One of the many popular and distinct online communities that make up Reddit is IAmA ("I am a"), which runs verified question and answer sessions (AMAs, or "ask me anything") with all sorts of folk in interesting positions, with interesting jobs, or who are just plain interesting. You might consider it the crowdsourced, irreverent, collaborative offspring of chat shows, radio call-in programs, and the last ten years of online bulletin board evolution - this is what the kids do nowadays in place of turning on the TV or radio. In any case, I somehow entirely missed noting that a video AMA for Aubrey de Grey of the SENS Foundation has been running at Reddit to accumulate questions these past few days. Most AMAs are real-time posting sessions, but in this case the most upvoted questions will be passed on to de Grey to be answered in a video which will then be posted back to the community:

Aubrey de Grey is a leading scientist in the field of biomedical gerontology, the quest to develop true medical control of aging.

http://en.wikipedia.org/wiki/Aubrey_de_Grey

Dr. de Grey wrote in this week and mentioned that he had been urged on several occasions in the past few months to do an AMA. There was a lot of interest in the possibility that he could do his AMA as a video reply to a selection of representative questions, in the way that Richard Dawkins did some time ago ... We'll take your top ten best questions for Aubrey de Grey and send them to him later this week to be answered on video.

Once you get past the lowest common denominator popular communities - Reddit really doesn't work well unless you create an account and start ruthlessly pruning what you see - Reddit is a fairly pro-longevity, pro-biotechnology, and pro-science community, supportive of the goal of extending the healthy human life span through medical science, and the sooner the better. It has been pleasant to see that emerging ever more readily in the online communities of the past ten years.

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

No great surprise here, given that calorie restriction in mammals slows almost all measures of aging investigated to date: "Long-term caloric restriction (CR) has been reported to extend the life spans, delay the onset and decrease the incidence of a broad spectrum of age-associated diseases. However, its effect on rat explorative behaviour is still unclear. In the present study, a number of behavioural measures were continuously monitored in 3-, 12-, 24-25-, 28-29- and 35-44-month-old male Wistar rats that were fed either ad libitum or placed on a caloric restricted diet. A gradual decline in locomotor activity of the ad libitum fed rats has been determined during aging in the open field test. In the CR groups, 3-month-old rats exhibited lower levels of exploratory behavior, compared to rats on the control diet. 24-25-month-old CR rats exhibited higher levels of exploratory behaviour, compared to ad libitum fed animals of the same age. Chronic dietary restriction nullified the age-dependent decline in locomotor activity and explorative behaviour of rats."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22590739

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

It is taken as a tenet around here that involuntary death is a bad thing, and the process of getting to be dead despite your own wishes on the matter is arguably worse - it involves a great deal of ongoing suffering and pain as the body progressively fails. Greatly diminishing the incidence of death is one aim of the longevity science movement, achieved through the elimination of degenerative aging, the greatest cause of death. Can we say why being dead is bad, however? That is supposedly a harder job than declaring suffering to be bad and worthy of amelioration - though most philosophers fail to consider the economic costs of destruction, and in the end it should all come down to "I've decided I don't like it, and so I'll work towards doing something about it through progress in medical science." Reasons beyond personal choice are unnecessary, but here is a brief tour of some of the philosophy of death and nonexistence: "We all believe that death is bad. But why is death bad? In thinking about this question, I am simply going to assume that the death of my body is the end of my existence as a person. But if death is my end, how can it be bad for me to die? After all, once I'm dead, I don't exist. If I don't exist, how can being dead be bad for me? ... there's a puzzle raised by the Roman philosopher Lucretius, who thought it a mistake to find the prospect of my death upsetting. Yes, as the deprivation account points out, after death we can't enjoy life's pleasures. But wait a minute, says Lucretius. The time after I die isn't the only period during which I won't exist. What about the period before my birth? If nonexistence is so bad, shouldn't I be upset by the eternity of nonexistence before I was born? But that's silly, right? Nobody is upset about that. So, he concludes, it doesn't make any sense to be upset about the eternity of nonexistence after you die, either. It isn't clear how best to reply to Lucretius. One option, presumably, is to agree that we really do need to treat those two eternities of nonexistence on a par, but to insist that our prebirth nonexistence was worse than we thought. Alternatively, we might insist that there's an asymmetry that explains why we should care about the one period but not the other. But what is that difference? Perhaps this: When I die, I have lost my life. In contrast, during the eternity before my birth, although I'm not alive, I have not lost anything. You can't lose what you never had. So what's worse about death is the loss."

Link: http://chronicle.com/article/Is-Death-Bad-for-You-/131818/

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

It is taken as a tenet around here that involuntary death is a bad thing, and the process of getting to be dead despite your own wishes on the matter is arguably worse - it involves a great deal of ongoing suffering and pain as the body progressively fails. Greatly diminishing the incidence of death is one aim of the longevity science movement, achieved through the elimination of degenerative aging, the greatest cause of death. Can we say why being dead is bad, however? That is supposedly a harder job than declaring suffering to be bad and worthy of amelioration - though most philosophers fail to consider the economic costs of destruction, and in the end it should all come down to "I've decided I don't like it, and so I'll work towards doing something about it through progress in medical science." Reasons beyond personal choice are unnecessary, but here is a brief tour of some of the philosophy of death and nonexistence: "We all believe that death is bad. But why is death bad? In thinking about this question, I am simply going to assume that the death of my body is the end of my existence as a person. But if death is my end, how can it be bad for me to die? After all, once I'm dead, I don't exist. If I don't exist, how can being dead be bad for me? ... there's a puzzle raised by the Roman philosopher Lucretius, who thought it a mistake to find the prospect of my death upsetting. Yes, as the deprivation account points out, after death we can't enjoy life's pleasures. But wait a minute, says Lucretius. The time after I die isn't the only period during which I won't exist. What about the period before my birth? If nonexistence is so bad, shouldn't I be upset by the eternity of nonexistence before I was born? But that's silly, right? Nobody is upset about that. So, he concludes, it doesn't make any sense to be upset about the eternity of nonexistence after you die, either. It isn't clear how best to reply to Lucretius. One option, presumably, is to agree that we really do need to treat those two eternities of nonexistence on a par, but to insist that our prebirth nonexistence was worse than we thought. Alternatively, we might insist that there's an asymmetry that explains why we should care about the one period but not the other. But what is that difference? Perhaps this: When I die, I have lost my life. In contrast, during the eternity before my birth, although I'm not alive, I have not lost anything. You can't lose what you never had. So what's worse about death is the loss."

Link: http://chronicle.com/article/Is-Death-Bad-for-You-/131818/

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

Much of the mainstream aging research community has little interest in building therapies for aging, being focused on investigation only - though, fortunately, this situation is changing rapidly these days. The past stigma associated with public discussion of treating and ultimately preventing aging has largely evaporated within the scientific world.

Among those researchers who are interested in therapies for aging, most are focused on the slow boat of metabolic alteration: work that will have comparatively little pay-off even if successful, but which fits more readily into established research programs and the prejudices of research funding institutions.

The principal downside of metabolic alteration strategies, from my point of view, is that even if successful they cannot produce any significant longevity benefit in a person already old. All it can do is slow down aging by a modest amount - which isn't terribly useful those already aged and damaged. Even under the most optimistic estimates it will take another twenty years and many billions of dollars to see the evolution of a robust market in commercially available human metabolic enhancements to slow aging. It is a challenging field of research, and progress to date has been slow even in this era of rapid advances in biotechnology.

There is another disadvantage, which is illustrated by the different degrees to which life span is enhanced by similar strategies applied in mice versus humans. It is taken for granted in the literature, and thus probably not emphasized to the degree it should be, that an extension of life by 50% in mice based on some genetic or metabolic alteration - such as calorie restriction or growth hormone knockout - is probably not going to map to a similar extension of life in humans. If humans could achieve that sort of life extension through simply eating well and eating less or being growth hormone mutants, we'd have known about it by now. Consider Laron dwarfism, for example, or the generation after generation of practitioners of various degrees of calorie restriction that exist in many cultures.

With an eye to this second disadvantage, I'll point out an open access paper that considers the evolution of aging from the point of view of the maintenance gap. This is the gap between the cost of maintenance required to keep an organism from aging and the resources actually devoted to maintenance - both of which are subject to evolutionary selection pressures, which operate to maximize success in genetic propagation rather than the comfort or longevity of individual members of a species. The paper was published last year, but showed up in a recent issue of Biogerontology.

The maintenance gap: a new theoretical perspective on the evolution of aging

One of the prevailing theories of aging, the disposable soma theory, views aging as the result of the accumulation of damage through imperfect maintenance. Aging, then, is explained from an evolutionary perspective by asserting that this lack of maintenance exists because the required resources are better invested in reproduction. However, the amount of maintenance necessary to prevent aging, 'maintenance requirement' has so far been largely neglected and has certainly not been considered from an evolutionary perspective. To our knowledge we are the first to do so, and arrive at the conclusion that all maintenance requirement needs an evolutionary explanation.

Increases in maintenance requirement can only be selected for if these are linked with either higher fecundity or better capabilities to cope with environmental challenges to the integrity of the organism. Several observations are suggestive of the latter kind of trade-off, the existence of which leads to the inevitable conclusion that the level of maintenance requirement is in principle unbound. Even the allocation of all available resources to maintenance could be unable to stop aging in some organisms.

This has major implications for our understanding of the aging process on both the evolutionary and the mechanistic level. It means that the expected effect of measures to reallocate resources to maintenance from reproduction may be small in some species. We need to have an idea of how much maintenance is necessary in the first place. Our explorations of how natural selection is expected to act on the maintenance requirement provides the first step in understanding this.

The point to take away from this argument is that we should expect to find a broad variation between species in their response to similar forms of metabolic and genetic alteration aimed at extending life span. So far, that is what is seen, with we humans having the short end of the stick - though obviously there is an ocean of data yet to be obtained on this topic. On the whole, though, it seems like one more slowly building argument for the research community to focus on repair-based strategies for treating aging: build biotechnologies that are explicitly designed to repair forms of biological damage that existing repair systems either cannot handle or handle too slowly. SENS is the most obvious example, though I expect other, competing repair-focused visions to emerge in the years ahead as the SENS Foundation obtains further scientific support and promising research results.

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

Insulin-like growth factor 1 (IGF-1) is one of the more studied areas of known overlap between metabolism and longevity, but given the innate complexity of biology in mammals there is always some debate over the degree to which IGF-1-related mechanisms are actually determinants of life span, or even correlated with life span. Here is a study in sheep, not the usual species in investigations of the biochemistry of aging: "Longevity in livestock is a valuable trait. When productive animals live longer fewer replacement animals need to be raised. However, selection for longevity is not commonly the focus of breeding programs as direct selection for long-lived breeding stock is virtually impossible until late in the animal's reproductive life. Additionally the underlying genetic factors or genes associated with longevity are either not known, or not well understood. In humans, there is evidence that insulin-like growth factor 1 receptor (IGF1R) is involved in longevity. Polymorphism in the IGF1R gene (IGF1R) has been associated with longevity in a number of species. Recently, 3 alleles of ovine IGF1R were identified, but no analysis of the effect of IGF1R variation on sheep longevity has been reported. In this study, associations between ovine IGF1R variation, longevity and fertility were investigated [in] 1716 New Zealand sheep belonging to 6 breeds and 36 flocks. ... Ovine IGF1R C was associated with age when adjusting for flock [and] a weak negative [correlation] between fertility and longevity traits was observed."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22585783

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

Researchers continue to investigate why the ApoE4 gene variant is associated with Alzheimer's disease: "A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report ... a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not. [Scientists] found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's. ... In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm ... In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue. When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent."

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3512

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

Researchers continue to investigate why the ApoE4 gene variant is associated with Alzheimer's disease: "A well-known genetic risk factor for Alzheimer's disease triggers a cascade of signaling that ultimately results in leaky blood vessels in the brain, allowing toxic substances to pour into brain tissue in large amounts, scientists report ... a gene called ApoE4 makes people more prone to developing Alzheimer's. People who carry two copies of the gene have roughly eight to 10 times the risk of getting Alzheimer's disease than people who do not. [Scientists] found that ApoE4 works through cyclophilin A, a well-known bad actor in the cardiovascular system, causing inflammation in atherosclerosis and other conditions. The team found that cyclophilin A opens the gates to the brain assault seen in Alzheimer's. ... In the presence of ApoE4, increased cyclophilin A causes a breakdown of the cells lining the blood vessels in Alzheimer's disease in the same way it does in cardiovascular disease or abdominal aneurysm ... In studies of mice, the team found that mice carrying the ApoE4 gene had five times as much cyclophilin A compared to other mice in cells known as pericytes, which are crucial to maintaining the integrity of the blood-brain barrier. Blood vessels died, blood did not flow as completely through the brain as it did in other mice, and harmful substances like thrombin, fibrin, and hemosiderin, entered the brain tissue. When the team blocked the action of cyclophilin A, either by knocking out its gene or by using the drug cyclosporine A to inhibit it, the damage in the mice was reversed. Blood flow resumed to normal, and unhealthy leakage of toxic substances from the blood vessels into the brain was slashed by 80 percent."

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3512

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

Naked mole-rats are becoming very well studied. Researchers are attempting to find the root causes of cancer immunity and exceptional longevity in this species, with an eye to creating beneficial medical biotechnologies for humans. Fight Aging! has seen a couple of items on naked mole-rats already this month, which is illustrative of the present pace:

• More on NRG-1 in Naked Mole-Rats
• Enhanced Proteasome Activity in Naked Mole Rats

Present theories are varied, but on the longevity side of the house the consensus appears to lean towards an increased resistance to forms of cellular membrane damage - naked mole rat membranes are built of a more resilient mix of proteins than those of comparable species. This is known as the membrane pacemaker hypothesis of aging:

The membrane pacemaker hypothesis predicts that long-living species will have more peroxidation-resistant membrane lipids than shorter living species. ... Resistance to oxidative damage is of particular importance in mitochondria, cellular power plants that progressive damage themselves with the reactive oxygen species they produce as a byproduct of their operation - and that gives rise to a chain of further biochemical damage that spreads throughout the body, growing ever more harmful as you age. Less damage to the mitochondria should mean slower aging, and thus more resistant mitochondrial membranes should also mean slower aging.

Continuing the naked mole-rat theme for May, here is another just-published open access paper on the resilience of naked mole-rat biology (abstract, and full article):

Studies comparing similar-sized species with disparate longevity may elucidate novel mechanisms that abrogate aging and prolong good health. We focus on the longest living rodent, the naked mole-rat. This mouse-sized mammal lives ?8 times longer than do mice and, despite high levels of oxidative damage evident at a young age, it is not only very resistant to [cancer] but also shows minimal decline in age-associated physiological traits.

...

Like other experimental animal models of lifespan extension, naked mole-rat fibroblasts are extremely tolerant of a broad spectrum of cytotoxins including heat, heavy metals, DNA-damaging agents and xenobiotics, showing [median lethal dose] values between 2- and 20-fold greater than those of fibroblasts of shorter-lived mice. Our new data reveal that naked mole-rat fibroblasts stop proliferating even at low doses of toxin whereas those mouse fibroblasts that survive treatment rapidly re-enter the cell cycle and may proliferate with DNA damage. Naked mole-rat fibroblasts also show significantly higher constitutive levels of both p53 and Nrf2 protein levels and activity, and this increases even further in response to toxins.

...

Enhanced cell signaling via p53 and Nrf2 protects cells against proliferating with damage, augments clearance of damaged proteins and organelles and facilitates the maintenance of both genomic and protein integrity. These pathways collectively regulate a myriad of mechanisms which may contribute to the attenuated aging profile and sustained healthspan of the naked mole-rat. Understanding how these are regulated may be also integral to sustaining positive human healthspan well into old age and may elucidate novel therapeutics for delaying the onset and progression of physiological declines that characterize the aging process.

You might also look back a few years at other research into the role of Nrf2 in determining species longevity. The details can be a little overwhelming, but the big picture remains one of damage at the level of cells and protein machinery: less damage and more resilience to damage means a longer life span.

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

Researchers here analyze the proteome of the hypothalamus and argue for an important role in coordinating bodily responses to ongoing changes caused by aging: "The aging process affects every tissue in the body and represents one of the most complicated and highly integrated inevitable physiological entities. The maintenance of good health during the aging process likely relies upon the coherent regulation of hormonal and neuronal communication between the central nervous system and the periphery. Evidence has demonstrated that the optimal regulation of energy usage in both these systems facilitates healthy aging. However, the proteomic effects of aging in regions of the brain vital for integrating energy balance and neuronal activity are not well understood. The hypothalamus is one of the main structures in the body responsible for sustaining an efficient interaction between energy balance and neurological activity. Therefore, a greater understanding of the effects of aging in the hypothalamus may reveal important aspects of overall organismal aging and may potentially reveal the most crucial protein factors supporting this vital signaling integration. In this study, we examined alterations in protein expression in the hypothalami of young, middle-aged, and old rats. ... Based upon our rigorous analyses, we show that endogenous physiological responses to aging may be strongly orchestrated by the expression level of the GIT2 protein. The relevance of the hypothalamic expression level of this protein to the aging process in both neuronal and energy-controlling tissues reinforces the importance of this organ in the potential future development of targeted pharmacotherapeutics designed to interdict a multitude of age-related disorders."

Link: http://dx.doi.org/10.1371/journal.pone.0036975

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

A possible method of boosting muscle repair, and thus treating muscle wasting conditions - such as the sarcopenia that attends aging: "a lipid signaling molecule called sphingosine-1-phosphate or 'S1P' can trigger an inflammatory response that stimulates the muscle stem cells to proliferate and assist in muscle repair. ... mdx mice, which have a disease similar to Duchenne Muscular Dystrophy, exhibit a deficiency of S1P, [and] boosting their S1P levels improves muscle regeneration ... The ability of muscles to regenerate themselves is attributed to the presence of a form of adult stem cells called 'satellite cells' that are essential for muscle repair. Normally, satellite cells lie quietly at the periphery of the muscle fiber and do not grow, move or become activated. However, after muscle injury, these stem cells 'wake up' through unclear mechanisms and fuse with the injured muscle, stimulating a complicated process that results in the rebuilding of a healthy muscle fiber. S1P is a lipid signaling molecule that controls the movement and proliferation of many human cell types. ... S1P is able to 'wake up' the stem cells at the time of injury. It involves the ability of S1P to activate S1P receptor 2, one of its five cell surface receptors, leading to downstream activation of an inflammatory pathway controlled by a transcription factor called STAT3. [This results] in changes in gene expression that cause the satellite cell to leave its 'sleeping' state and start to proliferate and assist in muscle repair. ... If these findings are also found to be true in humans with Duchenne Muscular Dystrophy, it may be possible to use similar approaches to boost S1P levels in order to improve satellite cell function and muscle regeneration in patients with the disease. Drugs that block S1P metabolism and boost S1P levels are now being tested for the treatment of other human diseases including rheumatoid arthritis. If these studies prove to be relevant in Duchenne patients, it may be possible to use the same drugs to improve muscle regeneration in these patients. Alternatively, new agents that can specifically activate S1P receptor 2 could also be beneficial in recruiting satellite cells and improving muscle regeneration in muscular dystrophy and potentially other diseases of muscle."

Link: http://www.sciencedaily.com/releases/2012/05/120515070307.htm

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

You might recall that late last year I pointed out a large Japanese longitudinal study on incidental moderate exercise and lifetime medical costs:

The authors followed up 27,738 participants aged 40-79?years and prospectively collected data on their medical expenditure and survival covering a 13-year-period. ... The present results indicate that the multiadjusted lifetime medical expenditure from the age of 40?years for those who walked ?1?h per day was significantly lower by 7.6% in men and non-significantly lower by 2.7% in women than for those who walked <1?h per day. This decrease in lifetime medical expenditure was observed in spite of a longer life expectancy (1.38?years for men and 1.16?years for women) among those who walked ?1?h per day.

In another, more open access recent paper, the same authors have crunched the numbers for variations in weight among study participants. The story is much the same, as one would expect:

Although four previous studies have examined the association between obesity and lifetime medical expenditure, the results were inconsistent. ... We therefore conducted a 13-year prospective observation of 41,965 Japanese adults aged 40-79?years living in the community, which accrued 392,860 person-years. We examined the association between BMI and lifetime medical expenditure, based on individual medical expenditure and life table analysis. We collected data for survival and all medical care utilisation and costs, excluding home care services provided home health aides, nursing home care and preventive health services in participants of this cohort study.

...

In spite of their short life expectancy, obese men and women had approximately 14.7% and 21.6% higher lifetime medical expenditure in comparison with normal weight participants, respectively.

Don't get fat, don't stay fat, and don't be a couch potato. Thus speaks the weight of evidence - but then we all knew that, right? Being unhealthy has definitive material costs in the long term: years of life shaved off, the rot of your body and mind, and the monetary cost of medical services you would otherwise not have needed. There are plenty of people in this world, far too many, who don't presently have the luxury of choice when it comes to being healthy: the genetically impaired, the immune-damaged, the infected, the wounded. Why fritter away your choice for the sake of eating and laziness? It is almost a gesture of contempt.

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