The second volume of the new open access journal Pathobiology of Aging and Age-related Disease is available online. I thought I'd point out one of the papers, which argues that the biology of long-lived mouse species should be considered evidence for the importance of chronic inflammation in determining life span.

Growth hormone, inflammation and aging

Mutant animals characterized by extended longevity provide valuable tools to study the mechanisms of aging. Growth hormone and insulin-like growth factor-1 (IGF-1) constitute one of the well-established pathways involved in the regulation of aging and lifespan. Ames and Snell dwarf mice characterized by GH deficiency as well as growth hormone receptor / growth hormone binding protein knockout (GHRKO) mice characterized by GH resistance live significantly longer than genetically normal animals.

During normal aging of rodents and humans there is increased insulin resistance, disruption of metabolic activities and decline of the function of the immune system. All of these age related processes promote inflammatory activity, causing long term tissue damage and systemic chronic inflammation. However, studies of long living mutants and calorie restricted animals show decreased pro-inflammatory activity with increased levels of anti-inflammatory adipokines such as adiponectin. At the same time, these animals have improved insulin signaling and carbohydrate homeostasis that relate to alterations in the secretory profile of adipose tissue including increased production and release of anti-inflammatory adipokines.

This suggests that reduced inflammation promoting healthy metabolism may represent one of the major mechanisms of extended longevity in long-lived mutant mice and likely also in the human.

Regular readers will recall that there is a mountain of evidence to link aging and chronic inflammation. If you have higher levels of inflammation, you will have a worse - and usually shorter - time ahead. It causes damage, and that damage adds up; the easiest way in younger life to raise inflammation levels is to become fat, as visceral fat tissue works a number on your metabolism. But everyone's immune system runs off the rails given time, falling into a state wherein it is constantly roused but increasingly ineffective in its designated jobs. Many of the aspects of aging are clearly connected to immune system decline: raised levels of inflammation, increased numbers of senescent cells, increased risk of cancer, and more.

This all argues for some form of safer, more mature version of the immune system reboot therapies that can presently be accomplished, but are not available outside of trials at this time. A large fraction of the immune system's failure with age stems from structural issues: it has evolved to be very, very good at its job in early life, but at the cost of inevitably and predictably failing as it runs out of capacity later on.

Throughout our lives, we have a very diverse population of T cells in our bodies. However, late in life this T cell population becomes less diverse ... [one type of cell] can grow to become more than 80 percent of the total [T-cell] population. The accumulation of this one type of cell takes away valuable space from other cells, resulting in an immune system that is less diverse and thus less capable in effectively locating and eliminating pathogens.

But if the slate could be wiped clean (achieved by chemotherapy at the present time, which is far from ideal) and the immune system repopulated (using stem cells to generate a population of patient-matching immune cells), then this issue vanishes, and people could benefit from a strong immune system for decades longer than is presently the case. That would likely make a significant difference to the course of later life, even in the absence of other advances in medical technology.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers make paralyzed rats walk through a mix of chemical stimulation and structured physical therapy; only a little regrowth in the spine occurs, but the lower spinal column can take over some of the lost functionality under the right circumstances: "a severed section of the spinal cord can make a comeback when its own innate intelligence and regenerative capacity is awakened. ... After a couple of weeks of neurorehabilitation with a combination of a robotic harness and electrical-chemical stimulation, our rats are not only voluntarily initiating a walking gait, but they are soon sprinting, climbing up stairs and avoiding obstacles when stimulated. ... until now the spinal cord expressed so little plasticity after severe injury that recovery was impossible. ... under certain conditions, plasticity and recovery can take place in these severe cases - but only if the dormant spinal column is first woken up. To do this, [researchers] injected a chemical solution of monoamine agonists into the rats. These chemicals trigger cell responses by binding to specific dopamine, adrenaline, and serotonin receptors located on the spinal neurons. This cocktail replaces neurotransmitters released by brainstem pathways in healthy subjects and acts to excite neurons and ready them to coordinate lower body movement when the time is right. ... Five to 10 minutes after the injection, the scientists electrically stimulated the spinal cord with electrodes implanted in the outermost layer of the spinal canal, called the epidural space. ... a stimulated rat spinal column - physically isolated from the brain from the lesion down - developed in a surprising way: It started taking over the task of modulating leg movement, allowing previously paralyzed animals to walk over treadmills. These experiments revealed that the movement of the treadmill created sensory feedback that initiated walking - the innate intelligence of the spinal column took over, and walking essentially occurred without any input from the rat's actual brain. This surprised the researchers and led them to believe that only a very weak signal from the brain was needed for the animals to initiate movement of their own volition. ... newly formed fibers bypassed the original spinal lesion and allowed signals from the brain to reach the electrochemically-awakened spine. And the signal was sufficiently strong to initiate movement over ground."

Link: http://www.sciencedaily.com/releases/2012/05/120531145714.htm

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

There is death and then there is information theoretic death - a person who is cryopreserved is a good deal less dead than someone who went to the grave. The fine structure and data of the mind still exist, in a cold-stored stasis, and thus might be restored through foreseeable future technology. Here are some notes on the legal situation with respect to cryopreserved people: "This article series seeks to compare the legal protection of cryonics patients under their present legal status to the legal protection which would be afforded them if they were recognized as persons under the law, thinking ahead to such future time as it becomes reasonably possible to put legal and political pressure towards enhanced legal recognition of cryonics patients. The previous article examined laws that directly affect what happens to a person's body after legal death, both in the period immediately after declaration of legal death, and indefinitely thereafter. We saw that the amount of prospective autonomy a person is permitted in this regard can vary significantly from jurisdiction to jurisdiction, with more or less consideration afforded to the wishes of the person's next of kin, religious beliefs, societal norms and other public interests. Two other legal structures which can and are used by cryonicists to promote the success and timeliness of cryopreservation, maintenance, and resuscitation are wills and trusts."

Link: http://www.evidencebasedcryonics.org/2012/05/05/legal-protection-of-cryonics-patients-part-2/

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Published at Impact Aging you'll find descriptions of the presentations given at the Second International Conference on the Genetics of Aging and Longevity, held in Moscow recently. It's a good representative sample if you'd like to know what the mainstream of aging and longevity science looks like. What I wanted to draw your attention to was this presentation and question:

Vladimir Anisimov (N.N. Petrov Research Institute of Oncology, Russia) in his presentation "Do we really have a medicine against aging?" showed results of experiments on effects of antidiabetic biguanides and rapamycin on biomarkers of aging, life span, spontaneous and chemically-induced carcinogenesis in outbred, inbred and transgenic HER-2/neu mice and in rats.

The mTOR inhibitor rapamycin prevents age-related weight gain, decreases rate of aging, increases life span and decreases carcinogenesis in transgenic HER-2/neu cancer-prone mice. Rapamycin dramatically delayed tumors onset, decreased a number of tumors per animal and tumor size. Lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 years. Importantly, rapamycin was administrated intermittently (every other 2 weeks) starting from the age of 2 months. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group.

...

Treatment of female outbred SHR mice with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. Same treatment started at the age of 9 months insignificantly increased mean life span by 6%, whereas treatment started at the age of 15 months failed to increase life span. When started at the age of 3 and 9 months, metformin delayed time of the first tumor detection by 22% and 25%, correspondingly.

...

These results suggest that both metformin and rapamycin may be useful in prevention of cancer and extension of lifespan when used in rational and appropriate ages, doses and schedules.

Asking and attempting to answer questions like "does medicine for aging exist" is going to make you unpopular in some quarters no matter how you answer. The large and energetic "anti-aging" marketplace, eternally plagued by the dishonesty of its bad apples, has been crying "yes, yes, get your treatments for aging here" for about as long as mankind has existed. The invention of fraud no doubt followed the discovery of the concepts of value and trade by only a few heartbeats. When no-one could in fact do much of anything about aging, one might say "so what?" Fraud and lies about extending life were no different then than fraud and lies about anything else that didn't exist and couldn't be made to exist - such as the ownership rights to certain bridges, for example.

In these later days of science and reason, however, in which we stand upon the verge of building real and meaningful ways to treat aging, that commercial "anti-aging" market is a millstone around the necks of the scientific community. It is in fact a large part of the reason why up until very recently the aging research field was extremely hostile towards anyone talking seriously about treating aging.

So you are going to see care taken when people in the scientific community speak on such topics. For my part, I think it's completely fair to put forward that, by modern standards of drug development, you could point to rapamycin and metformin and say "these are candidate treatments for aging." By this I mean that they are likely to produce minimal benefits, have potentially ugly side-effects, and are not yet really tested for that specific usage in humans - which describes both a fair chunk of the drug discovery pipeline and many drugs out there in widespread use. We are willing to call those therapies for the conditions they are used to treat.

But let's be clear: as prospective therapies for aging, these drugs are terrible. Truly bad. They are far worse than exercise or calorie restriction - they produce lesser benefits and you get unpleasant side-effects into the bargain. So given all of that I don't think it is unreasonable to say that yes, treatments for aging exist at the present time, and they are awful.

(It is worth pointing out that a gain in life span of 20% in mice is not all that in the grand scheme of things. Exercise can do better, and calorie restriction does twice as well. Further, it is not seriously expected that any gain of 20% in life span in mice through metabolic alteration will translate to a similarly meaningful gain in human life span - which has to do with many of the differences that cause us to be long-lived already for our size. For example, calorie restriction is not thought to be capable of producing more than a few years of gain in maximal human life span, even while it produces large gains in health and resistance to age-related disease).

The real path to the future, to my eyes, is to skip over all of this longevity-enhancing drug discovery nonsense, interesting though it may be, and focus on repair of specific forms of cellular and molecular damage - such as the detailed methodologies proposed in the SENS vision. If SENS or similar programs for research and development fail to become a dominant approach to longevity science, and the foreseeable future thus remains a heaping helping of more longevity-enhancing drug discovery nonsense, then therapies for aging will continue to be generally awful.

I consider it to be unfortunate that the bulk of the pro-longevity aging research camp is focused on an inefficient path forward that will in the end lead to lesser benefits. It is their belief that this is the only practical way ahead: a laborious slog towards complete understanding of aging and metabolism, followed by an even more complex navigation through re-engineering that metabolism to age more slowly. The sheer scale and difficulty of that task is why many scientists feel that meaningful engineered longevity - more healthy years through science - is a long way away indeed.

...

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers "have collaborated on a project to restore neuron function to parts of the brain damaged by Huntington's disease (HD) by successfully transplanting HD-induced pluripotent stem cells into animal models. ... Induced pluripotent stem cells (iPSCs) can be genetically engineered from human somatic cells such as skin, and can be used to model numerous human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory. In the current study, experimental animals with damage to a deep brain structure called the striatum (an experimental model of HD) exhibited significant behavioral recovery after receiving transplanted iPS cells. The researchers hope that this approach eventually could be tested in patients for the treatment of HD. ... the transplanted cells will be genetically identical to the patient and therefore no medications that dampen the immune system to prevent graft rejection will be needed. ... transplanted iPSCs initially formed neurons producing GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system, which plays a critical role in regulating neuronal excitability and acts at inhibitory synapses in the brain. GABAergic neurons, located in the striatum, are the cell type most susceptible to degeneration in HD."

Link: http://www.vai.org/News/News/2012/05_29_Huntingtons.aspx

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Researchers "have collaborated on a project to restore neuron function to parts of the brain damaged by Huntington's disease (HD) by successfully transplanting HD-induced pluripotent stem cells into animal models. ... Induced pluripotent stem cells (iPSCs) can be genetically engineered from human somatic cells such as skin, and can be used to model numerous human diseases. They may also serve as sources of transplantable cells that can be used in novel cell therapies. In the latter case, the patient provides a sample of his or her own skin to the laboratory. In the current study, experimental animals with damage to a deep brain structure called the striatum (an experimental model of HD) exhibited significant behavioral recovery after receiving transplanted iPS cells. The researchers hope that this approach eventually could be tested in patients for the treatment of HD. ... the transplanted cells will be genetically identical to the patient and therefore no medications that dampen the immune system to prevent graft rejection will be needed. ... transplanted iPSCs initially formed neurons producing GABA, the chief inhibitory neurotransmitter in the mammalian central nervous system, which plays a critical role in regulating neuronal excitability and acts at inhibitory synapses in the brain. GABAergic neurons, located in the striatum, are the cell type most susceptible to degeneration in HD."

Link: http://www.vai.org/News/News/2012/05_29_Huntingtons.aspx

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Via EurekAlert!: researchers "studied 713 women aged 70 to 79 years who took part in the Women's Health and Aging Studies. This study was designed to evaluate the causes and course of physical disability in older women living in the community. ... A number of studies have measured the positive impact of exercise and healthy eating on life expectancy, but what makes this study unique is that we looked at these two factors together. ... Researchers found that the women who were most physically active and had the highest fruit and vegetable consumption were eight times more likely to survive the five-year follow-up period than the women with the lowest rates. ... Study participants' physical activity was measured through a questionnaire that asked the amount of time the spent doing various levels of physical activity, which was then converted to the number of calories expended. The women were then followed up to establish the links between healthy eating, exercise and survival rates. Key research findings included: More than half of the 713 participants (53%) didn't do any exercise, 21% were moderately active, and the remaining 26% were in the most active group at the study's outset. During the five-year follow up, 11.5% of the participants died. Serum carotenoid levels were 12% higher in the women who survived and total physical activity was more than twice as high. Women in the most active group at baseline had a 71% lower five-year death rate than the women in the least active group. Women in the highest carotenoid group at baseline had a 46% lower five-year death rate than the women in the lowest carotenoid group. When taken together, physical activity levels and total serum carotenoids predicted better survival."

Link: http://www.eurekalert.org/pub_releases/2012-05/w-eaa053012.php

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Aubrey de Grey of the SENS Foundation presented at TEDxChicago 2012 a month ago or so, and video of the event recently made its way to YouTube:

Dr. Aubrey de Grey is a biomedical gerontologist. As the Chief Science Officer of the SENS Foundation (a foundation working to develop widespread access to rejuvenation biotechnologies), author of numerous journal articles and books, and board member of a handful of editorial and scientific advisory boards, it is incontestable that Dr. Aubrey de Grey has dedicated his life to the science of combating the aging process. He received his BA and Ph.D. from the University of Cambridge, however, his original field was computer science.? Dr. de Grey is a Fellow of both the Gerontological Society of America and the American Aging Association and sits on the editorial and scientific advisory boards of numerous journals and organisations. He has appeared on countless shows, was even featured in the Max Wexler documentary, How to Live Forever, and has also spoken at a number of world-renowned events, including TED.

A great many of de Grey's conference presentations and other appearances are archived in the depths of YouTube, as it happens. At some point when you have a spare few minutes, you might take a look at the full list. There are probably a few in there that you haven't seen, such as this presentation given earlier this year at TechFest 2012 in Bombay:

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

The Guardian talks to researcher Tom Kirkwood: "We've known for some time that ageing is extremely variable; that everybody is different and that the differences of individuals' experience of ageing are greater than differences in earlier stages of life ... And why so variable? ... Because of the nature of the ageing process. I've been involved in this field for more than 35 years and when I entered it people fondly believed that ageing was programmed; that there was a mechanism inside our bodies that determined how long we would live. It was kind of written into our genes that we would die at a certain age. What we've been able to show is that the idea of this genetically programmed ageing makes no sense at all. There is no evidence. ... But, surely, genetic influences - a family susceptibility to cardiovascular problems, for instance - play a part in determining longevity? Only to a degree. [For example] a Danish study shows that such influences only explain about a quarter of the factors determining a lifespan. ... What we now know is that the genetic factors that influence your longevity are not genes that measure out the passage of time; the reason we age and die is because, as we live our lives, our bodies accumululate a great variety of small faults in the cells, and the molecules that make up the cells in our body - so ageing is driven by this accumulation of faults. The genes that influence longevity are those that influence how well the body copes with damage, how aggressive our repair mechanisms are; they're genes that regulate the house-keeping and maintenance and repair." All the more reason to focus research on the development of biotechnologies that can do a far better job of repair.

Link: http://www.guardian.co.uk/society/2012/may/29/tom-kirkwood-research-dispels-myths-ageing

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

Small steps towards understanding the greater regenerative capacity of one species: "When the spinal cord is severed in humans and other mammals, the immune system kicks in, activating specialised cells called glia to prevent bleeding into it. ... Glia are the workmen of the nervous system. The glia proliferate, forming bigger cells that span the wound site in order to prevent bleeding into it. They come in and try to sort out problems. A glial scar forms. ... However, the scar prevents axons, threadlike structures of nerve cells that carry impulses to the brain, of neighbouring nerve cells from penetrating the wound. The result is paralysis. ... The axons upstream and downstream of the lesion sites are never able to penetrate the glial scar to reform. This is a major barrier in mammalian spinal cord regeneration. In contrast, the zebra fish glia form a bridge that spans the injury site but allow the penetration of axons into it. The fish can fully regenerate its spinal cord within two months of injury. ... Scientists discovered the protein, called fibroblast growth factor (fgf), controlled the shape of the glia, and accounted for the difference in the response to spinal cord injury between humans and zebra fish. The scientists showed the protein could be manipulated in the zebra fish to speed up tissue repair even more. ... The hope is that fgf could eventually be used to promote better results in spinal cord repair in people."

Link: http://www.monash.edu.au/news/show/fish-study-raises-hopes-for-spinal-cord-injury-repair

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm

A thesis on culture and the urge to longevity is discussed by Ronald Bailey at Reason Magazine:

Cave's fascinating new book, Immortality, posits that civilization is a major side effect of humanity's attempts to live forever. He argues that our sophisticated minds inexorably recognize that, like all other living things, we will one day die. Simultaneously, Cave asserts, "The one thing that these minds cannot imagine is that very state of nonexistence; it is literally inconceivable. Death therefore presents itself as both inevitable and impossible. This is what I will call the Mortality Paradox, and its resolution is what gives shape to the immortality narratives, and therefore to civilization."

...

Cave identifies four immortality narratives that drive civilizations over time which he calls; (1) Staying Alive, (2) Resurrection, (3) Soul, and (4) Legacy. Cave gracefully marches through his four immortality narratives citing examples from history, psychology, and religion up to the modern day. "At its core, a civilization is a collection of life extension technologies: agriculture to ensure food in steady supply, clothing to stave off cold, architecture to provide shelter and safety, better weapons for hunting and defense, and medicine to combat injury and disease," he writes.

Cave is something of a deathist, at first glance looking like he believes that progress means overcoming the primal urge to immortality of the self and the fear of death, but at least he is a deathist who has produced an interesting work on our deep cultural heritage. It should go without saying that history is silent when it comes to the choices we make now in building the future - it can only persuade, not veto. Preferences on life, death, and the quest for rejuvenation biotechnology are personal choices.

But onwards: I think that it is useful to realize that much of our present culture - and that includes the culture of longevity science and its supporters - has very ancient roots indeed. Unbroken lines can be traced from the incentives and psychology of stone age shamans through to the magical thinking and oral fixations of today. Little but technology separates us from our ancestors of five or ten thousand years past, and what to what use do we put that technology? We use it to make our greatest myths real: we are building the world that our ancestors chose to imagine, and which we too imagine, driven by our shared human condition and neural physiology.

Spend a little time with ancient myth, and you'll soon see there is little fundamental difference between the tales of thousands of years past and the folktales of a few hundred years ago. Our present popular entertainments merely continue the theme, a thousand more frills but the same underlying psychology at work. We humans identify with a certain set of stories, and those stories are found repeated throughout our mythologies. In turn, mythology drives technology, as technology is, at heart, a way to satisfy human desires.

As to those parts of mythology that we haven't got to yet - such as unbounded longevity, enabled through biotechnology - well, give it time. We have managed flight, standing atop mountains, journeying to the moon, transmuting the elements, growing food in abundance beyond the wildest dreams of past centuries, changing the course of floods and rivers, and far more. Even the oldest myths will in due course be reconstructed in the real world, even if that means we will build cities in the clouds, cats that can talk, and spirits for companionship. Given sufficiently advanced biotechnology and an understanding of the fundaments of intelligence, the world of a century from now will be populated by people who do not age and disembodied machine intelligences - easily enough matched to the roles of hidden peoples and household spirits in legend.

Interestingly, in the past I have sketched more or less the opposite thesis to Cave above - that our heritage of myths surrounding progress, death, and mortality are a basis for the widespread knee-jerk rejection of longevity science observed in present day populations:

• Our Beauteous But Destructive Heritage of Myth, Legend, and Stories
• Dying to Live Forever
• "Every Story is the Story of the Fall"

"Every story is the story of the Fall" - except the one that matters, the one we're all writing together with quills of science, will and toil in the real world. That story is a grand arc of irresistible rise, of the defeat of obstacles and surpassing of limitations to our true potential. But you wouldn't know it from the myths that we find most comforting, as illustrated by their widespread nature.

...

The story of the Fall is an old and simple one; the world is one of shortages, pain, suffering and death, yet we humans can conceive of a world absent these troubles. Nostalgia is a part of the human condition also - we see earlier times in our own lives as better than they were, and it's a short leap from there to draw a line of decay from an imagined golden age to the imperfect present. The Fall is an alignment of the mythic world - a better, imaginary world - with the arrow of time; for a variety of reasons, we have come to put that mythic world in the past rather than the future.

...

This is an age of progress and biotechnology. Yet we folk who might be the first ageless humans stand atop a bone mountain. Its slopes are the stories of the dead, created, told, and appreciated by people who knew their own mortality. It is an enormous, pervasive heritage, forged by an army of billions, and no part of our culture or our endeavors is left untouched by it. This is one part of the hurdle we must overcome as we strive to convince people that a near future of rejuvenation biotechnology is plausible, possible, and desirable.

This dichotomy might be another facet of the difficulty in explaining modern attitudes towards longevity and aging. Why are people on the one hand so enthused by the "anti-aging" marketplace, and at the same time so quick to reject real and meaningful science aimed at extending the health human life span? I've thought on this for a decade and still have no satisfying answer.

Source:
http://www.longevitymeme.org/newsletter/latest_rss_feed.cfm