn victim and doubles the area in need of healing. Now a relatively new technology has the potential to heal burns in a way that's much less invasive than skin grafts. With just a small skin biopsy and a ready-made kit, surgeons can create a suspension of the skin's basal cells - the stem cells of the epidermis - and spray the solution directly onto the burn with results comparable to those from skin grafts. ... After removing a small swatch of skin near the burn site (the closer the biopsy, the better for precise matching of color and texture), the surgeon places it in the kit's tiny incubator along with an enzyme solution. The enzyme loosens the critical cells at the skin's dermal-epidermal junction, and the surgeon harvests them by scraping them off the epidermal and dermal layers and suspending them in solution. The resulting mixture is then sprayed onto the wound, repopulating the burn site with basal cells from the biopsy site."


Another Promising Targeted Cancer Therapy

The use of targeting mechanisms makes existing anti-cancer methodologies, such as radiation or toxic chemicals, work far more effectively and inflict less harm upon the patient. Via EurekAlert!: researchers used "a radiolabeled antibody to deliver targeted doses of radiation, followed by a stem cell transplant, to successfully treat a group of leukemia and pre-leukemia patients for whom there previously had been no other curative treatment options. All fifty-eight patients, with a median age of 63 and all with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome - a pre-leukemic condition - saw their blood cancers go into remission. ... The key to success in this study was use of a radiolabeled antibody that has therapeutic iodine 131 attached and is designed to target leukemic bloods cells that carry a marker on the surface of the cell known as CD45. ... Delivered intravenously, the radiation looks for the CD45 antigen receptor on the surface of blood cells. This approach results in a two- to four-fold increase in the amount of radiation that reaches cancerous cells as compared to standard external beam radiation, which also radiates normal surrounding organs and tissue. The more radiation that can be applied, the more cancer cells will be killed in preparation for donor stem cells to take over the diseased immune system and kill off the remaining cancer cells." The survival rate after 3 years is around a third - somewhat better than the expected zero for existing options.


Evaluating an Industry that Doesn't Exist

Imagine an industry poised to burst into existence. The signs are there: the advocates, the tinkerers, the potential business models and user demand, the promising early scientific work yet to be fully exploited. But how you determine whether this is real or all an illusion? How to find out whether an explosion of progress and growth is just about to happen, or whether the seeds of this nascent industry will continue to germinate at low levels of activity for years longer? There is only one useful method: invest a significant amount of money and see how much interest, activity, and follow-on investment it attracts.

This is one of the lines of reasoning behind the most adventurous of venture capital deals, behind research prizes, and behind large philanthropic donations to young fields of research. Today I have in mind Peter Thiel's $3 million matching fund for SENS research, a donation made back in 2006 when the Methuselah Foundation and SENS Foundation were one and the same. The terms of this donation made it a very explicit fishing expedition, a tool for evaluating the state of the longevity science industry that has yet to exist - an industry based on the SENS approach to repair and reversal of aging versus the present mainstream approach of metabolic manipulation to slow aging.

From now until the end of 2009, Mr. Thiel promises to match every Dollar donated to the Methuselah Foundation for SENS research with a 50 cent matching contribution from himself, up to a maximum of $3 Million of matching funds.


Thiel has given us, all of us, a worthy challenge: raise $6 million in 3 years for Aubrey de Grey's Strategies for Engineered Negligible Senescence (SENS) research and he will match that with a further $3 million. That level of funding would place SENS research on a par with the new Paul F. Glenn Laboratories for the Biological Mechanisms of Aging. in other words, an organization capable of shaping the application of billions of dollars of medical research funding - and the opinions and work of tens of thousands of the most important scientists in relevant fields - in the years ahead simply by the merits of its existence.

The challenge to raise funding is a proxy for the challenge to prove your cause worthy and likely to succeed. To raise $6 million from the philanthropic community, you need compelling science that stands up to peer review, widespread support, a strong message, and the organizational success gene - the people who build a community to make it work.

The end of 2009 approaches. As of now, in the three years since the Thiel matching fund was set up, a little over half has been matched. Some $3 million in donations and pledges have been raised for SENS research, and $1,472,000 remains of the fund. A lot of progress and networking has happened behind the scenes, both inside and outside the scientific community. A number of Methuselah Foundation volunteers and associates have gone on to found and assist in diverse other efforts, such as Genescient, the LifeStar Institute, and the Biogerontology Research Foundation.

But it's hard to evaluate the value of advocacy and increasing diversity in organizations that carry the SENS ideas; it's easy to evaluate dollars raised. By that standard we as a community are not as far advanced as we thought we were, even though progress and growth is ongoing. The lion's share of all investment and philanthropic donation to longevity science in the past few years has not gone to SENS-like research, but towards metabolic manipulation instead. Consider the Sirtris acquisition, the Paul F. Glenn Laboratories, and so forth. From my perspective, the increase in scientific understanding of metabolism and aging produced by those efforts will have great value in the long term, but I don't see that applied biotechnology that merely slows aging will have any great impact on our longevity.

As I've pointed out numerous times in the past, we in middle age today only get one shot at a twenty year development cycle for longevity-enhancing medical technology. If by 2030 all that has been achieved is a reliable slowing of aging, then we will benefit very little from that. The only way to significantly enhance healthy life expectancy in the old is to aim for rejuvenation: repair and restoration, not slowing down the accumulation of damage.

So SENS and SENS-like ideals for longevity science are not where we'd like to be. Growth is slower, and fundraising has not hit the heights we'd like. A large matching fund looks likely to expire only half-used, and not through any lack of effort on the part of fundraisers. Take five minutes to mope, and then think about what we can do to change this state of affairs.

How Excess Fat Causes Inflammation

Researchers are delving deeper into the mechanisms that link fat tissue with chronic inflammation, a source of damage to the body that raises the risk of age-related disease: "Researchers have new evidence to explain how saturated fatty acids, which soar in those who are obese, can lead the immune system to respond in ways that add up to chronic, low-grade inflammation. The new results could lead to treatments designed to curb that inflammatory state, and the insulin resistance and type 2 diabetes that come with it. One key [is] an immune receptor (called Toll-like receptor 4 or Tlr4) at the surface of blood cells, including a particularly 'angry' class of macrophages known to pump out toxic molecules and spur inflammation. It now appears that fatty acids may in essence 'hijack' those immune cells via Tlr4. ... Tlr4 is out there to sense bacterial products, but one of those looks a lot like fatty acids. They don't know it's not bacteria. ... Scientists had suspected that Tlrs might be the 'sensors' linking obesity to inflammation. Indeed, earlier studies had supported that notion. In the new study, the researchers show that this interaction is particularly important in the bloodstream. Mice lacking Tlr4 only in blood cells grew obese when they were fed a high-fat diet, but they were largely spared the metabolic consequences of their obesity. The mice were fat, but metabolically they continued to 'look pretty normal.'"


An Interview With Kevin Perrott

Kevin Perrott of the LifeStar Institute is featured in this Edmonton Sun article: "Kevin Perrott sees a future without heart disease, arthritis or cancer. And it's right around the corner ... if people can get over their unfounded fear of stem-cell research. 'The potential is totally limitless,' Perrott says, his eyes widening with enthusiasm, 'But we have to get everybody on the same wavelength.' The problem, he says, is that the ethical debate over stem cells hasn't kept up with the research. Perrott, a local businessman and PhD student, hopes to change that. Earlier this year he founded the LifeStar Institute Canada to build public support for stem-cell research. ... In the near future, someone needing a kidney transplant could have a new organ manufactured out of cells taken from their own skin, potentially bringing an end to organ donor wait lists. It also opens the door for 'personalized cell replacement therapies.' For example, heart attack victims who've suffered permanent organ damage could be treated so that the dead tissue regenerates itself. Parkinson's disease, Alzheimer's disease and other incurable conditions could potentially be reversed."


Matters Dietary

On the whole, a good 99% of discussion on the topic of the human diet is nonsense - that marketplace of ideas and goods is just as bad as the anti-aging marketplace. If you pick out a group at random, the odds are very good that you'll be pointing to a coven of fools who have found ways to make money from ignorance and hope. There are always potential customers whose desire for immediate solutions and answers overwhelms their desire for actually working solutions and correct answers.

The areas where science has robust things to say about diet, advice proven beyond any reasonable doubt, largely revolve around levels of calorie intake and recommended levels of micronutrients. Calorie restriction, for example, is undeniably good for you. Keeping your micronutrient intake up to scratch is also a good thing. After that, we devolve into studies for, studies against, and debates that can be argued well in either direction. So, given the existance of the diet industry and its idiocies, I tend not to talk too much about diet. This is for much the same reasons that I don't talk much about skin rejuvenation or hair restoration. There are occasional flashes of good science amidst the foolish braying of the sellers, but most of the broader discussion is worthless and a distraction.

Here, for a change, are a couple of recent items on aging and diet: we know that advanced glycation endproducts (AGEs) and insulin signaling are both important to the way in which metabolism determines degeneration and life span, the latter probably more so. But how does diet enter into this? AGEs are generated in the body, but also consumed. Insulin signaling is intimately tied to levels of sugar in the blood, which changes with the level of glucose in the diet.

A 'spoonful of sugar' makes the worms' life span go down

By adding just a small amount of glucose to C. elegans usual fare of straight bacteria, they found the worms lose about 20 percent of their usual life span. They trace the effect to insulin signals, which can block other life-extending molecular players. Although the findings are in worms, Cynthia Kenyon of the University of California, San Francisco, says there are known to be many similarities between worms and people in the insulin signaling pathways.

Reduction in glycotoxins from heat-processing of foods reduces risk of chronic disease

Researchers from Mount Sinai School of Medicine report that cutting back on the consumption of processed and fried foods, which are high in toxins called Advanced Glycation End products (AGEs), can reduce inflammation and actually help restore the body's natural defenses regardless of age or health status. These benefits are present even without changing caloric or nutrient intake.


"What is noteworthy about our findings is that reduced AGE consumption proved to be effective in all study participants, including healthy persons and persons who have a chronic condition such as kidney disease," said the study's lead author Helen Vlassara, MD, Professor and Director of the Division of Experimental Diabetes and Aging at Mount Sinai School of Medicine.

"This suggests that oxidants may play a more active role than genetics in overwhelming our body's defenses, which we need to fight off disease. It has been said that nature holds the power, but the environment pulls the trigger. The good news is that unlike genetics, we can control oxidant levels, which may not be an accompaniment to disease and aging, but instead due to the cumulative toxic influence of AGEs," said Dr. Vlassara.

Calorie restriction is going to reduce your intake of AGEs and glucose, of course, even if you manage to keep eating exactly the same foods as you did before. Though in practice most practitioners find they have to drop highly processed or sugared foods from their diet in order to meet the calorie limits. So some presently unknown fraction of the health and longevity benefits of calorie restriction may stem from lowered intake of AGEs and glucose.

A Glance at Recent Autologous Transplant Research and Applications

Much of modern stem cell research and clinical application is focuses on autologous therapies: extracting useful cells from the patient, such as stem cells, culturing the cells to multiply their numbers, potentially altering or reprogramming them for better therapeutic effect, and then returning them to the body to spur regeneration. The use of the patient's own cells circumvents almost all of the biggest issues surrounding transplants between people - such as rejection by the immune system, and the need for potentially dangerous drugs to suppress that rejection.

This is all foundation work that may later become important to engineered longevity. One thing that may prove useful is the ability to take important types of cell from the patient (such as stem cells, or long-lived cell types that are not normally replaced), repair whatever molecular damage they have accumulated, grow an entire replacement population from the repaired cells, and then return them to the body. In this way, medical technology may revert the function of specific cell populations to a youthful state - this is the hope, in any case, though the situation is complicated by the existence of remaining still-damaged cells and other forms of age-related damage that cannot be solved through cell replacement, such as intracellular and extracellular aggregates.

Here are some recent examples of work in this field that caught my eye, and which hopefully together provide some insight as the to the state of research and development at the present time. As is usually the case, what is possible is far ahead of what has been pushed at great expense into clinical trials:

Tissue-engineering researchers create replacement knee ligaments from recipients' own cells

In a development that could lead to more complete recovery from torn anterior cruciate ligament (ACL) injuries in humans, University of Michigan researchers have grown and repaired knee ligaments in rats from bone marrow stem cells harvested from the rats' own bones.

Spinal Cord Injury Patients Demonstrate Progress after Stem Cell Therapy at the XCell-Center

he XCell-Center has released results from a follow-up study of 115 spinal cord injury patients treated with autologous bone marrow stem cells. Overall, nearly 60% improved following treatment. These results support the premise that spinal cord injury patients can be treated safely and effectively with autologous stem cell therapy. The most common improvement, reported by more than 6 out of every 10 patients, was the return of feeling to the hands, feet, arms, legs or trunk.

Reprogramming Patient's Eye Cells May Herald New Treatments Against Degenerative Disease

The team sampled progenitor eye cells, which regenerate the eye's cornea, from laboratory rats. By reprogramming them to resemble stem cells they acquired the properties necessary to replace or restore neurons, cardiomyocytes, and hepatocytes, cell types which are degenerated in Parkinson's disease, heart disease, and liver disease.

Start of Phase III Clinical Trial "PERFECT" Using Autologous CD133+ Bone Marrow Stem Cells

Miltenyi Biotec announces the treatment of the first patient in a phase III clinical trial termed PERFECT. The trial aims at determining whether intramyocardial injection of autologous CD133+ bone marrow stem cells improves heart function in addition to coronary artery bypass grafting (CABG) in patients with chronic ischemic heart disease and reduced pumping function.

The Case for Autophagy

This open access review paper looks at the evidence pointing towards the process of autophagy as a central metabolic determinant of longevity: "The accumulation of cellular damage is a feature common to all aging cells and leads to decreased ability of the organism to survive. The overall rate at which damage accumulates is influenced by conserved metabolic factors (longevity pathways and regulatory proteins) that control lifespan through adjusting mechanisms for maintenance and repair. Autophagy, the major catabolic process of eukaryotic cells that degrades and recycles damaged macromolecules and organelles, is implicated in aging and in the incidence of diverse age-related pathologies. Recent evidence has revealed that autophagic activity is required for lifespan extension in various long-lived mutant organisms, and that numerous autophagy-related genes or proteins are directly regulated by longevity pathways. These findings support the emerging view that autophagy is a central regulatory mechanism for aging in diverse eukaryotic species."


Talking to Your Children About Cryonics

A good article from h+ Magazine: "'Daddy, when are you going to die?' asks my daughter Zenobia, age five. 'Yeah, how much longer do you really think you can live?' says big sister, Tallulah, age nine. I'm only 57, and healthy, but my two larvae are obsessed with my expiration date because their grandfather passed away last summer. I am twelve years older than their mother, so the kids know I'm scheduled - in the traditional societal view - as the next family member to croak. 'Hey, you brats!' I retort. 'I'm not going anywhere. I'm going to boss you around forever.' ... 'You can't,' scoffs Tallulah. 'Every animal dies. Even whales and trees.' I contemplate emailing her teacher to suggest up-to-date science books by Aubrey de Grey and K. Eric Drexler. 'If my body dies,' I announce, 'I'm going to have scientists freeze me immediately, because my brain will still be alive. I'll stay frozen until future smart people wake me up in a world where everybody lives forever.' ... I show my daughters the website of a cryonics organization in Silicon Valley. 'When I die,' I instruct them. 'I'll have a medal around my neck that says 'Cool Me Off.' On that medal there's a phone number. Call it and somebody will tell you what to do.'"


Two Videos: Aubrey de Grey and an Unofficial SENS Foundation Promotional

While meandering the byways of the internet, I came across a rather nicely done promotional video short for the work of the SENS Foundation. I don't believe it is in any way authorized, but it's the sort of simple, quality product that this community excels in producing. Take a look and see what you think.

On a related note, I see that videos from the recent Singularity Summit are available online. Here is Aubrey de Grey speaking about the Methuselarity:

More on the Methuselarity as a concept, and how it relates to longevity escape velocity, can be found back a little way in this year's Fight Aging! archives. At some point, the advance in biotechnology and its applications to medicine will begin to add more than one year of remaining life expectancy with each passing year of progress - at which time everyone who can make use of these technologies of longevity will be functionally immortal. Vulnerable to accident and ill will, but no longer aging to death.

This goal lies a way away yet - largely because the research and development community required has yet to be assembled. This is far more a matter of organization and persuasion at present than a matter of getting the job done. In order to get the job done, you need a sufficient number of workers and the investment of resources to fund their research. Making this happen is today's challenge.

The Importance of Protein Folding

Here is a glance at why protein folding is important: "Research indicates that ALS, in common with other neurological disorders, such as Alzheimer's and Parkinson's disease, is caused by our own proteins, which form aberrant aggregates that are fatally toxic to our nerve cells. However, it has not been known what causes these proteins to aggregate. [Researchers] have now revealed what happens with proteins during the very first, critical step towards forming larger aggregates.
It turns out that the protein superoxide dismutase interchanges between its normal structure and a misfolded form. During a brief moment the structure becomes partially misfolded to expose sticky patches that normally are hidden in the interior. These patches cause two or several protein molecules to stick together, thereby forming the cornerstone of the larger structures that are believed to underlie ALS. ... Knowledge of the misfolded protein structure potentially makes possible future efforts to rationally design drugs that prevent the misfolding event and hence the development of ALS." This is why projects like Folding@home are important to the future of medical science: understanding a misfold makes it possible to work towards correcting it.


A Bioethicist on Humanism and Longevity Science

Some thoughts on humanism and longevity science from a social justice variety of bioethicist: "If humanists reflected critically and consistently upon their basic moral convictions, I believe they would become strong advocates of aging research and the aspiration to decelerate human aging. However, most humanists are not (at least yet) strong advocates of this scientific research; indeed many probably oppose this research or at the least do not think it an important priority. In this post I will explain why this is a mistake given the foundational moral premises of humanism. ... A 21st century humanist recognizes the fact that no person, regardless of race, gender, nationality or *age*, deserves to suffer morbidity and mortality. And thus we ought to aspire to reduce these risks when it is feasible to do so, whether it be by providing access to clear drinking water, bed nets to protect against malaria or developing new drugs that re-programme our metabolism and help protect against chronic diseases. ... The average age of life expectancy, at birth, in the world today is 67. This means that most people born today will live long enough to suffer one of the chronic diseases of aging, like cancer or heart disease. This is a fate suffered by millions every year now, especially in the developing world (contrary to what most people in the developed world think). 21st humanists ought to be among the strongest and loudest advocates of biogerontology."