Researchers are turning up a great many human genetic variants associated with natural differences in longevity - a complex, patchwork array of them, each contributing a small amount to the whole: "Aging is a complex phenotype with multiple determinants but a strong genetic component significantly impacts on survival to extreme ages. The dysregulation of immune responses occurring with increasing age is believed to contribute to human morbidity and mortality. Conversely, some genetic determinants of successful aging might reside in those polymorphisms for the immune system genes regulating immune responses. Here we examined the main effects of single loci and multi-locus interactions to test the hypothesis that the adenosine deaminase (ADA) and tumor necrosis factor alpha (TNF-?) genes may influence human life-expectancy. ... SNPs have been determined for 1071 unrelated healthy individuals from Central Italy (18-106 years old) divided into three gender-specific age classes ... Single-locus analysis showed that only ADA 22G>A is significantly associated with human life-expectancy in males ... a significant two-loci interaction occurs in females between ADA 22G>A and TNF-? -238G>A ... both two-loci and three-loci interaction are significant associated with increased life-expectancy over 88years in males. In conclusion, we report that a combination of functional SNPs within ADA and TNF-? genes can influence life-expectancy in a gender-specific manner and that males and females follow different pathways to attain longevity."

Link: http://www.ncbi.nlm.nih.gov/pubmed/21865054

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

From the Technology Review: "I was observing an intimate demonstration of how stem-cell technologies may one day combine with personal genomics and personal medicine. I was the first journalist to undergo experiments designed to see if the four-year-old process that creates induced pluripotent stem (iPS) cells can yield insight into the functioning and fate of a healthy individual's heart cells. Similar tests could be run on lab-grown brain and liver cells, or eventually on any of the more than 200 cell types found in humans. ... This is the next step in personalized medicine: being able to test drugs and other factors on different cell types. ... the cardiomyocytes derived from iPS cells are a huge improvement over the cadaver cells sometimes used to test potential drug compounds. Unlike the cadaver cells, IPS-­generated cells beat realistically and can be supplied in large quantities on demand. What's more, iPS-generated cells can have the same genetic makeup as the patients they came from, which is a huge advantage in tailoring drugs and treatments to individuals. ... Virtually everything about iPS cells is overhyped. But for the purpose of testing drug candidates, I think the possibilities are considerable, and we and lots of other people are pursuing this. There are lots of problems. Are iPS cells really normal? How do you get enough pure differentiated cells? But the potential is definitely there."

Link: http://www.technologyreview.com/biomedicine/38348/

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

A copy number variation is either a large deletion or repeat of a sequence in your DNA. We all have them, and some people have more than others:

Copy-number variants (CNVs) are a source of genetic variation that increasingly are associated with human disease. However, the role of CNVs in human lifespan is to date unknown. To identify CNVs that influence mortality at old age, we analyzed genome-wide CNV data in 5178 participants of Rotterdam Study (RS1) and positive findings were evaluated in 1714 participants of the second cohort of the Rotterdam Study (RS2) and in 4550 participants of Framingham Heart Study (FHS). First, we assessed the total burden of rare (frequency 1%) CNVs for association with mortality during follow-up. ... We observed that the burden of common but not of rare CNVs influences mortality. ... A higher burden of large (?500 kb) common deletions associated with 4% higher mortality.

We might speculate on what this means - and it's interesting to do so in light of the present debate over the role of nuclear DNA damage in aging. Is having generally more ragged DNA a bad thing in and of itself, or is it instead a marker for poor quality in other important biological processes, such that the DNA repair and copy checking mechanisms that exist to prevent this sort of issue from coming about in the first place? Only a handful of CNVs have been linked to raised risk of specific diseases, but that there is a general correlation with mortality rate suggests that researchers will find many more specific issues and areas of enhanced risk if they go looking for them.

Fortunately, the long age in which we humans were at the complete mercy of our inherited DNA is coming to a close - it'll be a fading memory only a century from now, something to look back on with mild horror, much as we look back on the comparatively recent ages in which infectious disease was a scourge. One of the great benefits of biotechnology is that every advance will allows the medical community to balance a small part of the genetic heritage we came into this world with. Some people enter the game with a bad hand: that matters less now than it did in the past, and it won't be too many decades more before it hardly matters at all - the sooner the better, I say.

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

Cryonics provider Alcor dedicates a section of their website to challenges and problems, and it is well worth reading: "When you buy a house, the seller is legally obliged to disclose any known defects. When you review a company's annual report, it tells you every problem that could affect the corporate share value. Since arrangements for cryopreservation may have a much greater impact on your life than home ownership or stock investments, we feel an ethical obligation to disclose problems that affect cryonics in general and Alcor specifically. We also believe that an organization which admits its problems is more likely to address them than an organization which pretends it has none. Thus full disclosure should encourage, rather than discourage, consumer confidence. ... As of 2011, Alcor is nearly 40 years old. Our Patient Care Trust Fund is endowed with more than 7 million dollars and is responsible for the long-term care of over 100 cryopatients. In almost every year since its inception Alcor has enjoyed positive membership growth. We are the largest cryonics organization in the world - yet in many respects we are still a startup company. We have fewer than a dozen employees in Scottsdale, Arizona and approximately 20 part-time independent contractors in various locations around the USA, mostly dedicated to emergency standby and rescue efforts. We serve fewer than 1,000 members and the protocols that aid our pursuit of the goal of reversible suspended animation continue to be developed. At the present time the technology required for the realization of our goal far exceeds current technical capabilities. Cryonics will not be comparable with mainstream medicine until our patients can be revived using contemporary technology, and we expect to wait for decades to see this vision fulfilled. Nevertheless, we have made important progress by introducing brain vitrification to improve patient tissue structure preservation. Alcor shares some of the characteristics of startup companies. The organization is understaffed in some important areas and lacks as much capitalization as would be desired to support maximum growth. Limited resources prevent the organization from hiring as many highly qualified and experienced personnel as desired, and sometimes we have to postpone enhancements to equipment and procedures." I think that this is a great document, and Alcor staff are to be congratulated for publishing it - absolutely the right thing to do.

Link: http://alcor.org/problems.html

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

Cryonics provider Alcor dedicates a section of their website to challenges and problems, and it is well worth reading: "When you buy a house, the seller is legally obliged to disclose any known defects. When you review a company's annual report, it tells you every problem that could affect the corporate share value. Since arrangements for cryopreservation may have a much greater impact on your life than home ownership or stock investments, we feel an ethical obligation to disclose problems that affect cryonics in general and Alcor specifically. We also believe that an organization which admits its problems is more likely to address them than an organization which pretends it has none. Thus full disclosure should encourage, rather than discourage, consumer confidence. ... As of 2011, Alcor is nearly 40 years old. Our Patient Care Trust Fund is endowed with more than 7 million dollars and is responsible for the long-term care of over 100 cryopatients. In almost every year since its inception Alcor has enjoyed positive membership growth. We are the largest cryonics organization in the world - yet in many respects we are still a startup company. We have fewer than a dozen employees in Scottsdale, Arizona and approximately 20 part-time independent contractors in various locations around the USA, mostly dedicated to emergency standby and rescue efforts. We serve fewer than 1,000 members and the protocols that aid our pursuit of the goal of reversible suspended animation continue to be developed. At the present time the technology required for the realization of our goal far exceeds current technical capabilities. Cryonics will not be comparable with mainstream medicine until our patients can be revived using contemporary technology, and we expect to wait for decades to see this vision fulfilled. Nevertheless, we have made important progress by introducing brain vitrification to improve patient tissue structure preservation. Alcor shares some of the characteristics of startup companies. The organization is understaffed in some important areas and lacks as much capitalization as would be desired to support maximum growth. Limited resources prevent the organization from hiring as many highly qualified and experienced personnel as desired, and sometimes we have to postpone enhancements to equipment and procedures." I think that this is a great document, and Alcor staff are to be congratulated for publishing it - absolutely the right thing to do.

Link: http://alcor.org/problems.html

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

Good news from the dental research community: scientists "have developed a revolutionary new way to treat the first signs of tooth decay. Their solution is to arm dentists with a peptide-based fluid that is literally painted onto the tooth's surface. The peptide technology is based on knowledge of how the tooth forms in the first place and stimulates regeneration of the tooth defect. ... This may sound too good to be true, but we are essentially helping acid-damaged teeth to regenerate themselves. It is a totally natural non-surgical repair process and is entirely pain-free too. ... It contains a peptide known as P 11-4 that -- under certain conditions - will assemble together into fibres. In practice, this means that when applied to the tooth, the fluid seeps into the micro-pores caused by acid attack and then spontaneously forms a gel. This gel then provides a 'scaffold' or framework that attracts calcium and regenerates the tooth's mineral from within, providing a natural and pain-free repair. The technique was recently taken out of the laboratory and tested on a small group of adults whose dentist had spotted the initial signs of tooth decay. The results from this small trial have shown that P 11-4 can indeed reverse the damage and regenerate the tooth tissue. ... If these results can be repeated on a larger patient group, then I have no doubt whatsoever that in two to three years time this technique will be available for dentists to use in their daily practice."

Link: http://www.sciencedaily.com/releases/2011/08/110823115402.htm

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

Researchers are spending a fair amount of time on understanding why regeneration in mammals differs from - and is much worse than - regeneration in lower animals like salamanders. A salamander can grow back a limb any time it needs to, a mouse or a human not so much. But we can do the full regeneration trick to a far lesser degree, as humans and mice can both regrow the tip of a finger or toe when very young or very lucky, for example. You might also recall the MRL mice, an engineered species that can regenerate much more effectively than is normal for most mice.

One of the questions that researchers aim to answer is whether the mechanisms for salamander-like regeneration lie buried in mammalian biology, perhaps turned off for reasons involving cancer suppression. If they are there, perhaps they can be restored via drugs or genetic engineering for long enough to regrow major damage to limbs and organs. That's all speculative at this point, and looking more so after this latest research publication:

Tissue-specific adult stem cells are responsible for the ability of mammals to re-grow the tips of fingers or toes lost to trauma or surgery, say researchers at the Stanford University School of Medicine. The finding discredits a popular theory that holds that previously specialized cells regress, or dedifferentiate, in response to injury to form a pluripotent repair structure called a blastema.

"We've shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types," said Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The controversy about limb regeneration in mammals should be over."

If you want to take the glass half full view, this might mean that it will be a shorter path to pushing these stem cells into doing more with less - rather than the alternative and longer path of trying to recreate salamander-like blastema behavior in mammals. But it's anyone's guess as to how much regeneration these cells are capable of if manipulated; no doubt less than we'd all like.

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

Researchers are spending a fair amount of time on understanding why regeneration in mammals differs from - and is much worse than - regeneration in lower animals like salamanders. A salamander can grow back a limb any time it needs to, a mouse or a human not so much. But we can do the full regeneration trick to a far lesser degree, as humans and mice can both regrow the tip of a finger or toe when very young or very lucky, for example. You might also recall the MRL mice, an engineered species that can regenerate much more effectively than is normal for most mice.

One of the questions that researchers aim to answer is whether the mechanisms for salamander-like regeneration lie buried in mammalian biology, perhaps turned off for reasons involving cancer suppression. If they are there, perhaps they can be restored via drugs or genetic engineering for long enough to regrow major damage to limbs and organs. That's all speculative at this point, and looking more so after this latest research publication:

Tissue-specific adult stem cells are responsible for the ability of mammals to re-grow the tips of fingers or toes lost to trauma or surgery, say researchers at the Stanford University School of Medicine. The finding discredits a popular theory that holds that previously specialized cells regress, or dedifferentiate, in response to injury to form a pluripotent repair structure called a blastema.

"We've shown conclusively that what was thought to be a blastema is instead simply resident stem cells that are already committed to become specific tissue types," said Irving Weissman, MD, director of Stanford's Institute for Stem Cell Biology and Regenerative Medicine. "The controversy about limb regeneration in mammals should be over."

If you want to take the glass half full view, this might mean that it will be a shorter path to pushing these stem cells into doing more with less - rather than the alternative and longer path of trying to recreate salamander-like blastema behavior in mammals. But it's anyone's guess as to how much regeneration these cells are capable of if manipulated; no doubt less than we'd all like.

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

So far research on cellular reprogramming has largely focused on manipulation of cells outside the body. Here a researcher suggests that the future of medicine will involve achieving much the same thing inside the body: "To date, somatic cell reprogramming has been achieved in vitro. It would be of great importance to explore whether the anti-aging agents, e.g. rapamycin, could function to enhance stem cell function, protect stem cell pluripotency and even promote reprogramming in vivo. It is also very interesting to verify whether some or all adult organs/tissues do possess some significant regenerative capacity due to the suspected in vivo reprogramming. Furthermore, it has been reported that agents which effectively function for a common human disease by enhancing self-renewal could lose efficacy in older individuals due to the age-associated decline of replication. Thus understanding and realization of in vivo cell reprogramming is not only a fundamental theoretical question but also a very promising strategy for anti-aging and regenerative medicine. Reprogramming of somatic cells has been enthusiastically hoped to become an arsenal to against aging as it would leads to personalized stem-cell-based rejuvenation therapies. What we learn from research of stem cell and reprogramming could help us to develop two potential anti-aging approaches in adult and older: i) to protect, ameliorate or reverse the age-associated loss function of stem cell in vivo and ii) to replace the lost stem cells by reprogrammed pluripotent cells."

Link: http://impactaging.com/papers/v3/n8/full/100364.html

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

Researchers here outline one possible mechanism for the known association between chronic stress and biomarkers of health: "While the human mind and body are built to respond to stress - the well-known "fight or flight" response, which lasts only a few minutes and raises heart rate and blood glucose levels - the response itself can cause significant damage if maintained over long periods of time. When stress becomes chronic, this natural response can lead to a number of disease-related symptoms, including peptic ulcers and cardiovascular disorders. To make matters worse, evidence indicates that chronic stress eventually leads to DNA damage, which in turn can result in various neuropsychiatric conditions, miscarriages, cancer, and even aging itself. ... The newly uncovered mechanism involves ?-arrestin-1 proteins, ?2-adrenoreceptors (?2ARs), and the catecholamines, the classic fight-or-flight hormones released during times of stress - adrenaline, noradrenaline, and dopamine. Arrestin proteins are involved in modifying the cell's response to neurotransmitters, hormones, and sensory signals; adrenoceptors respond to the catecholamines noradrenaline and adrenaline. Under stress, the hormone adrenaline stimulates ?2ARs expressed throughout the body, including sex cells and embryos. Through a series of complex chemical reactions, the activated receptors recruit ?-arrestin-1, creating a signaling pathway that leads to catecholamine-induced degradation of the tumor suppressor protein p53, sometimes described as "the guardian of the genome." The new findings also suggest that this degradation of p53 leads to chromosome rearrangement and a build-up of DNA damage both in normal and sex cells." p53 is very important in a range of core cellular processes - anything touching on it usually turns out to be influential.

Link: http://www.kurzweilai.net/how-stress-causes-dna-damage

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

Mitochondria in your cells damage themselves in the course of their vital, life-sustaining operations, and these damaged mitochondria contribute to aging. It's a progressive and complicated process of many steps, by which incidents of atomic-scale damage in the power plants of your cells steadily overwhelm evolved countermeasures and repair systems, corrupting a fraction of your cells and blossoming into a flow of damaged molecules throughout the body. That in turn produces the roots of atherosclerosis and many other age-related forms of degeneration and malfunction.

We would like to be able to do something about this - by hook or by crook restore the damage state of an old person's mitochondria to the way things were when he was young. There are many possible paths forward, most understood in some detail at this time, and which will either be be shown to fail or succeed within the next decade or two. The work proceeds, but very, very slowly. It's not a broad and well populated field of research, sad to say.

The importance of mitochondria is one of the reasons that autophagy is also important when it comes to the progression of aging. Autophagy is the name given to a collection of varied recycling machinery and processes that operate within cells, destroying damaged components - such as mitochondria. It shouldn't be a great leap to think that improving the recycling mechanisms might also improve the situation vis a vis malfunctioning mitochondria. This is probably the case, based on what researchers know of mitophagy, the processes of autophagy concerned with removing damaging mitochondria.

Insofar as the bottom line of health and longevity goes, there is plenty of evidence to suggest that dialing up autophagy extends life, and a further array of evidence to suggest that known life-extending techniques such as calorie restriction depend heavily on autophagy as a principle mechanism of action.

Based on what's coming out of the labs in recent years, I think the research community isn't too far away from conducting studies that will definitively show - or definitively disprove, which would be unexpected - benefits to longevity from improved mitoautophagy alone. Take this, for example:

[Researchers] have defined a specific protein complex that allows cells to rid themselves of damaged mitochondria, which are the energy producing machines of the cell. ... The study highlights the interaction between Hsp90-Cdc37 and Ulk1, a kinase that the authors show is required for the degradation and elimination of damaged mitochondria. Hsp90-Cdc37 stabilizes and activates Ulk1, which in turn phosphorylates its substrate Atg13, which is then released from the complex. Atg13 then eliminates damaged mitochondria via the autophagy pathway. Thus, the study links Hsp90-Cdc37-Ulk1-Atg13 in a direct pathway that is essential for efficient mitochondrial clearance.

"The new study shows that the key regulatory mechanism of this process is the Hsp90-Cdc37 chaperone, which functions as an on-off switch that is critical for the correct functioning of the Ulk1 kinase," Cleveland said. "Thus, if we can control this switch, we can significantly improve the therapeutic window."

Meaning this is a target for designed drug compounds to boost autophagy specifically aimed at clearing out more of the damaged mitochondria than would otherwise be the case. How far would this get us? A good guess would be in the same ballpark as calorie restriction mimetics: it's a similar mechanism. So in other words this may do good things for health in humans, but don't expect spectacular results when it comes to life span.

The problem with attacking mitochondria by boosting autophagy is that we already know that certain forms of mitochondrial damage manage to elude autophagic processes: that's how we end up in the bad place. So boosting autophagy just slows things down, and does't solve the underlying problem. A different type of approach is needed for a real solution, one based on repair rather than slowing existing processes of damage - and as it happens making progress along the paths towards mitochondrial repair shouldn't be any harder than safely and effectively adjusting the processes of autophagy.

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