Amazing Science

Time magazine's new cover story is the about the ultimate tech company cage match: GOOGLE VS. DEATH. In Silicon Valley parlance, this mortal coil is a bug, not a feature, and Time gives GOOG pretty generous odds.

It’s worth pointing out that there is no other company in Silicon Valley that could plausibly make such an announcement. Smaller outfits don’t have the money; larger ones don’t have the bones. Apple may have set the standard for surprise unveilings but, excepting a major new product every few years, these mostly qualify as short-term. Google’s modus operandi, in comparison, is gonzo airdrops into deep “Wait, really?” territory. Last week Apple announced a gold iPhone; what did you do this week, Google? Oh, we founded a company that might one day defeat death itself.

Also worth pointing out? No company can plausibly claim to defeat death. It's de facto implausible! "Might," doesn't quite cover it. Probably. "One day." Outlook hazy, but hey, it gives Time and Google an excuse to talk about "moon shots," Larry Page's pet phrasefor outlandish, presumably genius ideas. Page, who helped found Singularity University, has had a life-extension fetish for a while. Last year, the company hired transhumanist cheerleader Ray Kurzweil to build "the ultimate AI."

The death-curing company Time is referring to is Calico. According to a press release put out at the same time as the article, Calico "will focus on health and well-being, in particular the challenge of aging and associated diseases." Calico's CEO and founding investor is Arthur D. Levinson, the former CEO of Genentech, the biotech corporation. Even with this new role to alter the basic nature of human existence, Levinson "will remain Chairman of Genentech and a director of Hoffmann-La Roche, as well as Chairman of Apple."

Medicine is well on its way to becoming an information science: doctors and researchers are now able to harvest and mine massive quantities of data from patients. And Google is very, very good with large data sets. While the company is holding its cards about Calico close to the vest, expect it to use its core data-handling skills to shed new light on familiar age-related maladies. Sources close to the project suggest it will start small and focus entirely on researching new technologies.

What’s certain is that looking at medical problems through the lens of data and statistics, rather than simply attempting to bring drugs to market, can produce startlingly counterintuitive opinions. “Are people really focused on the right things?” Page muses. “One of the things I thought was amazing is that if you solve cancer, you’d add about three years to people’s average life expectancy. We think of solving cancer as this huge thing that’ll totally change the world. But when you really take a step back and look at it, yeah, there are many, many tragic cases of cancer, and it’s very, very sad, but in the aggregate, it’s not as big an advance as you might think.”Page, in other words, is a man for whom solving—not curing—cancer may not be a big enough task.

Solving death over curing cancer is a pretty high class problem. But before we start working ourselves into a frenzy about who has access to Google's "solution"—decrying some dystopian double feature of Elysiumand In Time, where only the poor die young—consider the hubris of Page's claims.

The fact that Time is laundering that belief is a bubble indicator. How do you know when everyone is too intoxicated on the phantom power of pampered billionaires? When they tell you they can solve death and you believe them.

Tiny fish that live in temporary pools in Africa reach sexual maturity faster than any other animal with a backbone, say scientists.

One of the studied species of killifish - Nothobranchius kadleci - started to reproduce at the age of 17 days. Researchers found that some eggs reached hatching stage in 15 days meaning they also have the shortest minimum generation time in vertebrates.

In the wild, these fishes live in extreme conditions of temporary pools that only occur during the rainy season when savannah depressions are filled with water. Dr. Martin Reichard and colleagues from the Institute of Vertebrate Biology, Academy of Sciences of the Czech Republic studied the aging processes of two species of wild-caught fishes from southern Mozambique under laboratory conditions. "It is biologically very relevant for these fish to be able to sexually mature very fast because their habitat may dry out in three to four weeks," Dr. Reichard said. "If they mature very fast, they can produce a new generation."

Researchers from the Instituto de Medicina Oncológica y Molecular de Asturias have found that a protein responsible for accelerated aging disorders can dramatically slow down the spread of cancers.

The team revealed that prelamin A, responsible for accelerated ageing in a condition called progeria, can prevent the progression of malignant or cancerous tumours. They achieved this by using mosaic mouse models, genetically modified mice bearing the protein prelamin A in half of their cells.

Ageing and cancer are intimately related processes, but their links are complex. The risk of developing tumours increases with age, but some of the mechanisms favouring ageing can also slow down the appearance and development of cancer. The results from this study represent an advance in the understanding of the underlying biological mechanisms that link age and cancer development, as well as possible new drug targets in the future.

"Mice with prelamin A in all their cells age more quickly and do not live longer than 4-5 months, which extremely hampers the study of cancer, as there is no time for the disease to fully develop,"indicates Jorge de la Rosa.

Researchers previously developed mice that have an underactive ZMPSTE24 gene that mimic the ageing disorder progeria to test for possible treatments. This causes the protein prelamin A to accumulate and in turn results in progeria. To better study the association of ageing and cancer development, the team developed a mosaic model where ZMPSTE24 was underactive in half of the cells and working normally in the other half of the cells.

"Mosaic mice, however, live as long as normal mice, up to two to three years, and they keep 50% of cells with prelamin A in all their tissues throughout lifespan, which has permitted us to study the effect of this protein on cancer," comments Juan Cadiñanos.

The team found that the mosaic mice were completely healthy, without any of the physical deformities shown by mice with prelamin A-induced progeria: reduced size and weight, loss of fat, infertility and premature death. This suggests that it might not be necessary to correct the defects in all the cells of patients with progeria, but only some. These results provide hope for a successful treatment of patients with progeria in the future.

The aging of whole organisms is called organismal senescence. In general, aging is characterized by the declining ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate consequence of aging. Senescence occurs both on the level of the whole organism (organismal senescence) as well as on the level of its individual cells (cellular senescence). Senescence is by far the leading cause of death across the globe, in industrialized nations, the proportion is reaching 90%.

In a pioneering experiment, scientists in Japan clone a mouse from white blood cells collected from the tail of a living donor.

Circulating blood cells collected from the tail of a donor mouse were used to produce the clone, a team at the Riken BioResource Centerreports in the journal Biology of Reproduction. The female mouse lived a normal lifespan and could give birth to young, say the researchers.

Scientists at a linked institute recently created nearly 600 exact genetic copies of one mouse. Mice have been cloned from several different sources of donor cells, including white blood cells found in the lymph nodes, bone marrow and liver.

This technique is applicable for generating genetic copies of invaluable strains of mice. The Japanese research group investigated whether circulating blood cells could also be used for cloning.

Their aim was to find an easily available source of donor cells to clone scientifically valuable strains of laboratory mice.

The team, led by Atsuo Ogura, of Riken BioResource Center in Tsukuba, took blood from the tail of a donor mouse, isolated the white blood cells, and used the nuclei for cloning experiments, using the same technique that produced Dolly the sheep in Edinburgh.

The process, known as somatic cell nuclear transfer, involves transferring the nucleus from an adult body cell - such as a blood or skin cell - into an unfertilised egg that has had its nucleus removed.

Scientists in Japan have years of experience in cloning mice. A team at a linked institute recently revealed they had produced almost 600 mice from one donor mouse after 25 consecutive rounds of cloning. The research is aimed at large-scale production of high-quality animals for farming or conservation purposes, they say.

A decade ago, Francis Collin's research lab at NIH helped discover the cause of the Hutchinson-Gilford progeria syndrome: a mutation in the lamin-A gene. Just a single letter substitution in the genetic code (C to T) creates a toxic version of the protein. The abnormal protein is missing a segment, and is no longer digestible by an enzyme called ZMPSTE24—essentially a molecular scissors. Without that final snip, the lamin-A protein causes molecular havoc.More recently, children who are completely missing the ZMPSTE24 enzyme have been identified, and they have an even more severe form of progeria called “restrictive dermopathy”. Many questions remain but now we are able to get a close up of ZMPSTE24 and understand how, and where, it normally modifies lamin-A.

Using x-ray crystallography, a team based at the UK’s University of Oxford figured out the enzyme’s molecular structure [2, 3]. A cross section of the 3D structure (seen above) reveals a cavernous inner chamber where the authors believe the final snip of lamin-A takes place. It also shows us how mutations in ZMPSTE24, which inhibit lamin-A processing, can also lead to these rare aging disorders.

Knowing ZMPSTE24’s structure will help us better understand its clipping functions. It could also shed light on how this enzyme works in the normal aging processes—as well as in the accelerated aging of progeria. Ultimately, we hope it will also inform drug development for this devastating disease.

Video Link: http://www.youtube.com/watch?v=7RHhRqDlImg

References:

[1] Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, Scott L, Erdos MR, Robbins CM, Moses TY, Berglund P, Dutra A, Pak E, Durkin S, Csoka AB, Boehnke M, Glover TW, Collins FS. Nature. 2003 May 15;423(6937):293-8. Epub 2003 Apr 25.

[2] The structural basis of ZMPSTE24-dependent laminopathies. Quigley A, Dong YY, Pike AC, Dong L, Shrestha L, Berridge G, Stansfeld PJ, Sansom MS, Edwards AM, Bountra C, von Delft F, Bullock AN, Burgess-Brown NA, Carpenter EP. Science. 2013 Mar 29;339(6127):1604-7.

[3] Biochemistry. A protease for the ages. Michaelis S, Hrycyna CA. Science. 2013 Mar 9;339(6127):1529-30.

A new research published in the March 8, 2013  issue of Science finally proves that a single anti-ageing enzyme in the body can be targeted, with the potential to prevent age-related diseases and extend lifespans.

“Drugs that combat ageing may be available within five years,” said study senior author Prof David Sinclair from Harvard Medical School, and the University of New South Wales.

The target enzyme, SIRT1, is switched on naturally by calorie restriction and exercise, but it can also be enhanced through activators. The most common naturally-occurring activator is resveratrol, which is found in small quantities in red wine, but synthetic activators with much stronger activity are already being developed.

Although research surrounding resveratrol has been going for a decade, until now the basic science had been contested. The study shows all of the 117 drugs tested work on the single enzyme through a common mechanism. This means that a whole new class of anti-ageing drugs is now viable, which could ultimately prevent cancer, Alzheimer’s disease and type 2 diabetes.

“Ultimately, these drugs would treat one disease, but unlike drugs of today, they would prevent 20 others. In effect, they would slow ageing,” Prof Sinclair said. “In the history of pharmaceuticals, there has never been a drug that tweaks an enzyme to make it run faster.”

“Our drugs can mimic the benefits of diet and exercise, but there is no impact on weight,” Prof Sinclair said. “The first therapeutic to be marketed will be for diabetes.” There have been limited trials in people with type 2 diabetes and the skin inflammatory disease, psoriasis. There were benefits to the metabolism in the first group and a reduction in skin redness in the second.

The drugs can be administered orally, or topically. So far, there have been no drugs developed targeting ageing skin, but one major skin care range has developed a crème with resveratrol in it. “While any drug would be strictly prescribed for certain conditions, one day, they could be taken orally as a preventative. This would be in much the same way as statin drugs are commonly prescribed to prevent, instead of simply treating, cardiovascular disease.”

In animal models, overweight mice given synthetic resveratrol were able to run twice as far as slim mice and they lived 15 per cent longer. “Now we are looking at whether there are benefits for those who are already healthy. Things there are also looking promising,” the scientist said.

“We’re finding that ageing isn’t the irreversible affliction that we thought it was,” Prof Sinclair said. “Some of us could live to 150, but we won’t get there without more research.”

In 1934, in a famous experiment at Cornell University, it was discovered that
laboratory mice could live twice as long as expected if they were fed a low-calorie diet that included enough nutrients to avoid malnutrition. This phenomenon has since been observed in species ranging from worms to primates, but not in humans. Reducing calorie intake leads to longer lives by
modifying a number of the biochemical pathways that sense nutrients, including pathways that involve insulin and various other biomolecules. Chemical and genetic methods can also increase longevity by modifying these pathways, which suggests that it might be possible to develop drugs
that can increase lifespan without reducing calorie intake.

Mice, humans and other creatures respond to prolonged fasting through a number of adaptive changes that include mobilizing and burning fatty acids. The liver has an important role in this response, secreting a hormone called fibroblast growth factor-21 (FGF21) that coordinates these processes among tissues. Previous experiments on transgenic mice with high levels of this hormone have shown that it suppresses the activity of growth hormone and reduces the production of insulin-like growth factor, which prevents growth and can lead to hibernation-like behavior.

Here Zhang et al. from the University of Texas Southwestern Medical Center compare groups of wild-type mice and transgenic mice with high levels of FGF21. They find that the transgenic mice have a longer median survival time than wild-type mice (38 months vs 28 months), and that the transgenic female mice on average live for 4 months longer than their male counterparts. However, unlike in other examples of increased longevity, they find that decreased food intake is not required. Instead, they find that transgenic mice eat more food than wild-type mice, yet remain profoundly insulin-sensitive.

The results suggest that the longer survival times are caused by a reduction in the production of insulin-like growth factor, but they also suggest that the mechanism responsible for the increased longevity is independent of the three pathways that are usually associated with such increases. Further research is needed to understand this mechanism in greater detail and could, perhaps, pave the way for the use of FGF21-based hormone therapy to extend lifespan without the need for a low-calorie diet.

Transposable elements are mobile strands of DNA that insert themselves into chromosomes with mostly harmful consequences. Cells try to keep them locked down, but in a new study, Brown University researchers report that aging cells lose their ability to maintain this control. The result may be a further decline in the health of senescent cells and of the aging bodies they compose.

Even in our DNA there is no refuge from rogues that prey on the elderly. Parasitic strands of genetic material called transposable elements—transposons—lurk in our chromosomes, poised to wreak genomic havoc. Cells have evolved ways to defend themselves, but in a new study, Brown University researchers describe how cells lose this ability as they age, possibly resulting in a decline in their function and health. Barbara McClintock, awarded the Nobel Prize in 1983, made the original discovery of transposons in maize. Since then scientists have found cases in which the chaos they bring can have long-term benefits by increasing genetic diversity in organisms, but in most cases the chaos degrades cell function, such as by disrupting useful genes. "The cell really is trying to keep these things quiet and keep these things repressed in its genome," said John Sedivy, professor of medical science in the Department of Molecular Biology, Cell Biology, and Biochemistry and senior author of the new study published online in the journal Aging Cell. "We seem to be barely winning this high-stakes warfare, given that these molecular parasites make up over 40 percent of our genomes." Cells try to clamp down on transposons by winding and packing transposon-rich regions of the genome around little balls of protein called nucleosomes. This confining arrangement is called heterochromatin, and the DNA that is trapped in such a tight heterochromatin prison cannot be transcribed and expressed. What the research revealed, however, is that carefully maintaining a heterochromatin prison system is a younger cell's game.

Two leading neurology researchers have proposed a theory that could unify scientists’ thinking about several neurodegenerative diseases and suggest therapeutic strategies to combat them. The theory and backing for it are described in the September 5, 2013 issue of Nature.

Mathias Jucker and Lary Walker outline the emerging concept that many of the brain diseases associated with aging, such as Alzheimer’s and Parkinson’s, are caused by specific proteins that misfold and aggregate into harmful seeds. These seeds behave very much like the pathogenic agents known as prions, which cause mad cow disease, chronic wasting disease in deer, scrapie in sheep, and Creutzfeldt-Jakob disease in humans.

Walker is research professor at Yerkes National Primate Research Center, Emory University. Jucker is head of the Department of Cellular Neurology at the Hertie Institute for Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases.

Unlike prion diseases, which can be infectious, Alzheimer’s, Parkinson’s, and other neurodegenerative diseases can not be passed from person to person under normal circumstances. Once all of these diseases take hold in the brain, however, it is increasingly apparent that the clumps of misfolded proteins spread throughout the nervous system and disrupt its function.

The authors were the first to show that a protein that is involved in Alzheimer’s disease – known as amyloid-beta – forms prion-like seeds that stimulate the aggregation of other amyloid-beta molecules in senile plaques and in brain blood vessels. Since then, a growing number of laboratories worldwide have discovered that proteins linked to other neurodegenerative disorders also share key features with prions.

Age-related neurodegenerative disorders remain stubbornly resistant to the discovery of effective treatments. Jucker and Walker propose that the concept of pathogenic protein seeding not only could focus research strategies for these seemingly unrelated diseases, but it also suggests that therapeutic approaches designed to thwart prion-like seeds early in the disease process could eventually delay or even prevent the diseases.

Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.

A new study demonstrates what researchers consider conclusive evidence that the red wine compound resveratrol directly activates a protein that promotes health and longevity in animal models. What’s more, the researchers have uncovered the molecular mechanism for this interaction, and show that a class of more potent drugs currently in clinical trials act in a similar fashion. Pharmaceutical compounds similar to resveratrol may potentially treat and prevent diseases related to aging in people, the authors contend.

For the last decade, the science of aging has increasingly focused onsirtuins, a group of genes that are believed to protect many organisms, including mammals, against diseases of aging. Mounting evidence has demonstrated that resveratrol, a compound found in the skin of grapes as well as in peanuts and berries, increases the activity of a specific sirtuin, SIRT1, that protects the body from diseases by revving up the mitochondria, a kind of cellular battery that slowly runs down as we age. By recharging the batteries, SIRT1 can have profound effects on health.

Mice on resveratrol have twice the endurance and are relatively immune from effects of obesity and aging. In experiments with yeast, nematodes, bees, flies and mice, lifespan has been extended.

“In the history of pharmaceuticals, there has never been a drug that binds to a protein to make it run faster in the way that resveratrol activates SIRT1,” said David Sinclair, Harvard Medical School professor of genetics. “Almost all drugs either slow or block them.”

In 2006, Sinclair’s group published a study showing that resveratrol could extend the lifespan of mice, and the company Sirtris Pharmaceuticals, which was started by HMS researchers, was founded to make drugs more potent than resveratrol. Sinclair is a co-founder of Sirtris, a GlaxoSmithKline company, and remains a scientific advisor. Sirtris currently has a number of sirtuin-activating compounds in clinical trials.