To what degree does nuclear DNA damage contribute to aging? That remains a debated question. Here, researchers show that, at least in immune cells, there are perhaps more forms of large DNA damage than thought in the old: "researchers compared the DNA of identical (monozygotic) twins of different age. They could show that structural modifications of the DNA, where large or small DNA segments change direction, are duplicated or completely lost are more common in older people. The results may in part explain why the immune system is impaired with age. During a person's life, continuous alterations in the cells' DNA occur. The alterations can be changes to the individual building blocks of the DNA but more common are rearrangements where large DNA segments change place or direction, or are duplicated or completely lost. ... The results showed that large rearrangements were only present in the group older than 60 years. The most common rearrangement was that a DNA region, for instance a part of a chromosome, had been lost in some of the blood cells. ... Rearrangements were also found in the younger age group. The changes were smaller and less complex but the researchers could also in this case show that the number of rearrangements correlated with age. ... We were surprised to find that as many as 3.5 percent of healthy individuals older than 60 years carry such large genetic alterations. We believe that what we see today is only the tip of the iceberg and that this type of acquired genetic variation might be much more common. ... The researchers believe that the increased number of cells with DNA alterations among elderly can have a role in the senescence of the immune system. If the genetic alterations lead to an increased growth of the cells that have acquired them, these cells will increase in number in relation to other white blood cells. The consequence might be a reduced diversity among the white blood cells and thereby an impaired immune system." Compare that with the other explanations for reduced diversity that involve persistent and pervasive viruses like CMV.

Link: http://www.eurekalert.org/pub_releases/2012-02/uu-itr012612.php

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

Researches find another way in which the brain declines with age: "New findings [reveal] a novel mechanism through which the brain may become more reluctant to function as we grow older. ... researchers examined the brain's electrical activity by making recordings of electrical signals in single cells of the hippocampus, a structure with a crucial role in cognitive function. In this way they characterised what is known as "neuronal excitability" - this is a descriptor of how easy it is to produce brief, but very large, electrical signals called action potentials; these occur in practically all nerve cells and are absolutely essential for communication within all the circuits of the nervous system. ... The [researchers] identified that in the aged brain it is more difficult to make hippocampal neurons generate action potentials. Furthermore they demonstrated that this relative reluctance to produce action potential arises from changes to the activation properties of membrane proteins called sodium channels, which mediate the rapid upstroke of the action potential by allowing a flow of sodium ions into neurons. ... Much of our work is about understanding dysfunctional electrical signalling in the diseased brain, in particular Alzheimer's disease. We began to question, however, why even the healthy brain can slow down ... Previous investigations elsewhere have described age-related changes in processes that are triggered by action potentials, but our findings are significant because they show that generating the action potential in the first place is harder work in aged brain cells. Also by identifying sodium channels as the likely culprit for this reluctance to produce action potentials, our work even points to ways in which we might be able modify age-related changes to neuronal excitability, and by inference cognitive ability." You might compare this with past work on potassium channels and memory in aging.

Link: http://www.sciencedaily.com/releases/2012/02/120201105124.htm

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

From the Wall Street Journal, a good example of the way in which much of present day research gravitates towards applications that patch over end-stage consequences of disease rather than addressing root causes and prevention: "Research into how iron, copper, zinc and other metals work in the brain may help unlock some of the secrets of degenerative diseases like Alzheimer's and Parkinson's. Iron and copper appear to accumulate beyond normal levels in the brains of people with these diseases, and a new [study] shows reducing excess iron in the brain can alleviate Alzheimer's-like symptoms - at least in mice. ... Research into the complicated, invisible roles these metals play in brain diseases has lagged behind study of the more-visible proteins that are damaged or clump together in the brains of Alzheimer's and Parkinson's sufferers. But better understanding metals' role in the brain could help shed light on a range of medical conditions and might offer a new route for developing treatments. ... [Researchers] examined the amount of iron in the brains of mice that were bred unable to produce the tau protein, which helps stabilize the structure of neurons. Tau damage is associated with Alzheimer's and Parkinson's. As the mice aged, they suffered symptoms similar to people with both diseases, including impaired short-term memory, and also exhibited an accumulation of iron in their brains. When the researchers gave them a drug removing excess iron, the symptoms reversed. This means normally functioning tau is necessary for removing iron in the brain ... The finding bolsters previous research showing that bringing down iron may be a path to new treatments. ... An accumulation of iron in neurons seems to be a final end-stage event in neurodegeneration, whether it be Alzheimer's or Parkinson's, [or] any [condition] related to tau abnormalities."

Link: http://online.wsj.com/article/SB10001424052970204740904577192901072611524.html

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

Are you presently working on a life science or medical degree? Are you interested in advancing aging and longevity science - research that aims to extend the healthy human life span and reverse the causes of age-related disease? Do you want to intern this summer at the SENS Foundation, one of the most important young non-profits in the world?

In the summer of 2012, the Academic Initiative will bring as many as three students to the SENS Foundation Research Center in Mountain View, California to participate in SENS research for three months. These students will receive monthly stipends and, if they are not local to the San Francisco Bay Area, a credit towards airfare.

Undergraduate, graduate, and medical students may apply, as may students who have graduated immediately prior to the summer. After an initial selection process, the most promising candidates will be interviewed over the phone by the SENS researchers they would work with. Each major research program at the Research Center will limit itself to one intern, such that each intern will be working on a different project and will be selected by different researchers. It will be important for applicants to have prior lab experience, and more experienced applicants are more likely to be accepted than relatively inexperienced ones.

The application is available online here. Applications are due by March 31, 2012. The most promising applicants will be interviewed in April. As always, if you have any questions, you can contact us.

Chances to work on the foundations of world-changing research programs don't wander past the window every day. Beyond that, the SENS Foundation is a great place for younger researchers - people who are serious about longevity science and have a genuine interest in advancing the state of the art - to come into contact with a network of more experienced peers, fundraisers, and advocates that will serve well in later years. Connections are what makes the world go round, and certainly what advances careers and opens doors.

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

Autophagy is very important to long term health, and shows up again and again as a pivotal part of the way in which various genetic manipulations and lifestyle choices can improve health and extend life. Here is a good article that delves into the mechanisms of autophagy and the present limits of scientific understanding: "Cells live longer than their internal components. To keep their cytoplasm clear of excess or damaged organelles, as well as invading pathogens, or to feed themselves in time of nutrient deprivation, cells degrade these unwanted or potentially harmful structures, and produce needed food and fuel, using a process they have honed over millions of years. Known as autophagy, this catabolic process involves the selection and the sequestration of the targeted structures into unique transport vesicles called autophagosomes, which then deliver the contents to lysosomes where they are degraded by lytic enzymes. ... Experimental evidence indicates that autophagosome biogenesis is probably a very complex process on several levels, including its regulation in response to different cellular and environmental cues, and the factors governing the choice of membrane sources. Is there any therapeutic value in determining the origin of the autophagosomal membranes? We think that elucidating this process could ultimately provide new drug targets for the treatment of diseases that can be alleviated or cured by the activation of autophagy, including specific muscular dystrophies, persistent infections, and neurodegenerative disorders (ataxias, Huntington's, and Parkinson's diseases). Understanding the sources and processes by which the autophagosome's lipid bilayers are delivered will undoubtedly reveal critical new proteins and articulate their functions, allowing researchers to pinpoint specific parts of the pathway."

Link: http://the-scientist.com/2012/02/01/the-enigmatic-membrane/

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

The extracellular matrix (ECM) surrounds and supports cells, both structurally and in a range of other ways, such as by mediating cell signalling. With age, however, the ECM changes for a variety of reasons - it is damaged by the actions of senescent cells, for example. This has consequences, such as on the capacity of stem cells to maintain tissue. Here is a review paper: "Aging is characterized by reduced tissue and organ function, regenerative capacity, and accompanied by a decrease in tissue resident stem cell numbers and a loss of potency. The impact of aging on stem cell populations differs between tissues and depends on a number of non cell-intrinsic factors, including systemic changes associated with immune system alterations, as well as senescence related changes of the local cytoarchitecture. The latter has been studied in the context of environmental niche properties required for stem cell maintenance. Here, we will discuss the impact of the extracellular matrix (ECM) on stem cell maintenance, its changes during aging and its significance for stem cell therapy. ... It is concluded that a remodeled ECM due to age related inflammation, fibrosis or oxidative stress provides an inadequate environment for endogenous regeneration or stem cell therapies." The question of whether an old body can fully benefit from stem cell therapies continues to arise - eventually the stem cell research community will have to start addressing the damage of aging in order to assure the performance of their therapies when treating the old.

Link: http://www.ncbi.nlm.nih.gov/pubmed/22285947

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

Could Coffee Reduce the Risk for Diabetes Development?

Lab tests show rats drinking coffee (black) had lower blood sugar levels than rats drinking water.

Coffee drinking is rarely associated as being a boon for someone’s health.  It’s derided for being too high in caffeine, disparaged as being a cause for tooth staining, and pilloried for being a high calorie diet buster.

While the negative health claims of coffee have elements of truth, the anti-coffee crusaders conveniently ignore the benefits of coffee, such as its ability to reduce a person’s risk of liver cancer and alcohol-related liver disease.

But there’s another reason to grab your cup o’ Joe before leaving for work tomorrow:  It may reduce your risk for diabetes.

With the recent health concerns of former Poison front man Bret Michaels, diabetes has been in the news headlines quite a bit lately.  Michaels suffers from type I diabetes and has become the diabetic community’s front man in helping garner attention to a condition that affects hundreds of millions of people worldwide.  Michaels recently appeared on Donald Trump’s “Celebrity Apprentice,” earning hundreds of thousands of dollars for his charity, the American Diabetes Association, in the process.

The hope is that that money will go a long way in helping discover a cure for a disease affects 23.6 million people in the United States alone, as diabetics cope with their disease day after day through insulin therapy, diet alterations and various other treatments.

No one is immune from getting diabetes, and while type I diabetes is usually acquired at birth, type II diabetes—or adult onset diabetes—can occur at any time in life.

But researchers think that people may be able to reduce their risk for type II diabetes by drinking coffee.

Dr. Fumihiko Horio found this link after feeding a group of laboratory rats either water or coffee.  Through blood testing, they found that the rats fed coffee showed an improvement in their sensitivity to insulin and had lower blood sugar levels compared to the water-drinking rats.  Researchers believe coffee’s prevention qualities is due to its high caffeine content, calling caffeine “one of the most effective anti-diabetic compounds in coffee.”

This latest round of research is in contradistinction to a 2008 study that said coffee tended to increase blood sugar levels among diabetics.  In that study, researchers followed 10 people with type II diabetes to see what, if any, effect high levels of caffeine had on their blood sugar levels.  They found that blood sugar levels increased by an average of eight percent when participants consumed a caffeine pill that contained about the same amount of caffeine as an eight ounce serving of coffee.

Of course the difference between the two studies is that one looked at how coffee prevented diabetes, while the other looked at how coffee affected people who already had diabetes.  Another difference is that one study used coffee, while the other used caffeine pills in place of coffee.

This fact alone suggests that it may be something other than caffeine that has diabetes preventive qualities, especially when past studies reached the same conclusions while using decaffeinated coffee.

More research is in the offing.  In the meantime, don’t beat yourself up over your coffee habit.  So long as you’re consuming coffee black and that you’re consuming no more than a couple cups a day, drinking coffee is a healthy habit to have.

Sources
latimesblogs.latimes.com
sciencedaily.com

Discuss this post in Frank Mangano’s forum!

Heterochromatin is the name given to the more tightly packaged structural forms of DNA and proteins found in the cell nucleus. It has been shown to be involved in cellular senescence, and is a part of the way in which genes are turned on or off, but like most things in the nucleus it is also involved in the deep, dark depths of many other mechanisms - down there in the basement clockwork of the tall towers of machinery that run a cell. Modern day research tools are making it ever easier to catalog the cogs, gears, and operations that take place on any one level of one particular machine-tower, but it is still very hard and time-consuming to turn localized, disconnected understandings into realizations about the mechanism as a whole.

So researchers can presently say a great deal about heterochromatin and its localized behavior, but far less about how these descriptions of structure and low-level operations relate to higher level cellular mechanisms, and never mind how that all ties into trajectories of health and longevity for organisms as a whole. Cells are complicated, exceedingly so, and as a consequence the life sciences are at a point of simultaneously drowning in data while being unable to answer even a tiny fraction of all the questions about biology that are presently asked. This won't last, given the pace of progress in computational technologies, but it is rather like the prospect of starving amidst plenty for the near future.

You might recall that - in my opinion - the acid test as to whether a biological mechanism is interesting to those us who follow longevity science is not whether you can use it to shorten life span, but rather whether you can use it to extend health life. Even better is a case in which researchers can demonstrate both of those goals: turn the dial one way and life shortens, turn it the other and it lengthens - these are indications that there might be something worthy of further investigation in that research.

That all said, here is a demonstration that heterochromatin levels in flies can be used to dial lifespan up and down:

To understand the role of heterochromatin in animal aging, and the underlying molecular mechanisms, we altered heterochromatin levels in Drosophila by genetically manipulating Heterochromatin Protein 1 (HP1) levels ... we examined the life spans of flies with reduced or increased levels of HP1. These flies exhibit reduced or increased levels of heterochromatin, respectively, during development, as HP1 is an integral component of heterochromatin and controls heterochromatin levels.

We found that reducing HP1 levels by half [caused] a dramatic shortening of life span compared to isogenic controls. ... Conversely, a moderate overexpression of HP1, caused by basal activity of the hsp70 promoter, significantly extended life span, resulting in a 23% increase in median life span and a 12% increase in maximum life span. Similarly, at non-heat shock conditions (25°C), a second (independent) line of hsp70-HP1 flies also lived significantly longer than their control flies.

...

These results suggest that heterochromatin levels significantly influence life span, and moderately higher levels of heterochromatin promote longevity.

Too much boosting of heterochromatin via the methods the researchers used is fatal to flies, unfortunately. The full paper offers some thoughts on the potential mechanisms of increased longevity with increased heterochromatin levels, but there is no definitive line item to point to - at this stage, only plausible hypotheses about cellular integrity, a slower rate of decline in muscle strength, and so forth.

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

More evidence for the benefits of exercise: "Researchers from the University of Washington conducted a six-month clinical trial with 33 participants, 17 of whom were women. All showed early signs of Alzheimer's disease and were between the ages of 55 and 85. The experiment participants underwent a six-month intensive aerobic training program, spending 45 minutes to an hour four times each week on a stationary bicycle or treadmill. At the end of the six months, the participants saw improvement in mental agility, while the control group showed no improvement. Researchers are planning further studies to conduct larger and longer duration trials, following volunteers for years instead of months, for more conclusive data as to whether exercise can prevent full-blown cases of Alzheimer's. ... Other similar studies have been conducted, where researchers have measured the health benefits of resistance training for women between the ages of 65 and 75 who are most at risk for developing Alzheimer's. In one study, after one year of training, women who had completed the training showed better scores on mental acuity and conflict resolution tests than those who didn't."

View the Article Under Discussion: http://www.cavalierdaily.com/2010/04/21/remember-to-exercise-exercise-to-remember/

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

Viruses can be used as a form of targeted anti-cancer therapy, and human trials are soon set to start: "Particular parvoviruses normally infect rodents, but they are also infectious for human cells. However, they do not cause any disease symptoms in humans. Most importantly, these viruses have an astonishing property: They kill infected tumors cells without causing any damage to healthy tissue. ... Many different viruses have been tested before in cancer therapy, particularly for treating those types of cancer for which there are no effective established treatment methods. The [researchers] realized early on that parvovirus H-1 has important advantages over other viruses. Now they have been the first to prove that malignant glioblastomas regress completely as a result of treatment with these viruses. ... Parvoviruses pass the blood brain barrier so that they can be administered via the blood stream. In addition, they reproduce in cancer cells, which is particularly important for successful treatment of glioblastoma with its diffuse growth. Thus, the second generation viruses reach and eliminate even those cancer cells that have already settled at some distance from the primary tumor. ... researchers [expect] to be able to admit the first patients to the trial by the end of the year."

View the Article Under Discussion: http://www.sciencedaily.com/releases/2010/05/100504095106.htm

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

A general interest article on the aging of blood vessels from the Wall Street Journal: "Over time, however, the effects of high blood pressure, cholesterol, blood sugar and tobacco smoke provide a toxic milieu that injures the endothelium. That causes an inflammatory response intended to heal the artery wall, but that in the face of continuous injury only makes things worse. The progressive result is an accumulation of fatty deposits called plaque that can rupture or have their caps shear off, causing clots that lead to heart attacks. In addition, artery walls can stiffen, transforming compliant arteries into conduits like 'Styrofoam tubes' [that] increase both blood pressure and the workload on the heart. ... Both high body mass, particularly belly fat that accounts for a person's bulging waist line, and diabetes have a pernicious effect on the health of adult blood vessels. ... Even if your weight is under control, high cholesterol, high blood pressure, smoking, sedentary living and stress all are culprits that can accelerate vascular age."

View the Article Under Discussion: http://online.wsj.com/article/SB10001424052748703406604575278713597433300.html

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

Not all researchers are presently convinced that enough evidence exists to place mitochondrial DNA damage front and center as an important cause of aging. I would agree that the tools and measurements discussed below leave some room for argument over what they mean, but at this time the research community is very close to being able to repair mitochondrial DNA, not just talk about it. Thus I think that the best approach for the next few years is to actually go ahead and repair the damage in laboratory animals, and see what happens – that should settle the debate one way or another.

Protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage is well known to be necessary to longevity. The relevance of mitochondrial DNA (mtDNA) to aging is suggested by the fact that the two most commonly measured forms of mtDNA damage, deletions and the oxidatively induced lesion 8-oxo-dG, increase with age. The rate of increase is species-specific and correlates with maximum lifespan.

It is less clear that failure or inadequacies in the protection from reactive oxygen species (ROS) and from mitochondrial oxidative damage are sufficient to explain senescence. DNA containing 8-oxo-dG is repaired by mitochondria, and the high ratio of mitochondrial to nuclear levels of 8-oxo-dG previously reported are now suspected to be due to methodological difficulties. Furthermore, [mice lacking the MnSOD natural antioxidant] incur higher than wild type levels of oxidative damage, but do not display an aging phenotype. Together, these findings suggest that oxidative damage to mitochondria is lower than previously thought, and that higher levels can be tolerated without physiological consequence.

A great deal of work remains before it will be known whether mitochondrial oxidative damage is a “clock” which controls the rate of aging. The increased level of 8-oxo-dG seen with age in isolated mitochondria needs explanation. It could be that a subset of cells lose the ability to protect or repair mitochondria, resulting in their incurring disproportionate levels of damage. Such an uneven distribution could exceed the reserve capacity of these cells and have serious physiological consequences. Measurements of damage need to focus more on distribution, both within tissues and within cells. In addition, study must be given to the incidence and repair of other DNA lesions, and to the possibility that repair varies from species to species, tissue to tissue, and young to old.

In this context, you might also look at the membrane pacemaker theory regarding oxidative damage to mitochondria and longevity differences between species. It places an emphasis on resistance to damage and the consequences of damage over the actual levels of damage.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3455271/

Source:
http://www.fightaging.org/archives/2013/05/a-skeptical-view-of-mitochondrial-dna-damage-and-aging.php

Source:
http://www.longevitymedicine.tv/a-skeptical-view-of-mitochondrial-dna-damage-and-aging/

Another reason why you really don't want to live a lifestyle that makes you overweight: "For individuals 65 years of age and older, obesity, excess body fat around the waist and gaining weight after the age of 50 are associated with an increased risk of diabetes. ... Adiposity [body fat] is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, however, the relationships between different measures of body composition and diabetes in older adults [65 years of age or older] are not well described ... [researchers] examined the relationship between measures of overall body fat, fat distribution, changes in these measures, and diabetes risk among 4,193 men and women 65 years of age and older. ... The researchers found that BMI at baseline, BMI at 50 years of age, weight, fat mass, waist circumference, waist-hip ratio, and waist-height ratio were all strongly related to the risk of diabetes. ... For each measure, there was a graded increase in the risk of diabetes with increasing quintiles of adiposity. Participants in the highest category of adiposity had an approximately 2- to 6-fold increased risk of developing diabetes compared with those in the lowest category."

View the Article Under Discussion: http://www.eurekalert.org/pub_releases/2010-06/jaaj-owg061710.php

Read More Longevity Meme Commentary: http://www.longevitymeme.org/news/

Study:  Underage Drinking Increases Benign Breast Disease, Breast Cancer Risk

Teenage girls that drink alcohol are about five times more likely to develop what's often a precursor to breast cancer.

When we go to get something checked and the results come back benign, that’s usually a positive prognosis.  But if you get a benign prognosis and you’re a teenaged girl that drinks alcohol, a “benign” prognosis may be a bad prognosis.

According to a recent study conducted by researchers from the Washington University School of Medicine, young women who drink an average of 6.5 alcoholic beverages a week are five and a half times more likely to develop a condition called benign breast disease.  Benign breast disease, or fibrocystic breast disease, is similar to breast cancer in that it’s characterized by breast pain, discomfort, nipple discharge and lump formation, but unlike breast cancer, the lumps that form are usually non-life threatening.

At least, until now.  Because according to the study’s lead researcher, Graham Colditz, benign breast disease is a warning sign for eventual breast cancer development.

Colditz and his colleagues discovered this after looking into the health surveys of over 9,000 “tweens” and teenagers between the ages of nine and 15 years old.  Parts of the survey asked how often the girls drank alcohol and whether or not they’d been diagnosed with benign breast disease.

Reporting in the May issue of the journal Pediatrics, the St. Louis-based researchers found a relationship between benign breast disease diagnosis and the amount the girls drank.  The more they drank, the more likely they were to be diagnosed with benign breast disease.

Besides alcohol, other risk factors for fibrocystic breast disease include a high fat diet, excessive consumption of caffeine and whether there’s a family history of the disease.

Now, before you cast off this study by saying, “I know my daughter and there’s no way she drinks alcohol,” permit me to tell you a short story that a friend of mine recently told me.  A true story.

A friend of mine lives in New Hampshire and works as a substitute teacher at a local junior high school.  As a substitute teacher, it comes as no surprise that the kids are pretty unruly when he’s leading the classroom, as the word “substitute” has long been loosely translated by students to meaning, “Hey, the regular teacher is gone, so I can get away with more!!”

But what did come as a surprise was the recent arrest of an eighth grade girl due to underage drinking. Apparently, throughout the school year, she had been sneaking alcohol into the school by combining beer and soda pop, sipping her beverage throughout the day like it was nothing out of the ordinary.  The smell of beer on her breath finally did her in.

Moral of the story:  Don’t automatically assume your son or daughter isn’t drinking.  Because the father of this girl was stunned, even though 11 percent of underage drinkers take their first drink in the eighth grade.

For the sake of your kids’ short and long term health, remind them about the dangers of alcohol consumption—even if you’ve had the conversation dozens of times.  Remain ever vigilant of what they’re doing and with whom.

It’s a matter of life and death.

Sources:
sciencedaily.com
pubs.niaaa.nih.gov
health.google.com

Discuss this post in Frank Mangano’s forum!

Some people are more predisposed to suffer Parkinson’s disease than others, a fraction of those due to mutations in genes involved in mitochondrial quality control. The state of mitochondrial function shows up as an important component of many different conditions and indeed in aging itself. In Parkinson’s disease it is thought that mitochondrial dysfunction contributes to the conditions in which the population of dopamine-producing neurons in the brain die off, producing the characteristic symptoms of the disease.

It may be that more of Parkinson’s disease is genetic than was previously thought, and the odds of that being the case increase as the chain of molecular machinery involved in mitochondrial quality control is followed and new components identified. This sort of work also helps clarify the mechanisms associated with mitochondrial dysfunction in aging:

Mitofusin 2 (Mfn2) is known for its role in fusing mitochondria together, so they might exchange mitochondrial DNA in a primitive form of sexual reproduction. “Mitofusins look like little Velcro loops. They help fuse together the outer membranes of mitochondria. Mitofusins 1 and 2 do pretty much the same thing in terms of mitochondrial fusion. What we have done is describe an entirely new function for Mfn2.”

Mitochondria work to import a molecule called PINK. Then they work to destroy it. When mitochondria get sick, they can’t destroy PINK and its levels begin to rise. Once PINK levels get high enough, they make a chemical change to Mfn2, which sits on the surface of mitochondria. This chemical change is called phosphorylation. Phosphorylated Mfn2 on the surface of the mitochondria can then bind with a molecule called Parkin that floats around in the surrounding cell.

Once Parkin binds to Mfn2 on sick mitochondria, Parkin labels the mitochondria for destruction. The labels then attract special compartments in the cell that “eat” and destroy the sick mitochondria. As long as all links in the quality-control system work properly, the cells’ damaged power plants are removed, clearing the way for healthy ones. “But if you have a mutation in PINK, you get Parkinson’s disease. And if you have a mutation in Parkin, you get Parkinson’s disease. About 10 percent of Parkinson’s disease is attributed to these or other mutations that have been identified.” The discovery of Mfn2′s relationship to PINK and Parkin opens the doors to a new genetic form of Parkinson’s disease.

Link: http://www.sciencedaily.com/releases/2013/04/130425142357.htm

Source:
http://www.fightaging.org/archives/2013/04/joining-the-dots-in-genetic-parkinsons-disease.php

Source:
http://www.longevitymedicine.tv/joining-the-dots-in-genetic-parkinsons-disease/

Human calorie restriction studies continue onward at the normal sedate pace of all human research, as noted in a recent post on the CALERIE program. It remains the case that the vast majority of work on calorie restriction and its beneficial effects involves mice, flies, worms, and other laboratory animals. Most such species exhibit increased longevity and improved measures of long term health when on a calorie restricted diet, provided that they still receive suitable levels of nutrition. That this is so universal is one of the reasons to suggest calorie restriction with optimal nutrition as a lifestyle choice in humans.

Other reasons include the results from human studies to date; if there was a pill you could take that provided half the benefits that calorie restriction has been shown to produce in humans, then everyone would be falling over themselves to take it. It’s somewhat harder to convince people to eat less in this day and age, however, no matter how beneficial the results might be. The paper quoted below is illustrative of results from human studies, in that the measures taken tend to line up with what is seen in short-lived animals like mice and rats:

Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile

Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR-induced dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis and inflammation.

If you wander over to Extreme Longevity you can find a PDF copy of the full paper.

The fact that more easily gathered measures of metabolism like those noted above are similar for rat and human calorie restriction makes CR look like a good option – where these measures match up, the hope is that the long term rewards do so as well. Studies in rats can achieve what studies in humans cannot, which is to follow large numbers of rats for their entire lives and catalog the impressive long term health benefits, as well as the characteristic increase in life expectancy, that accompanies CR in rodent species. This is one of many examples, in which the researchers focus as much on exercise as CR:

Effects of dietary restriction and exercise on the age-related pathology of the rat

The most efficacious and commonly used intervention used to retard the aging processes is dietary restriction (DR). It increases mean and maximum life spans, delays the appearance, frequency, and severity of many age-related diseases, and more importantly, attenuates much of the physiological decline associated with age. Although the subject of intense research, the mechanism by which DR alters the aging processes is still unknown.

Physical exercise is another effective intervention shown to affect aging phenomena, especially when applied in combination with DR. Mild exercise in concert with DR is beneficial, but vigorous exercise coupled with DR could be deleterious. With regard to pathology, exercise generally exerts a salutary influence on age-related diseases, both neoplastic and non-neoplastic, and this effect may contribute to the increase in median life span seen with exercised rats.

Exercise coupled with 40% DR was found to suppress the incidence of fatal neoplastic disease compared to the sedentary DR group. Exercise with mild DR suppressed the incidence of multiple fatal disease and chronic nephropathy, and also delayed the occurrence of many age-related lesions compared to the ad libitum (AL) control group. However, these effects may have little bearing on the aging process per se, as maximum life span is only minimally affected. Although not as intensively studied as DR, results from studies that utilize exercise as a research probe, either alone or in combination with DR, have helped to assess the validity of proposed mechanisms for DR and aging itself.

Neither the retardation of growth rate nor the increase in physical activity, observed with either exercise or DR, appear to contribute to the anti-aging action of DR. Moreover, results from lifelong exercise studies indicate that the effects of DR do not depend upon changes in energy availability or metabolic rate. The mechanisms involving effects on adiposity or immune function are also inadequate explanations for the action of DR on aging. Of the proposed mechanisms, only one, as postulated by the Oxidative Stress Hypothesis of Aging, tenably accounts for the known effects of DR and exercise on aging.

Source:
http://www.fightaging.org/archives/2013/04/recent-calorie-restriction-research.php

Source:
http://www.longevitymedicine.tv/recent-calorie-restriction-research/

Damage to mitochondrial DNA accumulates as a side-effect of the operation of mitochondria in your cells, and per the mitochondrial free radical theory of aging proceeds to cause some fraction of degenerative aging though a long chain of ever worsening consequences.

Below you’ll find recently published research that shows long-lived mice to have less mitochondrial DNA damage, which is what you’d expect to see under this model. This reinforces the need for ways to repair or replace mitochondrial DNA throughout the body in order to remove this contribution to degenerative aging. A wide range of possible approaches exist, but currently little funding is devoted towards realizing them and there is no path to getting treatments to reverse aging through the regulatory process – the standard lament when it comes to rejuvenation biotechnology.

The single gene mutation of Ames dwarf mice increases their maximum longevity by around 40% but the mechanism(s) responsible for this effect remain to be identified. This animal model thus offers a unique possibility of testing the mitochondrial theory of aging.

In this investigation, oxidative damage to mitochondrial DNA (mtDNA) was measured for the first time in dwarf and wild type mice of both sexes. In the brain, 8-oxo,7,8-dihydro-2′-deoxyguanosine (8-oxodG) in mtDNA [a measure of oxidative stress] was significantly lower in dwarfs than in their controls both in males (by 32%) and in females (by 36%). The heart of male dwarfs also showed significantly lower mtDNA 8-oxodG levels (30% decrease) than the heart of male wild type mice, whereas no differences were found in the heart of females.

The results, taken together, indicate that the single gene mutation of Ames dwarfs lowers oxidative damage to mtDNA especially in the brain, an organ of utmost relevance for aging. Together with the previous evidence for relatively lower level of oxidative damage to mtDNA in both long-lived and caloric restricted animals, these findings suggest that lowering of oxidative damage to mtDNA is a common mechanism of life extension in these three different mammalian models.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23604907

Source:
http://www.fightaging.org/archives/2013/04/measures-of-mitochondrial-dna-damage-lower-in-long-lived-mice.php

Source:
http://www.longevitymedicine.tv/measures-of-mitochondrial-dna-damage-lower-in-long-lived-mice/

I mentioned GIFT/LIFT, the immune cell transplant approach to cancer therapy in a short list of research that might lead to cancer cures yesterday. This line of research derives from the fortuitous discovery of a cancer-immune lineage of laboratory mice, followed by the finding that this immunity is transferable via transplant of granulocyte or other forms of leukocyte immune cells.

This discovery raises the possibility that effective cancer treatments can be established by finding donors with appropriately equipped immune cells and then transplanting those cells into patients, even in advance of a complete understanding of how this all works. That complete understanding might enable an effective cure for cancer therapy based on altering a patient’s own immune cells, or a much more reliable way to determine useful donors, but it’ll take much longer to get to that point, possibly decades. Thus there is considerable incentive to take the shortcut if there’s one to be had, in the same way as first generation stem cell transplant therapies continue to be established usefully far in advance of the complete understanding of how they work.

You can look back in the archives for posts that cover this topic, though I should mention that the younger organizations mentioned as being involved in work on this are mostly defunct or going nowhere, it seems. Finding funding is an issue, though the Florida clinical trial partially funded by the Life Extension Foundation is apparently still ongoing. Good for them.

• The State of Leukocyte or Granulocyte Transplants to Kill Cancer
• LEF Funds Granulocyte Cancer Therapy
• Seeking Funding to Explain Granulocyte Cancer Therapy

Today a reader pointed me to recently published research on the cancer-immune mice, which is much appreciated. Follow-on research often drifts by me, as it’s harder to pick out papers from the flow once they start to focus on specific concerns and subtopics. This open access paper reinforces the previous work by Zheng Cui and others, demonstrating once more a transfer of cancer immunity between mice, but the authors note that the approach isn’t as general as hoped – meaning that there are other factors at work that will make it much more of a hard slog to either (a) find a donor with immune cells that will work on your cancer, or (b) figure out how what’s going on under the hood here. Why does it work for some cancers and not for others? So it’s the same old story: biology is always considerable more complicated than we’d like it to be.

Immune Cells from SR/CR Mice Induce the Regression of Established Tumors in BALB/c and C57BL/6 Mice

Mouse strains that survive injection of large numbers of cancer cells are rare. Such mice constitute important experimental models for cancer resistance at the cellular and molecular levels. The spontaneous regression/complete resistance (SR/CR) mice were derived from BALB/c mice and described by Cui and colleagues in 1999. The phenotype was characterized by the ability to resist challenges from a number of cancer cell lines. This resistance involved innate immune cells, including polymorphonuclear granulocytes (PMNs), macrophages, and NK cells.

Interestingly, adoptive transfer (AT) of SR/CR leukocytes rendered recipients resistant to the intraperitoneal injection of S180 [sarcoma cancer] cells and also induced the regression of solid tumors. [In] this study we tested whether the cancer resistance of the SR/CR mice could be transferred to cancer susceptible mice by AT of selected immune cells.

In contrast to previous observations, the cancer resistance was limited to S180 sarcoma cancer cells. We were unable to confirm previous observations of resistance to EL-4 lymphoma cells and J774A.1 monocyte-macrophage cancer cells. The cancer resistance against S180 sarcoma cells could be transferred to susceptible non-resistant [mice. In] the responding recipient mice, the cancer disappeared gradually following infiltration of a large number of polymorphonuclear granulocytes and remarkably few lymphocytes in the remaining tumor tissues. This study confirmed that the in vivo growth and spread of cancer cells depend on a complex interplay between the cancer cells and the host organism.

Here, hereditary components of the immune system, most likely the innate part, played a crucial role in this interplay and lead to resistance to a single experimental cancer type. The fact that leukocytes [could] be transferred to inhibit S180 cancer cell growth in susceptible recipient mice support the vision of an efficient and adverse event free immunotherapy in future selected cancer types.

The failure to replicate early work for more than one form of cancer suggests that the underlying mechanisms here are, as mentioned above, not as general or as simple as we’d like them to be. It is very effective when it does work, however, not just causing remission of cancer, but also granting immunity. This means that research will continue, though as usual never as rapidly nor with as much funding as we’d like.

Source:
http://www.fightaging.org/archives/2013/04/more-data-on-granulocyte-transplant-cancer-therapies.php

Source:
http://www.longevitymedicine.tv/more-data-on-granulocyte-transplant-cancer-therapies/

The electron transport chain is the core piece of biological machinery inside mitochondria, the cell’s power plants. It occupies a central place in the various free radical theories of aging as well. A good number of longevity-related mutations in laboratory animals appear to alter electron transport chain function as their primary mode of operation, and a good case is made for a large portion of degenerative aging to rest atop damage to the mitochondrial genes that encode proteins essential to proper electron transport chain function.

Most biogerontologists agree that oxygen (and nitrogen) free radicals play a major role in the process of aging. The evidence strongly suggests that the electron transport chain, located in the inner mitochondrial membrane, is the major source of reactive oxygen species in animal cells.

It has been reported that there exists an inverse correlation between the rate of superoxide/hydrogen peroxide production by mitochondria and the maximum longevity of mammalian species. However, no correlation or most frequently an inverse correlation exists between the amount of antioxidant enzymes and maximum longevity. Although overexpression of the antioxidant enzymes SOD1 and CAT (as well as SOD1 alone) have been successful at extending maximum lifespan in Drosophila, this has not been the case in mice. Several labs have overexpressed SOD1 and failed to see a positive effect on longevity. [Although overexpression of CAT has been shown to extend life in mice by some groups].

An explanation for this failure is that there is some level of superoxide damage that is not preventable by SOD, such as that initiated by the hydroperoxyl radical inside the lipid bilayer, and that accumulation of this damage is responsible for aging. I therefore suggest an alternative approach to testing the free radical theory of aging in mammals. Instead of trying to increase the amount of antioxidant enzymes, I suggest using molecular biology/transgenics to decrease the rate of superoxide production, which in the context of the free radical theory of aging would be expected to increase longevity.

Personally I think the better approach to testing theory here is to implement mitochondrial repair or replacement, both of which are very feasible, and see what effect that has on older animals. It will both extend life and produce some degree of rejuvenation if the mitochondrial free radical theory of aging is correct.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23604868

Source:
http://www.fightaging.org/archives/2013/04/considering-the-electron-transport-chain-in-aging.php

Source:
http://www.longevitymedicine.tv/considering-the-electron-transport-chain-in-aging/

The clam species Arctica islandica is very long-lived, reaching at least four centuries in the wild. Researchers are comparing its biochemistry with similar but shorter-lived species to see if they can pinpoint the mechanisms that lead to its exceptional longevity. Here is recent research on this topic:

The observation of an inverse relationship between lifespan and mitochondrial H2 O2 production rate would represent strong evidence for the disputed oxidative stress theory of aging. Studies on this subject using invertebrates are surprisingly lacking, despite their significance in both taxonomic richness and biomass. Bivalve molluscs represent an interesting taxonomic group to challenge this relationship. They are exposed to environmental constraints such as microbial H2 S, anoxia/reoxygenation, and temperature variations known to elicit oxidative stress. Their mitochondrial electron transport system is also connected to an alternative oxidase that might improve their ability to modulate [the reactive oxygen species (ROS) generated by mitochondria and which produce oxidative stress].

Here we compared H2 O2 production rates in isolated mantle mitochondria between the longest living metazoan & the bivalve Arctica islandica & and two taxonomically related species of comparable size. In an attempt to test mechanisms previously proposed to account for a reduction of ROS production in long-lived species, we compared oxygen consumption of isolated mitochondria and enzymatic activity of different complexes of the electron transport system in the two species with the greatest difference in longevity.

We found that A. islandica mitochondria produced significantly less [of the reactive oxygen species] H2 O2 than those of the two short-lived species in nearly all conditions of mitochondrial respiration tested, including forward, reverse, and convergent electron flow. Alternative oxidase activity does not seem to explain these differences. However, our data suggest that reduced complex I and III activity can contribute to the lower ROS production of A. islandica mitochondria, in accordance with previous studies.

Reduced activity within mitochondria in this sense shows up in some longevity-inducing mutations in laboratory animals. Mitochondrial activity and composition (how much damage they cause per unit time, and how resistant they are to damage) appears to be very important as a determinant of longevity differences between species. This should increase our interest in ways to repair mitochondrial damage in humans as a potential rejuvenation therapy.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23566066

Source:
http://www.fightaging.org/archives/2013/04/examining-the-biochemistry-of-arctica-islandica-longevity.php

Source:
http://www.longevitymedicine.tv/examining-the-biochemistry-of-arctica-islandica-longevity/