How Cells Take Out the Trash
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Autophagy consists of a collection of cellular housecleaning processes responsible for recycling damaged cellular components. It is known to relate to longevity, as demonstrated in numerous animals studies in which aging is slowed via genetic or metabolic manipulation, and in which autophagy is seen to take place more energetically. This all seems logical, as aging is nothing more than an accumulation of unrepaired damage and the reactions to that damage, while autophagy seeks to minimize present damage before it causes more harm.

Since we've already touched on of autophagy and its relationship to longevity today, as well as the prospects for developing therapies based on increased levels of autophagy, I thought I'd point out this popular science article on the topic:

To keep themselves neat, tidy and above all healthy, cells rely on a variety of recycling and trash removal systems. If it weren't for these systems, cells could look like microscopic junkyards - and worse, they might not function properly.

One of the cell's trash processors is called the proteasome. It breaks down proteins, the building blocks and mini-machines that make up many cell parts. The barrel-shaped proteasome disassembles damaged or unwanted proteins, breaking them into bits that the cell can re-use to make new proteins. In this way, the proteasome is just as much a recycling plant as it is a garbage disposal.

Proteins aren't the only type of cellular waste. Cells also have to recycle compartments called organelles when they become old and worn out. For this task, they rely on an organelle called the lysosome, which works like a cellular stomach. Containing acid and several types of digestive enzymes, lysosomes digest unwanted organelles in a process termed autophagy.

While cells mainly use proteasomes and lysosomes, they have a couple of other options for trash disposal. Sometimes they simply hang onto their trash, performing the cellular equivalent of sweeping it under the rug. Scientists propose that the cell may pile all the unwanted proteins together in a glob called an aggregate to keep them from gumming up normal cellular machinery. If the garbage can't be digested by lysosomes, the cell can sometimes spit it out in a process called exocytosis. Once outside the cell, the trash may encounter enzymes that can take it apart, or it may simply form a garbage heap called a plaque. Unfortunately, these plaques outside the cell may be harmful, too.

Further study of the many ways cells take out the trash could lead to new approaches for keeping them healthy and preventing or treating disease.


TFE3 Promotes Autophagy
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Autophagy is the name given to a collection of processes that recycle damaged cellular components and unwanted or harmful molecules. Materials flagged for recycling are engulfed by one of the cell's lysosomes and then dismantled inside it. Greater levels of autophagy are observed in a majority of the means of extending life in laboratory animals through genetic or metabolic manipulation to slow aging, including calorie restriction, in which the body reacts to low levels of nutrients, raw materials for protein manufacture in cells, by stepping up its efforts to reclaim the needed raw materials from existing structures that are past their prime.

The association of enhanced longevity and enhanced autophagy shouldn't be a surprise: aging is the accumulation of unrepaired damage, and autophagy is a process that attempts to minimize the present level of cellular damage before it can cause more harm. At some point the research community will make inroads towards creating therapies based on boosted autophagy - though this doesn't appear to be happening anywhere near as rapidly as I expected it to. Here is an example of research into the regulation of autophagy, similar to many other papers published in past years, but the expected use of this sort of knowledge to build a treatment has yet to happen:

The discovery of a gene network regulating lysosomal biogenesis and its transcriptional regulator transcription factor EB (TFEB) revealed that cells monitor lysosomal function and respond to degradation requirements and environmental cues. We report the identification of transcription factor E3 (TFE3) as another regulator of lysosomal homeostasis that induced expression of genes encoding proteins involved in autophagy and lysosomal biogenesis [in] response to starvation and lysosomal stress.

We found that in nutrient-replete cells, TFE3 was recruited to lysosomes through interaction with active Rag guanosine triphosphatases (GTPases) and exhibited mammalian (or mechanistic) target of rapamycin complex 1 (mTORC1)-dependent phosphorylation. Phosphorylated TFE3 was retained in the cytosol through its interaction with the cytosolic chaperone 14-3-3. After starvation, TFE3 rapidly translocated to the nucleus and bound to the CLEAR (Coordinated Lysosomal Expression and Regulation) elements present in the promoter region of many lysosomal genes, thereby inducing lysosomal biogenesis.

Depletion of endogenous TFE3 entirely abolished the response [of] cells to starvation, suggesting that TFE3 plays a critical role in nutrient sensing and regulation of energy metabolism. Furthermore, overexpression of TFE3 triggered lysosomal exocytosis and resulted in efficient cellular clearance in a cellular model of a lysosomal storage disorder, Pompe disease, thus identifying TFE3 as a potential therapeutic target for the treatment of lysosomal disorders.


An Interview With Mikhail Batin
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Here is a Russian-language interview with Mikhail Batin of the Science for Life Extension Foundation, following on from the recent 3rd International Conference on the Genetics of Aging and Longevity in Sochi, Russia. The state of automated translation for Russian is still very rough around the edges, so the quoted material below is tidied up somewhat from the original:

Q: But with diseases such as cancer, cardiovascular disease, and diabetes, they occur not only in the old, but also in young people. What are your arguments that old age is a disease?

A: Well, the frequency of cancer in a person of age 70 is 200 times higher than at 20 years. All age-dependent disease incidence increases with age, and grows exponentially. Aging underlies these diseases. We just tend to think that it is normal when a person goes bad, developing poor vision, poor hearing, poor thinking - and this is not normal. Aging is an illness and people die because of it.

Q: Actually, people do not want to grow old, especially women. And those who have enough willpower to lead a healthy lifestyle, eat right, play sports. And experience shows that it is, in general, it helps them to get sick less and live longer. So, maybe that's enough? Need there any special measures to combat aging?

A: It helps, but not so much. Even the person leading a healthy lifestyle does not rule out the use of antibiotics, early diagnosis of diseases, etc. Yes, you need to eat less and move more, but that does not mean you cannot also do something significant, for example, to develop the means of reversing some processes of aging not affected by exercise and diet. The idea of ​​sufficiency is bad, let's instead go ahead and set big goals.

Q: And if people don't want to live long? There was a survey of Americans in which they were asked how much they want to live. Most chose a limit of 80-90 years. And to live to 120 years old is only desired by a few. So what to do - "an iron fist pounding mankind to happiness" or work to educate the public in order to change this position?

A: You know, people often want what other people want. This is common. They do not want to stand out from the masses. So people protect the present state of their world, it's such a conquering conservatism. Yet as soon as the radical possibilities to extend life emerge and become common, people will immediately want to use them. People do not refuse technology, they just do not want to think about making it.


An Interesting Comparison of Species Lifespan Differences
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One branch of investigation into the mechanisms and progression of aging uses comparisons between species of differing longevity as a way to identify where to work. The ultimate aim is to narrow down the exact biological differences between short-lived and long-lived species, a process that can probably be simplified by focusing first on the exceptional cases.

Surveys and theorizing of the sort quoted below are a part of the process of deciding which of the thousands of readily available species to study are most likely to yield useful information:

Maximum lifespan in birds and mammals varies strongly with body mass such that large species tend to live longer than smaller species. However, many species live far longer than expected given their body mass. This may reflect interspecific variation in extrinsic mortality, as life-history theory predicts investment in long-term survival is under positive selection when extrinsic mortality is reduced. Here, we investigate how multiple ecological and mode-of-life traits that should reduce extrinsic mortality (including volancy (flight capability), activity period, foraging environment and fossoriality), simultaneously influence lifespan across endotherms.

Using novel phylogenetic comparative analyses and to our knowledge, the most species analysed to date (n = 1368), we show that, over and above the effect of body mass, the most important factor enabling longer lifespan is the ability to fly. Within volant species, lifespan depended upon when (day, night, dusk or dawn), but not where (in the air, in trees or on the ground), species are active. However, the opposite was true for non-volant species, where lifespan correlated positively with both arboreality and fossoriality. Our results highlight that when studying the molecular basis behind cellular processes such as those underlying lifespan, it is important to consider the ecological selection pressures that shaped them over evolutionary time.

Those of you following along over the past decade or so as researchers picked out exceptional species in order to investigate the details of their biochemistry will not be too surprised to see flight linked with longevity. Bats and birds feature prominently in the lists of species with unusual longevity for their size, and there are a range of theories as to how the metabolic demands of flight might lead to the evolution of a longer-lived species.


A View of the Correlation Between Individual Wealth and Adult Life Expectancy
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A web of correlations links health, longevity, wealth, education, and intelligence. More intelligent and educated people tend to be wealthier. They also tend to live longer. All sorts of sensible causes can be proposed, such as those involving better access to medical services and a better ability to make use of that access, or the education, willpower, and peer pressure to make improved lifestyle choices. Don't get fat, keep exercising, and so forth: over the long term calorie restriction and regular exercise produce benefits to health and life expectancy in the average individual that are large in comparison to that provided by any presently available medical technology. There are less usual suggestions as well, such as the possibility of a biological connection between better health and greater intelligence.

Biology and health is very complex, and there is plenty of room to argue cause versus effect and relative impact even in deceptively simple associations such as these. The data showing these associations is robust, however, and here is another example:

[Economists] crunched the numbers and found that the richer you are, the longer you'll live. [They] parsed this data from the University of Michigan's Health and Retirement Study, a survey that tracks the health and work-life of 26,000 Americans as they age and retire. The data is especially valuable as it tracks the same individuals every two years in what's known as a longitudinal study, to see how their lives unfold.

The good news is that men of all incomes are living longer. Yet the data shows that the life expectancy of the wealthy is growing much faster than the life expectancy of the poor. Here's the sort of detail this remarkable data set can show. You can look at a man born in 1940 and see that during the 1980s, the mid-point of his career, his income was in the top 10% for his age group. If that man lives to age 55 he can expect to live an additional 34.9 years, or to the age of 89.9. That's six years longer than a man whose career followed the same arc, but who was born in 1920. For men who were in the poorest 10%, they can expect to live another 24 years, only a year and a half longer than his 1920s counterpart.

The story is rather different for women. At every income level, for both those born in 1920 and 1940, women live longer than men. But for women, the longevity and income trends are even more striking. While the wealthiest women from the 1940s are living longer, the poorest 40% are seeing life expectancy decline from the previous generation. "At the bottom of the distribution, life is not improving rapidly for women anymore. Smoking stands out as a possibility. It's much more common among women at lower income levels."


Effective Tissue Adhesion With a Nanoparticle Solution
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Researchers have developed an improvement upon sutures that has a range of potential applications beyond merely sealing injuries:

The principle is simple: nanoparticles contained in a solution spread out on surfaces to be glued bind to the gel's (or tissue's) molecular network. This phenomenon is called adsorption. At the same time the gel (or tissue) binds the particles together. Accordingly, myriad connections form between the two surfaces. This adhesion process, which involves no chemical reaction, only takes a few seconds. In their latest, newly published study, the researchers used experiments performed on rats to show that this method, applied in vivo, has the potential to revolutionize clinical practice.

In a first experiment, the researchers compared two methods for skin closure in a deep wound: traditional sutures, and the application of the aqueous nanoparticle solution with a brush. The latter is easy to use and closes skin rapidly until it heals completely, without inflammation or necrosis. The resulting scar is almost invisible.

In a second experiment, still on rats, the researchers applied this solution to soft-tissue organs such as the liver, lungs or spleen that are difficult to suture because they tear when the needle passes through them. At present, no glue is sufficiently strong as well as harmless for the organism. Confronted with a deep gash in the liver with severe bleeding, the researchers closed the wound by spreading the aqueous nanoparticle solution and pressing the two edges of the wound together. The bleeding stopped. To repair a sectioned liver lobe, the researchers also used nanoparticles: they glued a film coated with nanoparticles onto the wound, and stopped the bleeding. In both situations, organ function was unaffected and the animals survived.

"Gluing a film to stop leakage" is only one example of the possibilities opened up by adhesion brought by nanoparticles. In an entirely different field, the researchers have succeeded in using nanoparticles to attach a biodegradable membrane used for cardiac cell therapy, and to achieve this despite the substantial mechanical constraints due to its beating. They thus showed that it would be possible to attach various medical devices to organs and tissues for therapeutic, repair or mechanical strengthening purposes.


Is Parkinson's an Autoimmune Disease?
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This is an interesting view on the later stages Parkinson's disease that seems fairly orthogonal to the present mainstream focus on α-synuclein and its removal:

The cause of neuronal death in Parkinson's disease is still unknown, but a new study proposes that neurons may be mistaken for foreign invaders and killed by the person's own immune system. "This is a new, and likely controversial, idea in Parkinson's disease; but if true, it could lead to new ways to prevent neuronal death in Parkinson's that resemble treatments for autoimmune diseases."

For decades, neurobiologists have thought that neurons are protected from attacks from the immune system, in part, because they do not display antigens on their cell surfaces. "That idea made sense because, except in rare circumstances, our brains cannot make new neurons to replenish ones killed by the immune system. But, unexpectedly, we found that some types of neurons can display antigens."

Cells display antigens with special proteins called MHCs. Using postmortem brain tissue donated to the Columbia Brain Bank by healthy donors [researchers] first noticed - to their surprise - that MHC-1 proteins were present in two types of neurons. These two types of neurons - one of which is dopamine neurons in a brain region called the substantia nigra - degenerate during Parkinson's disease.

[The researchers] conducted in vitro experiments with mouse neurons and human neurons created from embryonic stem cells. The studies showed that under certain circumstances - including conditions known to occur in Parkinson's - the neurons use MHC-1 to display antigens. Among the different types of neurons tested, the two types affected in Parkinson's were far more responsive than other neurons to signals that triggered antigen display. The researchers then confirmed that T cells recognized and attacked neurons displaying specific antigens.

"Right now, we've showed that certain neurons display antigens and that T cells can recognize these antigens and kill neurons, but we still need to determine whether this is actually happening in people. We need to show that there are certain T cells in Parkinson's patients that can attack their neurons. This idea may explain the final step. We don't know if preventing the death of neurons at this point will leave people with sick cells and no change in their symptoms, or not."


Turning Cells into Programmable Medical Devices
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Targeted delivery of drugs and proteins to modify metabolism and cell behavior may in the future be accomplished by engineered cells. Cells already do a great many useful things, so why reinvent the wheel when there is existing machinery that can be adapted to new purposes? This is a line of research with the potential to radically change the face of medicine and our own biology, leading to a future in which most of us have large numbers of enhanced and altered cells in every organ, monitoring and reacting to local conditions in order to help maintain the body against the processes of aging and disease far more effectively than our present evolved mechanisms can manage.

A synthetic biology team has created a new technology for modifying human cells to create programmable therapeutics that could travel the body and selectively target cancer and other sites of disease. "The project addressed a key gap in the synthetic biology toolbox. There was no way to engineer cells in a manner that allowed them to sense key pieces of information about their environment, which could indicate whether the engineered cell is in healthy tissue or sitting next to a tumor."

The end result is a protein biosensor that sits on the surface of a cell and can be programmed to sense specific external factors. For example, the engineered cell could detect big, soluble protein molecules that indicate that it's next to a tumor. When the biosensor detects such a factor, it sends a signal into the engineered cell's nucleus to activate a gene expression program, such as the production of tumor-killing proteins or chemicals. Since this toxic program would be activated only near tumor cells, such an approach could minimize side effects as well as improve therapeutic benefits.

Called a Modular Extracellular Sensor Architecture (MESA), the biosensor platform is completely self-contained so that several different biosensors can be present in a single cell without interfering with one another, allowing bioengineers to build increasingly sophisticated functional programs. The platform is also highly modular, enabling the biosensors to be customized to recognize factors of relevance to various patients' needs. "By linking the output of these biosensors to genetic programs, one can build in a certain logical command, such as 'turn the output gene on when you sense this factor but not that factor.' In that way, you could program a cell-based therapy to specify which cells it should kill."


A Midlife Crisis for the Mitochondrial Free Radical Theory of Aging
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Here is an open access paper that covers some of the challenges that have faced the interpretation of just how and why it is that mitochondria have an important role in the aging process. The mitochondrial free radical theory of aging has been broadly considered, in several forms, but as for just about every theory of aging early models turned out to be too simple and straightforward. The reality on the ground is more complex, which is why you'll find a mass of data that supports this theory and another mass of data that contradicts it:

Since its inception more than four decades ago, the Mitochondrial Free Radical Theory of Aging (MFRTA) has served as a touchstone for research into the biology of aging. The MFRTA suggests that oxidative damage to cellular macromolecules caused by reactive oxygen species (ROS) originating from mitochondria accumulates in cells over an animal's lifespan and eventually leads to the dysfunction and failure that characterizes aging.

A central prediction of the theory is that the ability to ameliorate or slow this process should be associated with a slowed rate of aging and thus increased lifespan. A vast pool of data bearing on this idea has now been published. ROS production, ROS neutralization and macromolecule repair have all been extensively studied in the context of longevity. We review experimental evidence from comparisons between naturally long- or short-lived animal species, from calorie restricted animals, and from genetically modified animals and weigh the strength of results supporting the MFRTA.

Viewed as a whole, the data accumulated from these studies have too often failed to support the theory. Excellent, well controlled studies from the past decade in particular have isolated ROS as an experimental variable and have shown no relationship between its production or neutralization and aging or longevity. Instead, a role for mitochondrial ROS as intracellular messengers involved in the regulation of some basic cellular processes, such as proliferation, differentiation and death, has emerged. If mitochondrial ROS are involved in the aging process, it seems very likely it will be via highly specific and regulated cellular processes and not through indiscriminate oxidative damage to macromolecules.


Public Views on the Future of Technology
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A few things are of interest in this survey, with one being that a majority of people don't like specific instances of societal change resulting from technological advances if asked about them, which isn't much of a surprise given human nature. Another is that extended human longevity shows up as a desired goal for a larger minority than has been the case in the past - I would expect to see growth in this number when measured, given the events of the past few years. This being a survey there is little distinction made between the fantastical drawn from science fiction and the plausible drawn from science, which is unfortunate, but it is still worth a look.

The American public anticipates that the coming half-century will be a period of profound scientific change, as inventions that were once confined to the realm of science fiction come into common usage. This is among the main findings of a new national survey by The Pew Research Center, which asked Americans about a wide range of potential scientific developments - from near-term advances like robotics and bioengineering, to more "futuristic" possibilities like teleportation or space colonization.

Asked to describe in their own words the futuristic inventions they themselves would like to own, the public offered three common themes: 1) travel improvements like flying cars and bikes, or even personal space crafts; 2) time travel; and 3) health improvements that extend human longevity or cure major diseases. One in ten Americans (9%) list the ability to travel through time as the futuristic invention they would like to have, and an identical 9% would want something that improved their health, increased their lifespan, or cured major diseases.

At the same time, many Americans seem to feel happy with the technological inventions available to them in the here and now - 11% answered this question by saying that there are no futuristic inventions that they would like to own, or that they are "not interested in futuristic inventions." And 28% weren't sure what sort of futuristic invention they might like to own.

A substantial majority of Americans (81%) believe that within the next 50 years people needing an organ transplant will have new organs custom made for them in a lab. Belief that this development will occur is especially high among men, those under age 50, those who have attended college, and those with relatively high household incomes. But although expectations for this development are especially high within these groups, three-quarters or more of every major demographic group feels that custom organs are likely to become a reality in the next half-century.