Some mitochondrial DNA lineages are objectively better than others, as demonstrated by correlations with longevity in humans. Here is a correlation with dementia risk, which might be superficially explained by a greater ability to power fuel-hungry neurons, or greater resistance to mitochondrial damage over time: "Mitochondrial dysfunction is a prominent hallmark of Alzheimer's disease (AD). Mitochondrial DNA (mtDNA) damage may be a major cause of abnormal reactive oxidative species production in AD or increase neuronal susceptibility to oxidative injury during aging. The purpose of this study was to assess the influence of mtDNA sequence variation on clinically significant cognitive impairment and dementia risk in the population-based Health, Aging, and Body Composition (Health ABC) Study. We first investigated the role of common mtDNA haplogroups and individual variants on dementia risk and 8-year change on the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) among 1,631 participants of European genetic ancestry. Participants were free of dementia at baseline and incidence was determined in 273 cases from hospital and medication records over 10-12 follow-up years. Participants from haplogroup T had a statistically significant increased risk of developing dementia and haplogroup J participants experienced a statistically significant 8-year decline in 3MS, both compared with common haplogroup H. [Other variants were] associated with a significant decline in DSST score [or] 3MS score."

Link: http://www.ncbi.nlm.nih.gov/pubmed/22785396

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

The Methuselah Foundation formally launched the New Organ initiative earlier this year: a research and technology prize aimed at speeding up tissue engineering of replacement organs. Today the Foundation announced the New Organ 100:

Today, 3,000 people will die from organ failure, many due to the lack of replacement organs. In the U.S. alone, over 100,000 are stuck on a waiting list, and many more can't even get on a list.

We need a revolution in medicine, and we need it as soon as possible.

Regenerative medicine is coming of aging. Significant breakthroughs are beginning to happen, but the funding to move the science and technology forward remains woefully inadequate.

The Methuselah Foundation is announcing today the New Organ 100 to kickstart a visible, popular movement with a singular purpose: make regenerative medicine famous to achieve whole organ manufacturing within 10 years.

We invite you to be among the initial 100 New Organizers, the seeds of the movement who each make the same pledge: give $10 a month toward raising the New Organ Prize, and ask 10 friends and family to do the same.

The goal of the New Organ Prize is simple: to stimulate progress while demonstrating the rising demand for greater R&D funding. 100% of gifts go toward growing the prize. Every gift is matched by donors to support the New Organ Fund, which funds our operations and investments in startups advancing critical technologies, such as Organovo's 3D bioprinter and Silverstone Solutions' kidney-matching software.

Lee Downing was one of the lucky ones. When he got on the waiting list for a liver transplant, it was only 4,000 people long. After his transplant in 1988, he regained his health completely. He's been actively promoting organ donation ever since, working hard to enable others to receive the git of life that he was blessed with.

And after 24 years in the trenches, he's never felt as optimistic as he does now:

"It's pretty simple. We've tried everything, and we still haven't succeeded. I believe we need a revolutionary change in our approach to transplantation, and New Organ is it. Without it, more people are going to die, and even more people are to be added to the waiting list. The New Organ Prize, where modern medicine and state-of-the-art technology merge, may be the most significant impact we can make on the current paradigm of transplantation. It's going to safe lives."

No one has ever used a prize to build a movement for social change ... until now.

Will you join us?

The Methuselah Foundation has been steadily gearing up to focus attention on the big goals in tissue engineering for some years now. It's is worth remembering that the Foundation was one of the early investors in organ printing development company Organovo, for example - and the leaders of Organovo are prominently featured as sponsors and advocates in the New Organ 100 campaign.

If you agree with the New Organ goals - tissue engineered organs in the clinic, as fast as possible - then join in, spread the word, and donate.

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

A piece by author David Stipp gives an overview of the past few years of research into the effects of rapamycin: "The first strong evidence that a drug could slow aging in mammals came out in 2009 when scientists reported that chronically feeding doses of rapamycin to mice significantly extended their average and maximum lifespans. Yet rapamycin, a drug used to help prevent rejection of transplanted organs, causes multiple side effects in people, including elevated triglycerides and cholesterol, increasing the risk of heart disease; moderate immune suppression, perhaps increasing infection risks; and low blood platelet levels, which raises the specter of dangerous bleeding. In recent years another especially surprising and troubling side effect has come to the fore: Chronically taking large doses of rapamycin induces 'insulin insensitivity' in both rodents and humans, leading to rising blood sugar and potentially to type 2 diabetes. How do we reconcile such adverse effects with the drug's unprecedented ability to boost healthy aging and longevity, at least in mice? Some telling insights on this burning issue were recently published in two reports on rapamycin's effect on insulin and blood sugar: a mouse study that revealed a probable mechanism behind the effect and a theory paper suggesting that the purported diabetes risk has been overblown."

Link: http://www.davidstipp.com/rapamycins-anti-aging-promise-mirage-or-not/

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

Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."

Link: http://www.sciencedaily.com/releases/2012/07/120711141853.htm

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

Via ScienceDaily: researchers "have identified two key regulatory proteins critical to clearing away misfolded proteins that accumulate and cause the progressive, deadly neurodegeneration of Huntington's disease (HD). ... It's a lead we can vigorously pursue, not just for Huntington's disease, but also for similar neurodegenerative conditions like Parkinson's disease and maybe even Alzheimer's disease. ... In HD, an inherited mutation in the huntingtin (htt) gene results in misfolded htt proteins accumulating in certain central nervous system cells. ... [Researchers] focused on a protein called PGC-1alpha, which helps regulate the creation and operation of mitochondria, the tiny organelles that generate the fuel required for every cell to function. ... It's all about energy. Neurons have a constant, high demand for it. They're always on the edge for maintaining adequate levels of energy production. PGC-1alpha regulates the function of transcription factors that promote the creation of mitochondria and allow them to run at full capacity. ... the mutant form of the htt gene interfered with normal levels and functioning of PGC-1alpha, [and] elevated levels of PGC-1alpha in a mouse model of HD virtually eliminated the problematic misfolded proteins. ... PGC-1alpha influenced expression of another protein vital to autophagy - the process in which healthy cells degrade and recycle old, unneeded or dangerous parts and products, including oxidative, damaging molecules generated by metabolism. For neurons, which must last a lifetime, the self-renewal is essential to survival. ... Mitochondria get beat up and need to be recycled. PGC-1alpha drives this pathway through another protein called transcription factor EB or TFEB. ... If you can induce the bioenergetics and protein quality control pathways of nervous system cells to function properly, by activating the PGC-1alpha pathway and promoting greater TFEB function, you stand a good chance of maintaining neural function for an extended period of time."

Link: http://www.sciencedaily.com/releases/2012/07/120711141853.htm

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

It is unfortunate that popular culture, that ongoing conversation of countless threads that lies at the center of our diverse society, is so focused on drugs and pills as the sum of all medicine - anything that is consumed, and so especially when it comes to influencing the pace of aging. It is a terribly wrong, horribly damaging viewpoint, but one that is relentless propagated by the loudest voices, coincidentally also those who gain the most in the short term by creating a culture of customers for their products. When the world thinks of medicine for aging in terms of pills and potions, it shuts the door on support for real rejuvenation biotechnology, such as the detailed plans for development advocated by the SENS Foundation and others.

Part of the process of building the true medicine of rejuvenation - which will look like gene therapies, tailored cell alterations, engineered enzymes to strip away harmful metabolic side-products, and so on - is obtaining the support and at least superficial understanding of the public at large. That is still very much lacking, and some fraction of the blame for that can be pinned on the short-sighted idiots of the "anti-aging" marketplace who propagate lies and myths about aging and what can be done about it in order to sell products that do next to nothing. They have spent so much time and effort on this over the past decades that they have shaped the visions of popular culture to follow their message - and that harms us all by stripping away possible support for meaningful research and development, and making it harder to create that support.

The vast majority of commentary on aging, science, longevity, and what can be done about it is garbage at worst, and interesting but ultimately irrelevant to the future of our lives at best. Into the latter half falls work on calorie restriction mimetics such as metformin and rapamycin. They simply don't do enough to worth sinking billions of dollars into further research and development - though of course that research and development will happen anyway, regardless of my opinions on the matter. There are far better paths ahead than tinkering with compounds and genes that have modest effects, on a par with calorie restriction, and potentially serious side-effects to go along with that.

If results are what matter - and I think they are the only measure worth considering given the pace of death caused by aging - then world of aging and longevity research should focus on the SENS vision of targeted, deliberate repair of specific forms of damage, and move on from the tired old model of patching the end results of damage by trying a lot of compounds to find some that sort of do something beneficial. Nor should research spend their time on the comparatively new approach of trying to slow down the pace at which damage accumulates - again by trying a bunch of compounds to find some that sort of do something beneficial.

There are now far more effective paths forward for the treatment of aging than the approaches undertaken in past decades when biotechnology and the state of knowledge was too poor to do better. The world of aging science must up-end, change, become quite different. The SENS Foundation and the network of research groups working on related matters are doing the right thing. Big Pharma, the calorie restriction mimetic developers, the people searching for longevity genes or gene therapies to slow aging - they are heading down a side-path that will do little beyond generating new knowledge. Our lives will not be greatly lengthened by their efforts, as we will be old by the time that they produce therapies with modest effects on human life span by slowing down the pace at which damage accumulates. Ways to slow aging are of little value to those already aged. Our healthy lives will be significantly extended only by the successful development of methods of rejuvenation - of damage repair, ways to actually reverse the toll of aging on cells and systems.

Which, conveniently, are planned out and proposed in some detail.

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

From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."

Link: http://mariakonovalenko.wordpress.com/2012/07/03/dale-bredesen-alzheimers-is-a-problem-of-imbalance-not-toxicity/

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

From Maria Konovalenko: "I met Dr. Bredesen during the Buck Advisory Council meeting at the Buck Institute for Research on Aging in Novato, California on May 21. [The] Advisory Council consists of influential individuals who can contribute to Buck Institute's mission of advancing aging research. A very interesting crowd. ... Dale Bredesen opened the mini conference with his report on Alzheimer's research. The majority of scientists envision this horrible degenerative process as accumulation of toxic molecules, namely amyloid beta and tau proteins. Amyloid beta forms plaques between the cells and tau protein tangles inside the cells. These toxic proteins disrupt the functions of our neurons. ... So, Dr. Bredesen views Alzheimer's disease differently - as an imbalance between synaptic maintenance and synaptic reorganization. The thing is that for our brain to function properly we need to form connections between our neurons, and also we need to break down those connections that we no longer need. According to Dale Bredesen, this balance disrupts, it shifts towards synaptic reorganization, we loose our memory, face the horrors of loosing our consciousness and eventually we die. ... So how can we preserve this balance? Dr. Bredesen's lab studies the underlying mechanisms of neurodegeneration. There were able to find out that one of the things that contributes to the balance shift is the change in APP cleavage. APP is amyloid precursor protein. It is concentrated in synapses of our neurons. APP can break down into either two, or four parts. When it breaks down into 2 parts those proteins are sAPP alfa and CTF alfa. This is a 'good' combination. However, during aging amyloid precursor protein cleavage shifts towards the 'bad' combination, which is sAPP beta, Amyloid beta, Jcasp and C31. This is the shift in balance that leads to the onset of disease. The shift can be restored. The mouse strain that has one mutation that leads to not having APP to break down to Jcasp and C31 proteins leads to restoring memory in mice. But the most exciting thing is that Dr. Bredesen is testing a drug that shifts the APP cleavage balance back to normal."

Link: http://mariakonovalenko.wordpress.com/2012/07/03/dale-bredesen-alzheimers-is-a-problem-of-imbalance-not-toxicity/

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

Researchers examine possible molecular mechanisms for rheumatoid arthritis in a paper published earlier in the year: "Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory and destructive joint disorder that affects tens of millions of people worldwide. Normal healthy joints maintain a balance between the synthesis of extracellular matrix (ECM) molecules and the proteolytic degradation of damaged ones. In the case of RA, this balance is shifted toward matrix destruction due to increased production of cleavage enzymes and the presence of (autoimmune) immunoglobulins resulting from an inflammation induced immune response. Herein we demonstrate that a polyclonal antibody against the proteoglycan biglycan (BG) causes tissue destruction that may be analogous to that of RA affected tissues. The effect of the antibody is more potent than harsh chemical and/or enzymatic treatments designed to mimic arthritis-like fibril de-polymerization. ... The specific antigen that causes the RA immune response has not yet been identified, although possible candidates have been proposed, including collagen types I and II, and proteoglycans (PG's) such as biglycan. We speculate that the initiation of RA associated tissue destruction in vivo may involve a similar non-enzymatic decomposition of collagen fibrils via the immunoglobulins themselves that we observe here ex vivo."

Link: http://dx.doi.org/10.1371/journal.pone.0032241

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

As noted numerous times in the past here at Fight Aging!, chronic inflammation is a bad thing. Aging is the accumulation of damage, and the evidence strongly suggests inflammation to be a mechanism by which many different medical conditions cause damage and reduce life expectancy - such as autoimmune diseases, for example. Even the presence of excess visceral fat tissue appears to raise the risk of age-related disease and lower life span through boosting levels of inflammation. Furthermore, as you get older, and even in the best of circumstances and health, the immune system itself starts to fall into a malfunctioning state in which it causes ever greater levels of inflammation - thus producing ever more damage while at the same time failing to do its job.

Markers of inflammation correlate well with mortality rates, which is well worth keeping in mind given just how easy it is to slip into a lifestyle that greatly raises levels of inflammation.

So avoid inflammation as best you can. The easiest and some of the best tools are calorie restriction and exercise, both of which do far more for a generally healthy individual than any presently available medical technology. But not everyone has the luxury of being able to be a generally healthy individual: those suffering auto-immune disorders like rheumatoid arthritis are going suffer increasing inflammation and a lowered life expectancy until a cure arrives. So the future of health has to be as much about technological progress as it is about better using the tools that are to hand today.

Here are a couple of open access papers as a reminder of the bad things that inflammation does to you - and, for most of the younger members of the audience, via the agency of that surplus visceral fat tissue you happen to be carrying around.

Inflammation in Aging: Cause, Effect, or Both?

Aging is a progressive degenerative process tightly integrated with inflammation. Cause and effect are not clear. A number of theories have been developed that attempt to define the role of chronic inflammation in aging ... However, no single theory explains all aspects of aging; instead, it is likely that multiple processes contribute and that all are intertwined with inflammatory responses.

...

While there does not appear to be a "cure" for the complex process of aging, it should be possible to facilitate successful aging, namely, aging without significant loss of cognitive or physical function and relatively free of disease. There are lifestyle factors and potential interventions that can slow specific processes primarily through reduction or prevention of chronic inflammation and therefore forestall aging itself.

Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice

Alzheimer's disease (AD) is the most prevalent form of age-related dementia, and its effect on society increases exponentially as the population ages. Accumulating evidence suggests that neuroinflammation, mediated by the brain's innate immune system, contributes to AD neuropathology and exacerbates the course of the disease.

...

We found that a systemic immune challenge during late gestation predisposes [mice] to develop AD-like neuropathology during the course of aging. They display chronic elevation of inflammatory cytokines [and] significant impairments in working memory in old age. If this prenatal infection is followed by a second immune challenge in adulthood, the phenotype is strongly exacerbated, and mimics AD-like neuropathologic changes. ... Based on the similarity between the changes in immune-challenged mice and the development of AD in humans, we suggest that systemic infections represent a major risk factor for the development of AD.

Infections mean inflammation, of course - one of the many reasons that people exposed to a large burden of infectious disease tend not to live as long as their peers. They become more burdened by damage, from the disease process and from the inflammation that attends it, with each infection. One of the reasons that we live longer than our ancestors is that we are better at controlling and evading infectious disease: not just the diseases that kill people in youth, but the diseases that are survived.

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