The thyroid gland carries out a number of important functions, responding to changing conditions by varying its production of thyroid hormones that alter the behavior of metabolism elsewhere in the body. The behavior of the thyroid changes with age, but in a sufficiently subtle and varying manner to make its role in aging a challenging thing to study. Nonetheless, there is at this point enough data to conclude that some forms of reduced thyroid function tend to associate with increased longevity in a number of species.

This also ties in with other lines of research. Calorie restriction, for example, reduces thyroid hormone levels in the course of extending life and improving health. A predisposition to low thyroid hormone levels appear to be inherited in long-lived families. And so forth.

Here is a short and very readable open access review paper that looks at thyroid function in the context of aging and longevity:

The thyroid gland and the process of aging; what is new?

The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known.

Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels - progressively shifting to higher values with age - may contribute to the increased lifespan. [The] most striking findings concerning potential contribution of TSH and thyroid hormones to lifespan regulation, were obtained in the studies performed on centenarians (and almost centenarians). In 2009, Atzmon et al. published the results of studies on thyroid disease-free population of Ashkenazi Jews, characterized by exceptional longevity (centenarians). They have observed higher serum TSH level in these subjects as compared to the control group. [Moreover], the authors have observed an inverse correlation between FT4 and TSH levels in centenarians and [controls], and finally, they have distinctly concluded that increased serum TSH is associated with extreme longevity

The above-mentioned inverse correlation between FT4 and TSH in centenarians may suggest a potential role of decreased thyroid function in lifespan regulation, leading to remarkable longevity. Such a hypothesis seems to have been confirmed by the findings obtained in the Leiden Longevity Study, demonstrating the associations between low thyroid activity and exceptional familial longevity.

It should be stressed that reduced thyroid function with low levels of T4 is associated with extended longevity also in animals. For example, a very severe thyroid hypofunction with reduced core body temperature, as observed in Ames dwarf (df/df) and Snell mice [is] considered to substantially contribute to remarkable longevity in these rodents. [The] findings in animals are consistent with the results obtained in humans and may confirm a relevant role of thyroid hypofunction in lifespan extension.

Source:
http://www.fightaging.org/archives/2012/11/the-association-of-reduced-thyroid-function-with-longevity.php

Lobsters are one of the small number of species that might be ageless, or at the very least age very slowly and exhibit little to no decline until very late life. There is little money for aging research in lobsters, however: until now researchers possessed no way to accurately determine the age of a lobster, and no good estimate as to average or maximum life span in these species. This new development should hopefully lead to a better grasp of the degree to which lobsters do or do not age, and pin down numbers for life span:

For the first time, scientists have figured out how to determine the age of a lobster - by counting its rings, like a tree. Nobody knows how old lobsters can live to be; some people estimate they live to more than 100.

Scientists already could tell a fish's age by counting the growth rings found in a bony part of its inner ear, a shark's age from the rings in its vertebrae and a scallop or clam's age from the rings of its shell. But crustaceans posed a problem because of the apparent absence of any permanent growth structures. It was thought that when lobsters and other crustaceans molt, they shed all calcified body parts that might record annual growth bands.

[Researchers] took a closer look at lobsters, snow crabs, northern shrimp and sculptured shrimp. They found that growth rings, in fact, could be found in the eyestalk - a stalk connected to the body with an eyeball on the end - of lobsters, crabs and shrimp. In lobsters and crabs, the rings were also found in the so-called "gastric mills," parts of the stomach with three teeth-like structures used to grind up food.

http://www.huffingtonpost.com/huff-wires/20121130/us-lobster-aging/

Source:
http://www.fightaging.org/archives/2012/11/a-method-of-determining-lobster-age.php

Mitochondria and the damage they accumulate as a result of their operation are important in the process of degenerative aging. Further, declining mitochondrial function is a feature in many age-related conditions. Many researchers focus their studies on mitochondrial function, differences in mitochondria between species and how that determines life span, alterations in mitochondrial operation that occur in connection with life-extending interventions in laboratory animals, and similar areas. These days that often involves producing a great deal of data for later analysis:

In efforts to understand what influences life span, cancer and aging, scientists are building roadmaps to navigate and learn about cells at the molecular level. To survey previously uncharted territory, a team of [researchers] created an "atlas" that maps more than 1,500 unique landmarks within mitochondria that could provide clues to the metabolic connections between caloric restriction and aging.

The map, as well as the techniques used to create it, could lead to a better understanding of how cell metabolism is re-wired in some cancers, age-related diseases and metabolic conditions such as diabetes. "It's really a dynamic atlas for regulatory points in mitochondrial function - there are many interesting avenues that other scientists can follow up on. It could take years for researchers to understand what it all means, but at least now we have a list of the most important players."

[The scientists] conducted earlier research on the mitochondrial protein Sirt3, where they suggested a link between Sirt3 and the benefits of caloric restriction in situations such as the prevention of age-related hearing loss. The new research [more] broadly identifies pathways in mitochondria that could be behind the rewiring of metabolism. Their work uncovered regulatory processes that maintain mitochondrial health, control cells' ability to metabolize fat and amino acids, as well as stimulate antioxidant responses.

Link: http://www.news.wisc.edu/21305

Source:
http://www.fightaging.org/archives/2012/11/a-protein-map-for-mitochondrial-function.php

The most visible signs of Parkinson's disease are caused by the progressive destruction of a comparatively small population of dopamine-generating neurons in the brain. But why these cells? A full answer to that question might lead to ways to block progression of the condition:

Neuroinflammation and its mediators have recently been proposed to contribute to neuronal loss in Parkinson's, but how these factors could preferentially damage dopaminergic neurons has remained unclear until now. [Researchers] were looking for biological pathways that could connect the immune system's inflammatory response to the damage seen in dopaminergic neurons. After searching human genomics databases, the team's attention was caught by a gene encoding a protein known as interleukin-13 receptor alpha 1 chain (IL-13Ra1), as it is located in the PARK12 locus, which has been linked to Parkinson's.

IL-13r?1 is a receptor chain mediating the action of interleukin 13 (IL-13) and interleukin 4 (IL-4), two cytokines investigated for their role as mediators of allergic reactions and for their anti-inflammatory action. With further study, the researchers made the startling discovery that in the mouse brain, IL-13Ra1 is found only on the surface of dopaminergic neurons. "This was a 'Wow!' moment."

The scientists set up long-term experiments using a mouse model in which chronic peripheral inflammation causes both neuroinflammation and loss of dopaminergic neurons similar to that seen in Parkinson's disease. The team looked at mice having or lacking IL-13Ra1 and then compared the number of dopaminergic neurons in the brain region of interest. The researchers expected that knocking out the IL-13 receptor would increase inflammation and cause neuronal loss to get even worse. Instead, neurons got better.

If further research confirms the IL-13 receptor acts in a similar way in human dopaminergic neurons as in mice, the discovery could pave the way to addressing the underlying cause of Parkinson's disease. Researchers might, for instance, find that drugs that block IL-13 receptors are useful in preventing loss of dopaminergic cells during neuroinflammation.

Link: http://www.scripps.edu/news/press/2012/20121119conti.html

Source:
http://www.fightaging.org/archives/2012/11/towards-an-understanding-of-why-dopamine-neurons-are-vulnerable-in-parkinsons-disease.php

Metabolism is a very complex set of overlapping mechanisms, feedback loops, and networks of protein interactions. So even if there are only a few core methods of extending life by altering metabolism in a species, we should expect to see scores of different ways to trigger some or all of that alteration - and with widely varying side-effects. This is one of the present challenges facing those researchers who focus on how metabolism and genes determine natural variations in longevity: mapping it all for any one species is a vast task.

Here is one example of ongoing research drawn from among the many ways to make flies live longer:

Up-regulation of kynurenine (KYN) pathway of tryptophan (TRP) was suggested as one of the mechanisms of aging and aging-associated disorders. Genetic and pharmacological impairment of TRP - KYN metabolism resulted in prolongation of life span in Drosophila models.

Minocycline, an antibiotic with anti-inflammatory, antioxidant and neuroprotective properties independent of its antibacterial activity, inhibited KYN formation from TRP. Since minocycline is the only FDA approved for human use medication with inhibitory effect on TRP - KYN metabolism, we were interested to study minocycline effect on life- and health-spans in Drosophila model.

Minocycline prolonged mean, median and maximum life span of wild-type Oregon Drosophila melanogaster of both genders [and] might be a promising candidate drug for anti-aging intervention. [The] role of TRP - KYN metabolism in the mechanisms of minocycline-effect on life- and health-span might be elucidated by the future assessment of minocycline effects in Drosophila mutants naturally or artificially knockout for genes impacting the key enzymes of KYN pathway of TRP metabolism.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23185716

Source:
http://www.fightaging.org/archives/2012/11/kynurenine-tryptophan-metabolism-and-fly-longevity.php

A range of age-related conditions are characterized by a buildup or clumping of harmful proteins, and research tends to focus first on ways to safely break down these compounds. Here researchers are testing a new candidate method of breaking down the beta amyloid and tau associated with Alzheimer's disease:

Last March, researchers at UCLA reported the development of a molecular compound called CLR01 that prevented toxic proteins associated with Parkinson's disease from binding together and killing the brain's neurons. Building on those findings, they have now turned their attention to Alzheimer's disease, which is thought to be caused by a similar toxic aggregation or clumping, but with different proteins, especially amyloid-beta and tau.

And what they've found is encouraging. Using the same compound, which they've dubbed a "molecular tweezer," in a living mouse model of Alzheimer's, the researchers demonstrated for the first time that the compound safely crossed the blood-brain barrier, cleared the existing amyloid-beta and tau aggregates, and also proved to be protective to the neurons' synapses - another target of the disease - which allow cells to communicate with one another.

Even though synapses in transgenic mice with Alzheimer's may shut down and the mice may lose their memory, upon treatment, they form new synapses and regain their learning and memory abilities. ... For humans, unfortunately, the situation is more problematic because the neurons gradually die in Alzheimer's disease. That's why we must start treating as early as possible. The good news is that the molecular tweezers appear to have a high safety margin, so they may be suitable for prophylactic treatment starting long before the onset of the disease.

Link: http://www.eurekalert.org/pub_releases/2012-11/uoc--rrp111512.php

Source:
http://www.fightaging.org/archives/2012/11/molecular-tweezers-versus-alzheimers-disease.php

The developing technology of bioprinting, producing tissue structures using inkjet or other print technologies, has a promising future:

Desktop 3-D printers can already pump out a toy trinket, gear set or even parts to make another printer. Medical researchers are also taking advantage of this accelerating technology to expand their options for regenerative medicine.

Researchers have made great strides in coaxing cells to grow over artificial, porous scaffolds that can then be implanted in the body to replace hard tissue, such as bone. ... But now, instead of relying on poured molds, foam designs or donated biological materials, researchers can print custom scaffold structures with biocompatible, biodegradable polymers. ... These methods have allowed us to develop very complex scaffolds which better mimic the conditions inside the body. ... Engineers can carefully control the minute, internal structures of these porous scaffolds to best promote cellular growth. And these new printing methods also allow quick and cheap experiments that test various one-off designs.

Advancing bio-printing technologies can also be used for the biological material itself. Like color printing, biomaterial printing can switch among different organic materials as well as produce gradients and blending. Inkjet printing is preferred for depositing cells themselves, and as a demonstration of this in the 1980s an unmodified HP desktop printer was used to print out collagen as well as tissuelike structures. Printing, however, is tough on cells. Some studies have successfully kept more than 95 percent of cells intact through the process, but others have not done as well - losing more than half from damaged membranes.

The future of bio-printing may be the combination of these approaches - printing both highly specific scaffolds and cell structures. Recent research has shown that stem cell fate can be controlled by the surfaces onto which the cells are printed.

Link: http://blogs.scientificamerican.com/observations/2012/11/15/print-it-3-d-bio-printing-makes-better-regenerative-implants/

Source:
http://www.fightaging.org/archives/2012/11/the-state-of-bioprinting.php

Parkinson's disease involves a greatly accelerated loss of vital dopamine-generating neurons in the brain, leading to the characteristic symptoms in earlier stages of the condition. In recent years, scientists have focused on the role of ?-synuclein in the processes that cause this cell death:

The discovery of ?-synuclein has had profound implications concerning our understanding of Parkinson's disease (PD) and other neurodegenerative disorders characterized by ?-synuclein accumulation. In fact, as compared with pre-?-synuclein times, a "new" PD can now be described as a whole-body disease in which a progressive spreading of ?-synuclein pathology underlies a wide spectrum of motor as well as nonmotor clinical manifestations.

At this point ?-synuclein is taking on a similar role to beta-amyloid in Alzheimer's disease - a magnet for interest and research funds, while potential clinical intervention involves removing or other otherwise nullifying the buildup of this unwanted compound. Fairly compelling research results were recently published on this topic, wherein researchers managed to convincingly replicate the effects of Parkinson's in mice:

Misfolded protein transmits Parkinson's from cell to cell

A [team] injected a misfolded synthetic version of the protein ?-synuclein into the brains of normal mice and saw the key characteristics of Parkinson's disease develop and progressively worsen. The study [suggests] that the disease is spread from one nerve cell to another by the malformed protein, rather than arising spontaneously in the cells.

Parkinson's disease has two distinct features: clumps of protein called Lewy bodies and a dramatic loss of nerve cells that produce the chemical messenger dopamine. When [the] team injected the misfolded ?-synuclein into a part of the mouse brain rich in dopamine-producing cells, Lewy bodies began to form. This was followed by the death of dopamine neurons. Nerve cells that linked to those near the injection site also developed Lewy bodies, a sign that cell-to-cell transmission was taking place.

The study lends theoretical support to the handful of biotechnology companies that are sponsoring clinical trials of ?-synuclein antibodies for Parkinson's ... At least one mystery still remains: why do the Lewy bodies appear in the first place? ... Parkinson's disease is not a disorder in which somebody injects synuclein into your brain. So what sets it in motion?

As is also the case for Alzheimer's it remains much debated as to how and why some people exhibit Parkinson's disease while others do not - which is not to say that there is any shortage of theories on how the condition progresses from its earliest stages. Just as for many other age-related conditions the commonplace correlations apply: being overweight and sedentary increases your risk, exercise and calorie restriction reduce it.

On the subject of Lewy bodies in Parkinson's disease, I noticed a couple of recently published papers suggesting that their appearance is symptomatic of a later stage of the condition, or less relevant to Parkinson's disease specifically - meaning that investigating their biochemistry may be less important than work on ?-synuclein at this juncture:

• Neurodegeneration in Parkinson disease: Moving Lewy bodies out of focus
• Lewy pathology is not the first sign of degeneration in vulnerable neurons in Parkinson disease

Source:
http://www.fightaging.org/archives/2012/11/evidence-for--synucleins-central-role-in-parkinsons-disease.php

Anthony Atala is one of the present luminaries of tissue engineering, or at least that part of the field focused on building replacement organs and pseudo-organs - the latter being tissue structures that are not exactly the same as what they replace, but still get the job done, such as the substitute bladder tissue manufactured by Tengion. Atala is also on the SENS Foundation research advisory board, and so can be seen to look favorably on the agenda of engineering longer healthy human life spans.

I notice that a recent article has Atala giving some thoughts on timelines for organ regrowth, which you might compare to similar thoughts from another figure in the field, and to speculative timelines for the use of animal organs, such as those grown in engineered chimeras. Researchers are usually fairly reticent to put times and timelines on the table in public, for all the obvious reasons, so I think it worth taking note when they do:

How Close Are We to Making Like Salamanders and Regenerating Our Own Organs?

Right now, more than 116,000 people are on the U.S. organ transplant waiting list. But what if they could just regrow their own livers, hearts, and kidneys, even 3-D print them? Anthony Atala, the director of the Wake Forest Institute for Regenerative Medicine, is working to make that a reality. Speaking today at Ciudad de las Ideas, an annual conference about big ideas held in Puebla, Mexico, and sponsored by Grupo Salinas, Atala asked, "If a salamander can do it, why can't we?"

So how long until regenerative medicine can make the agonizingly long transplant waiting list a thing of the past? Within the next decade, Atala predicts, "we will see partial replacements of [some] organs - not the entire replacement, but many times that's all we need." Of course, the very necessary regulatory process will have to be carried out before there is widespread use of regenerated organs. Atala notes that the average drug takes 15.5 years to be approved in the United States, and regenerative medicine is neither drug nor medical device, but a combination thereof, which makes approval even more complicated.

"Very necessary" is complete nonsense when describing the enormously restrictive and costly regulatory straightjacket fastened around modern medicine. The FDA is an ever-increasing dead weight that does little but slow down - or block entirely - important progress in medical science. Its existence makes every new medical technology vastly more expensive to develop, and in many cases regulators have closed the door entirely on lines of development because there is no way that benefits could be profitably realized.

Worse, regulators can declare entire potential fields of medicine forbidden, as is the case for applications of longevity science. Aging is not a defined disease for the FDA, and all that is not explicitly permitted is forbidden in their regulatory rubric - so there is no path to legally commercialize a therapy for aging in the US, even when it becomes technically possible to do so. Thus there is little to no funding for such development.

The medicines that might have been and the progress that might have happened is all invisible, of course, so few people pay any attention to it - the broken window fallacy again, where the harm done and costs incurred are swept under the carpet, so people can suggest that we are all better off for it. How much further might medical science have advanced if the ruinous cost of clinical trial after trial after trial, under far more onerous requirements than existed even a few decades ago, were instead funneled into more research?

To explain the seeming gap between accelerating progress in the laboratory and lagging slowness in clinical medicine, one only has to point to the regulators. They are to blame, and the rest of us for not doing something about this squalid situation.

Source:
http://www.fightaging.org/archives/2012/11/regenerative-medicine-timelines-from-anthony-atala.php

Arguably metastasis is what makes cancer so dangerous: that a single malignant tumor of any size can seed further tumors throughout the body; that a diaspora of metastasized cells is exceedingly hard to eliminate once let lose. If metastasis could be blocked many forms of cancer would become tractable and far less threatening, which is a fair-sized step towards a robust cure for cancer - very much needed as a part of any package of biotechnologies aimed at greatly extending healthy human life. Thus it is promising to see signs of early progress along these lines:

In laboratory experiments, scientists have eliminated metastasis, the spread of cancer from the original tumor to other parts of the body, in melanoma by inhibiting a protein known as melanoma differentiation associated gene-9 (mda-9)/syntenin. ... With further research, the approach used by the scientists could lead to targeted therapies that stop metastasis in melanoma and potentially a broad range of additional cancers.

[Researchers] found that Raf kinase inhibitor protein (RKIP) interacted with and suppressed mda-9/syntenin. Mda-9/syntenin [was] shown in previous studies to interact with another protein, c-Src, to start a series of chemical reactions that lead to increased metastasis. ... Prior research suggests that RKIP plays a seminal role in inhibiting cancer metastasis, but, until now, the mechanisms underlying this activity were not clear.

Now that the researchers have demonstrated the ability of RKIP to inhibit mda-9/syntenin-mediated metastasis, they are focusing their attention on developing small molecules imitating RKIP that could be used as new treatments for melanoma.

Link: http://www.eurekalert.org/pub_releases/2012-11/vcu-rbc111412.php

Source:
http://www.fightaging.org/archives/2012/11/eliminating-metastasis-in-melanoma.php

In this modern age people tend to grow increasingly fat with advancing age. Near any given individual can choose not to do so, but considered in aggregate the masses tend to follow the available incentives more often than not: cheap food; cheap ways to get around without walking; lots of interesting activities that don't require you to move from your chair; and so forth. For your typical fellow in a developed country advancing age means more wealth, more calories, and less exercise, and this has the inevitable effect on waistline, metabolism, long-term health, and life expectancy. With more fat and more years spent fat, the costs pile up: more money spent on medical services, more disability, frailty, and age-related disease, and more years cut from your life expectancy.

So don't get fat, don't stay fat. The weight of evidence tells us that being fat isn't good for you - and for everyone in a developed region, excepting a tiny handful of people with profound genetic disorders, whether or not you are in fact fat is absolutely a choice.

Given the ready way in which we can alter the amount of fat in our bodies through diligence - or lack of same - and the way in which lifestyle choices change with age for most people, there is no desperate need for other explanations as to why people gather more fat with advancing years. Nonetheless, I'll point out a recent open access paper (the full text is PDF only): if I'm reading it right, the researchers here argue that one of the unfortunate low-level biochemical effects of the presence of advanced glycation endproducts (AGEs) in our tissues is that it encourages the growth of fat tissue, or adipose tissue to give it the more formal name - to be fat is to have adiposity, and growth of fat tissue is adipogenesis.

Since AGE levels rise with age, even if an individual doesn't increase their ingested levels of AGEs, this mechanism for AGEs to spur fat tissue growth leaves the door open for some interesting speculation. The researchers don't put any useful numbers to the putative effect, however, and thus I'm inclined to think it small in comparison to, say, how much a person eats or exercises:

An advanced glycation end products (AGEs)-the receptor for AGEs axis restores adipogenic potential of senescent preadipocytes through modulation of p53 function

Impaired adipogenic potential of senescent preadipocytes is a hallmark of adipose aging and aging-related adipose dysfunction. ... We show a novel pro-adipogenic function of AGEs in replicative senescent preadipocytes.

While our study is largely based on in vitro and ex vivo studies, we would predict that a chronic dietary intake of AGEs would positively contribute to adipose development during aging. ... To our knowledge, our study is the first report that AGEs are able to restore senescence-impaired adipogenic potential of aged preadipocytes. These findings implicate that AGEs-induced adipogenesis in senescent preadipocytes is likely to contribute to exacerbating aging-related adiposity.

If you look back in the Fight Aging! archives, you'll find much more information on AGEs and their role in degenerative aging - the established discussion of past years, rather than the new thoughts on fat tissue quoted above. The characteristic buildup of AGEs and similar compounds that occurs with age harms the integrity of tissue and biological systems in a number of ways:

• SENS5 Video: Talking About AGEs and Aging
• AGE Breakers Beyond Alagebrium
• A Raft of Papers on AGEs, ALEs, RAGE
• Commenting on the Utility of AGE-Breakers

Advanced glycation endproducts (AGEs) are a class of undesirable metabolic byproduct. The level of AGEs in the body rises with age and causes harm through a variety of mechanisms, such as by excessively triggering certain cellular receptors or gluing together pieces of protein machinery by forming crosslinks, thus preventing them from carrying out their proper function.

In past years a number of efforts were undertaken to develop drugs that can safely break down at least some forms of AGE. Early promising candidates in laboratory animals failed in humans because the most harmful forms of AGE are different for short-lived versus long-lived mammals - so what benefits a rat isn't of much utility for we humans. So far little progress has been made towards a therapy for the dominant type of AGE in humans, glucosepane, sad to say, as there is comparatively little interest in this field of research.

Source:
http://www.fightaging.org/archives/2012/11/arguing-that-ages-contribute-to-increased-fat-tissue-with-age.php

Last year a research group demonstrated that they could build tissue engineered sections of small intestine in mice. That same group is also working on producing structures of the large intestine using human cells, and here is an update on their progress:

[Researchers] have for the first time grown tissue-engineered human large intestine. ... Our aim is exact replacement of the tissue that is lacking. There are many important functions of the large intestine, and we can partially compensate for that loss through other medical advances, but there are still patients for whom this technology might be revolutionary if we can cross the translational hurdles. This is one of the advances that brings us toward our goal.

The human tissue-engineered colon includes all of the required specialized cell types that are found in human large intestine. The research team grew the tissue-engineered large intestine from specific groups of cells, called organoid units that were derived from intestinal tissue normally discarded after surgery. The organoid units grew on a biodegradable scaffold. After 4 weeks, the human tissue-engineered colon contained the differentiated cell types required in the functioning colon, and included other key components including smooth muscle, ganglion cells, and components of the stem cell niche. ... This proof-of-concept experiment is an important step in transitioning tissue-engineered colon to human therapy.

Link: http://eon.businesswire.com/news/eon/20121108006700/en/tissue-engineering/short-gut/complications-of-prematurity

Source:
http://www.fightaging.org/archives/2012/11/towards-tissue-engineered-large-intestines.php

Oxidative stress is a term you'll see a lot when reading the literature of aging research. The more reactive oxidant compounds there are in a cell, the more they will react with important proteins, modifying them and thus causing cellular machinery to run awry or require repair. Aging is characterized by rising levels of oxidative stress, caused by things such as increased presence of metabolic byproducts that are ever more inefficiently removed, accumulating damage to mitochondria, and so forth.

This is still something of a high level picture, however, and there is still a lot of room left for researchers to expand the understanding of how exactly oxidative damage progresses, or how it contributes to specific manifestations of aging, such as increased cellular senescence. Hence we see work of this nature:

Protein damage mediated by oxidation, protein adducts formation with advanced glycated end products and with products of lipid peroxidation, has been implicated during aging and age-related diseases, such as neurodegenerative diseases.

Increased protein modification has also been described upon replicative senescence of human fibroblasts, a valid model for studying aging in vitro. However, the mechanisms by which these modified proteins could impact on the development of the senescent phenotype and the pathogenesis of age-related diseases remain elusive.

In this study, we performed in silico approaches to evidence molecular actors and cellular pathways affected by these damaged proteins. A database of proteins modified by carbonylation, glycation, and lipid peroxidation products during aging and age-related diseases was built and compared to those proteins identified during cellular replicative senescence in vitro.

Common cellular pathways evidenced by enzymes involved in intermediate metabolism were found to be targeted by these modifications, although different tissues have been examined. ... An important outcome of the present study is that several enzymes that catalyze intermediate metabolism, such as glycolysis, gluconeogenesis, the citrate cycle, and fatty acid metabolism have been found to be modified. These results indicate a potential effect of protein modification on the impairment of cellular energy metabolism. Future studies should address this important issue by combining metabolomics and targeted proteomic analysis during cellular and organismal aging.

Link: http://dx.doi.org/10.1155/2012/919832

Source:
http://www.fightaging.org/archives/2012/11/work-on-better-understanding-oxidative-damage-in-aging.php

This research result is noted because it stands in opposition to the present consensus on vitamin D and long term health in humans; the evidence to date supports a correlation between higher levels of vitamin D, a lower risk of age-related disease, and a longer life expectancy. But here we see the opposite result. This sort of outright contradiction is usually indicative of some greater complexity under the hood yet to be outlined and understood - and there's certainly no shortage of complexity in metabolism:

Low levels of 25(OH) vitamin D are associated with various age-related diseases and mortality, but causality has not been determined. We investigated vitamin D levels in the offspring of nonagenarians who had at least one nonagenarian sibling; these offspring have a lower prevalence of age-related diseases and a higher propensity to reach old age compared with their partners.

We [assessed] vitamin D levels, [dietary] vitamin D intake and single nucleotide polymorphisms (SNPs) associated with vitamin D levels. We included offspring (n = 1038) of nonagenarians who had at least one nonagenarian sibling, and the offsprings' partners (n = 461; controls) from the Leiden Longevity Study.

The offspring had significantly lower levels of vitamin D (64.3 nmol/L) compared with controls (68.4 nmol/L), independent of possible confounding factors. ... Compared with controls, the offspring of nonagenarians who had at least one nonagenarian sibling had a reduced frequency of a common variant in the CYP2R1 gene, which predisposes people to high vitamin D levels; they also had lower levels of vitamin D that persisted over the 2 most prevalent genotypes. These results cast doubt on the causal nature of previously reported associations between low levels of vitamin D and age-related diseases and mortality.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23128285

Source:
http://www.fightaging.org/archives/2012/11/lower-vitamin-d-levels-correlated-to-human-longevity.php

We as a species are defined by our ability to create: given time we will build new wonders from all the matter we can lay our hands on. The true legacy of every generation is the new advances they create in technology - that progress in creation is the only thing likely be recalled in the distant future. Yet despite a history of creation piled upon creation, the urge to destroy is also strong; a certain love of destruction seems a hardwired part of human nature. See the broken window fallacy, for example, which is the 19th century formulation of an ancient truth: that people look upon the consequences of destruction selectively, and call it beneficial.

Suppose it cost six francs to repair the [window broken by a child], and you say that the accident brings six francs to the glazier's trade - that it encourages that trade to the amount of six francs - I grant it; I have not a word to say against it; you reason justly. The glazier comes, performs his task, receives his six francs, rubs his hands, and, in his heart, blesses the careless child. All this is that which is seen.

But if, on the other hand, you come to the conclusion, as is too often the case, that it is a good thing to break windows, that it causes money to circulate, and that the encouragement of industry in general will be the result of it, you will oblige me to call out, "Stop there! Your theory is confined to that which is seen; it takes no account of that which is not seen."

It is not seen that as [the owner of the window] has spent six francs upon one thing, he cannot spend them upon another. It is not seen that if he had not had a window to replace, he would, perhaps, have replaced his old shoes, or added another book to his library. In short, he would have employed his six francs in some way, which this accident has prevented.

The lesson of the broken window is that destruction is never beneficial. It is a cost, and that cost must be paid at the expense of some other benefit. This lesson is needed: the broken window fallacy was widespread two centuries ago and remains so now. You will hear commentary after every natural disaster suggesting that the resulting expenditures on repair will benefit the economy, for example.

What is the greatest ongoing disaster, the cause of the greatest destruction? The answer is degenerative aging. Aging destroys human capital: knowledge, skills, talents, the ability to work, the ability to create. It does so at a ferocious rate, a hundred thousand lives a day, and all that they might have accomplished if not struck down. If translated to a dollar amount, the cost is staggering - even shifts in life expectancy have gargantuan value. And why shouldn't they? Time spent alive and active is the basis of all wealth.

It is unfortunate, but many people advocate for the continuation of aging, for relinquishment of efforts to build medicines to extend health life. Among these are people who welcome aging and death because to their eyes it gives a young person the chance to step into a role vacated by an older person. This is another form of the broken window, however: the advocate for aging looks only at the young person, and dismisses what the older person might have done were they not removed from the picture by death or disability. So too, any apologism for aging based on clearing out the established figures because it provides a greater opportunity for younger people to repeat the same steps, follow the same paths, relearn the same skills, redo the same tasks ... these arguments are the broken window writ large.

Vast wealth and opportunity bleeds into the abyss on a daily basis, destroyed because the people who embody that wealth and opportunity decay and die. We would all be wealthier by far given the medical means to prevent these losses. In your thoughts on aging, don't ignore the vast invisible costs - the work never accomplished, the wonders never created, because those who could have done so never had the chance. The enforced absence of the age-damaged, the frail, the disabled, and the dead is in and of itself a form of damage; the loss of their skills and knowledge is something that must be repaired. That requires work and resources that might have gone to new creations, rather than catching up from loss.

So this continues, and the perpetual devotion of resources to repair and recover from the losses of death and disability is a great ball and chain shackled to our ability to create progress. But most people don't think of at all - it is invisible to them. Nonetheless, the costs of aging that we labor under are so vast that the introduction of ways to rejuvenate the old will lead to an blossoming of wealth and progress the likes of which has never before been seen.

Source:
http://www.fightaging.org/archives/2012/11/the-greatest-instance-of-the-broken-window-fallacy.php

A low-cost, reliable method of measuring biological age is greatly sought after by the research community. People and laboratory animals age at different rates - by which I mean that they accumulate damage and changes characteristic of aging at different rates. Thus two individuals of the same species and same chronological age might have different biological ages thanks to life style, environment, access to medicine, and so forth.

Some interventions, such as calorie restriction, can slow the pace at which an individual ages, but measuring this slowing is a challenging process. Biological age is a simple concept at the high level, but finding a quick and reliable way to actually measure it has yet to happen. Thus while researchers would like to have rapid answers as to how effective any given method of slowing aging might be, they must wait and run long-lasting studies. The bottom line measure for any slowing of aging is to wait for the individuals in question to live out their lives and thus measure by effect on life span. Even in short-lived mice this can require years and thus a great deal of money. In longer-lived animals, ourselves included, it is simply impractical to run the necessary studies.

When it comes to the forthcoming generation of therapies capable of limited rejuvenation - by repairing some of the damage that causes degenerative aging - the situation is much the same, as is the need for a quick and easy measure of biological age. A therapy that actually produces some degree of rejuvenation should make a laboratory animal biologically younger than peers with the same chronological age. But how to measure that change without employing the lengthy and expensive wait-and-see approach?

Given the present state of affairs, any quick measure of biological age will speed research, making it very much faster and cheaper to assess varied means of extending healthy life. Some experiments that would presently require a year or more could be conducted in a few weeks or months: apply the therapy and evaluate the resulting changes in measures of biological age.

Several lines of research look promising when it comes to yielding a way to reliably and consistently evaluate biological age. One involves measurement of DNA methylation levels, and despite initial setbacks it may yet prove possible to tease out a useful measure from changes in the dynamics of telomere length. There are others. Here, for example, is a recent paper in which researchers present a method based on measurement of metabolite levels:

A metabolic signature predicts biological age in mice

Our understanding of the mechanisms by which aging is produced is still very limited. Here, we have determined the sera metabolite profile of 117 wild-type mice of different genetic backgrounds ranging from 8-129 weeks of age. This has allowed us to define a robust metabolomic signature and a derived metabolomic score that reliably/accurately predicts the age of wild-type mice.

In the case of telomerase-deficient mice, which have a shortened lifespan, their metabolomic score predicts older ages than expected. Conversely, in the case of mice that over-express telomerase, their metabolic score corresponded to younger ages than expected.

Importantly, telomerase reactivation late in life by using a TERT based gene therapy recently described by us, significantly reverted the metabolic profile of old mice to that of younger mice ... These results indicate that the metabolomic signature is associated to the biological age rather than to the chronological age. This constitutes one of the first aging-associated metabolomic signatures in a mammalian organism.

This might turn out to be an indirect measure of telomerase activity and little else, as over-specific matching is always a potential issue when searching for patterns in a large and complex system such as mammalian metabolism. Testing this metabolic signature against other means of accelerating or slowing aging in mice - such as calorie restriction - is thus one obvious next step.

Source:
http://www.fightaging.org/archives/2012/11/a-possible-metabolic-signature-of-biological-age-in-mice.php

Myelin sheaths the axons of nerve cells, but the integrity of this sheathing degrades with age. Transplants of neural stem cells can be used to encourage myelin formation, and researchers are exploring this approach as a therapy for conditions involving more profound myelin loss.

There is always a demand in this sort of research for better and cheaper ways to obtain cells that have the desired effect. It is not trivial, for example, to isolate the right sort of neural stem cell, or establish a protocol for producing these cells from embryonic or induced pluripotent stem cells. A great deal of stem cell research these days involves the discovery of chemical signals, growth environments, and other necessary items to guide the growth of specific cell types.

Here is an example for myelin-forming cells, which will no doubt contribute to the next round of research and development of cell therapies aimed at regrowth of myelin:

Researchers have unlocked the complex cellular mechanics that instruct specific brain cells to continue to divide. This discovery overcomes a significant technical hurdle to potential human stem cell therapies; ensuring that an abundant supply of cells is available to study and ultimately treat people with diseases.

"One of the major factors that will determine the viability of stem cell therapies is access to a safe and reliable supply of cells. This study demonstrates that - in the case of certain populations of brain cells - we now understand the cell biology and the mechanisms necessary to control cell division and generate an almost endless supply of cells."

The study focuses on cells called glial progenitor cells (GPCs) that are found in the white matter of the human brain. These stem cells give rise to two cells found in the central nervous system: oligodendrocytes, which produce myelin, the fatty tissue that insulates the connections between cells; and astrocytes, cells that are critical to the health and signaling function of oligodendrocytes as well as neurons.

One of the barriers to moving forward with human treatments for myelin disease has been the difficulty of creating a plentiful supply of necessary cells, in this case GPCs. Scientists have been successful at getting these cells to divide and multiply in the lab, but only for limited periods of time, resulting in the generation of limited numbers of usable cells. ... Overcoming this problem required that [researchers] master the precise chemical symphony that occurs within stem cells, and which instructs them when to divide and multiply, and when to stop this process and become oligodendrocytes and astrocytes.

Link: http://www.urmc.rochester.edu/news/story/index.cfm?id=3669

Source:
http://www.fightaging.org/archives/2012/11/creating-myelin-producing-cells-to-order.php

Senescent cells are those that have left the cell cycle without being destroyed, either by the immune system or by one of the processes of programmed cell death. They remain active, however, exhibiting what is termed a senescence-associated secretory phenotype (SASP): these cells secrete all sorts of chemical signals that prove harmful to surrounding tissues and the body as a whole - through promotion of chronic inflammation, for example.

The number of senescent cells in tissue grows with age, and this increase in numbers is one of the root causes of aging. Researchers have demonstrated benefits in mice through destroying senescent cells without harming other cells. Regular targeted destruction of senescent cells could be the basis for therapies that remove this contribution to degenerative aging.

Any other approach would require understanding more about SASP and how to control or reverse the unpleasant effects of senescence - and here is an example of this sort of research, aimed at identifying controlling mechanisms with an eye to building therapies to reduce SASP:

With advancing age, senescent cells accumulate in tissues and the SASP-elicited proinflammatory state is believed to have a complex influence on age-related conditions. For example, two major SASP factors, IL-6 and IL-8, together with other SASP factors, attract immune cells to the tissue in which senescent cells reside; depending on the tissue context, this immune surveillance can promote processes such as wound healing, the resolution of fibrosis, and tumor regression. At the same time, SASP factors can compromise the integrity of the ECM, thus facilitating cancer cell migration. In addition, the systemic proinflammatory phenotype seen in the elderly is believed to affect a broad range of age-related pathologies, including diabetes, cancer, neurodegeneration and cardiovascular disease and contributes to an age-related decline of the adaptive immune system (immunosenescence).

Despite the great potential impact of the SASP on the biology of senescence and aging, the mechanisms that regulate SASP are poorly understood. ... Here, we report the identification of NF90 as an RNA-binding protein that binds to numerous mRNAs encoding SASP factors (collectively named SASP mRNAs) and coordinately influences their post-transcriptional fate in a senescence-dependent manner.

In young, early-passage, proliferating fibroblasts, high NF90 levels contributed to the repression of SASP factor production. This repression was elicited mainly via reduction in SASP factor translation ... By contrast, in senescent cells NF90 levels were markedly reduced, which allowed increased expression of numerous SASP factors. Our results are consistent with a role for NF90 as a coordinator of the inhibition of SASP factor production in early-passage, proliferating fibroblasts; in senescent cells, the lower levels of NF90 lead to SASP de-repression, permitting higher expression of SASP factors

Link: http://impactaging.com/papers/v4/n10/full/100497.html

Source:
http://www.fightaging.org/archives/2012/11/investigating-the-mechanisms-of-cellular-senescence.php

Mitochondria, the cell's herd of bacteria-like power plants, occupy an important position in processes of aging, metabolism, and many age-related conditions. Mitochondria produce damaging reactive oxidative molecules as a side-effect of their operation, and these can cause all sorts of havoc - such as by damaging mitochondrial DNA in ways that can propagate throughout the mitochondrial population of a cell, causing it to run awry and harm surrounding tissue. This happens ever more often as we age, and is one of the principle contributions to degenerative aging.

It is worth noting that a greater ability of mitochondria to resist this sort of self-inflicted oxidative damage is theorized to explain much of the longevity of many species that are unusually long-lived for their size - such as bats, naked mole-rats, and so forth.

Thus the researcher community is increasingly interested in finding ways to target therapies to mitochondria: to slow oxidative damage, fix that damage, repair other issues such as genetic disorders in mitochondrial DNA, or alter mitochondrial operation as a way of manipulating cellular behavior and metabolic processes. Building such a therapy usually means attaching a payload molecule to a delivery molecule or particle that will be (a) taken up by a cell, passing through the cell membrane, and then (b) swallowed by a mitochondrion within the cell, passing through that mitochondrion's membranes.

A range of different research groups are working on varied forms of delivery technology. Compare, for example, the repurposed protein machinery of rhTFAM with various plastinquione compounds or polymer nanoparticles. Or, more deviously, genetic engineering that makes a cell nucleus produce and export proteins to that cell's mitochondria. There are many others.

Diversity is a good thing - though of course not all of these strategies are equal in the sort of interventions that they can support. There is a world of difference between introducing more antioxidants into the mitochondria so as to blunt their creation of damaging, reactive byproducts and introducing new genes to repair damage to mitochondrial DNA. The former only gently slows the inevitable, while the latter reverses and repairs the harm done.

In any case, here is a paper representative of work taking place in the targeted antioxidant camp, much of which is taking place in Moscow research centers. Given a few years of promising studies, they are going on to explore the space of possible related compounds, in search of drug candidates that might do as well or better as those discovered to date.

Novel penetrating cations for targeting mitochondria

Novel penetrating cations were used for a design of mitochondria-targeted compounds and tested in model lipid membranes, in isolated mitochondria and in living human cells in culture. Rhodamine-19, berberine and palmatine were conjugated by aliphatic linkers with plastoquinone possessing antioxidant activity. These conjugates (SkQR1,SkQBerb, SkQPalm) and their analogs lacking plastoquinol moiety (C12R1,C10Berb and C10Palm) penetrated bilayer phospholipid membrane in their cationic forms and accumulated in isolated mitochondria or in mitochondria of living cells due to membrane potential negative inside.

Reduced forms of SkQR1, SkQBerb and SkQPalm inhibited lipid peroxidation in isolated mitochondria at nanomolar concentrations. In human fibroblasts SkQR1, SkQBerb and SkQPalm prevented fragmentation of mitochondria and apoptosis induced by hydrogen peroxide.

The novel cationic conjugates described here are promising candidates for drugs against various pathologies and aging as mitochondria-targeted antioxidants and selective mild uncouplers.

As a footnote I should remind folk that everyday antioxidant supplements do nothing for long-term health, and certainly don't end up in your mitochondria when you ingest them.

Source:
http://www.fightaging.org/archives/2012/10/broadening-study-of-mitochondrially-targeted-compounds.php

Myelin is the material sheathing axons in nerve cells. A number of conditions involve loss of myelin, such as multiple sclerosis (MS), but loss of myelin integrity occurs to a lesser degree for all of us as we age, and is thought to contribute to the characteristic cognitive decline of later years. Thus research into ways to regenerate myelin sheathing has broad potential application and is worth keeping an eye on:

We have identified a whole new target for drugs that might promote repair of the damaged brain in any disorder in which demyelination occurs. Any kind of therapy that can promote remyelination could be an absolute life-changer for the millions of people suffering from MS and other related disorders.

In 2005, [researchers] discovered that a sugar molecule, called hyaluronic acid, accumulates in areas of damage in the brains of humans and animals with demyelinating brain and spinal cord lesions. Their findings at the time [suggested] that hyaluronic acid itself prevented remyelination by preventing cells that form myelin from differentiating in areas of brain damage. The new study shows that the hyaluronic acid itself does not prevent the differentiation of myelin-forming cells. Rather, breakdown products generated by a specific enzyme that chews up hyaluronic acid - called a hyaluronidase - contribute to the remyelination failure.

This enzyme is highly elevated in MS patient brain lesions and in the nervous systems of animals with an MS-like disease. The research team [found] that by blocking hyaluronidase activity, they could promote myelin-forming cell differentiation and remyelination in the mice with the MS-like disease. Most significantly, the drug that blocked hyaluronidase activity led to improved nerve cell function. The next step is to develop drugs that specifically target this enzyme.

Link: http://www.sciencedaily.com/releases/2012/10/121031151611.htm

Source:
http://www.fightaging.org/archives/2012/11/promoting-remyelination-by-blocking-hyaluronidase.php