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TRAP-1 knock-out mice show signs of longer lives with fewer age-related diseases

TRAP-1 knock-out mice show signs of longer lives with fewer age-related diseases | Amazing Science | Scoop.it

While developing a new cancer drug, researchers at The Wistar Institute discovered that mice lacking a specific protein live longer lives with fewer age-related illnesses. The mice, which lack the TRAP-1 protein, demonstrated less age-related tissue degeneration, obesity, and spontaneous tumor formation when compared with normal mice. Their findings could change how scientists view the metabolic networks within cells.


In healthy cells, TRAP-1 is an important regulator of metabolism and has been shown to regulate energy production in mitochondria, organelles that generate chemically useful energy for the cell. In the mitochondria of cancer cells, TRAP-1 is universally overproduced.  


The Wistar team’s report, which appears in the journal Cell Reports (available online now), shows how “knockout” mice bred to lack the TRAP-1 protein compensate for this loss by switching to alternative cellular mechanisms for making energy.


“We see this astounding change in TRAP-1 knockout mice, where they show fewer signs of aging and are less likely to develop cancers,” said Dario C. Altieri. M.D., Robert and Penny Fox Distinguished Professor and director of The Wistar Institute’s National Cancer Institute-designated Cancer Center. “Our findings provide an unexpected explanation for how TRAP-1 and related proteins regulate metabolism within our cells.”


“We usually link the reprogramming of metabolic pathways with human diseases, such as cancer,” Altieri said. “What we didn’t expect to see were healthier mice with fewer tumors.”


Altieri and his colleagues created the TRAP-1 knockout mice as part of their ongoing investigation into their novel drug, Gamitrinib, which targets the protein in the mitochondria of tumor cells. TRAP-1 is a member of the heat shock protein 90 (HSP90) family, which are “chaperone” proteins that guide the physical formation of other proteins and serve a regulatory function within mitochondria. Tumors use HSP90 proteins, like TRAP-1, to help survive therapeutic attack. 

“In tumors, the loss of TRAP-1 is devastating, triggering a host of catastrophic defects, including metabolic problems that ultimately result in the death of the tumor cells,” Altieri said.  “Mice that lack TRAP-1 from the start, however, have three weeks in the womb to compensate for the loss of the protein.”


The researchers found that in their knockout mice, the loss of TRAP-1 causes mitochondrial proteins to misfold, which then triggers a compensatory response that causes cells to consume more oxygen and metabolize more sugar. This causes mitochondria in knockout mice to produce deregulated levels of ATP, the chemical used as an energy source to power all the everyday molecular reactions that allow a cell to function.

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Diet restriction suspends development in nematode worms and doubles lifespan

Diet restriction suspends development in nematode worms and doubles lifespan | Amazing Science | Scoop.it

Researchers at Duke University have found that taking food away from the C. elegans nematode worm triggers a state of arrested development: while the organism continues to wriggle about, foraging for food, its cells and organs are suspended in an ageless, quiescent state. When food becomes plentiful again, the worm develops as planned, but can live twice as long as normal.


The study found that C. elegans could be starved for at least two weeks and still develop normally once feeding resumed. Because the meter isn’t running while the worm is in its arrested state, this starvation essentially doubles the two-week lifespan of the worm. “It is possible that low-nutrient diets set off the same pathways in us to put our cells in a quiescent state,” said David R. Sherwood, an associate professor of biology at Duke University. “The trick is to find a way to pharmacologically manipulate this process so that we can get the anti-aging benefits without the pain of diet restriction.”


Over the last 80 years, researchers have put a menagerie of model organisms on a diet, and they’ve seen that nutrient deprivation can extend the lifespan of rats, mice, yeast, flies, spiders, fish, monkeys and worms anywhere from 30 percent to 200 percent longer than their free-fed counterparts.


Outside the laboratory and in the real world, organisms like C. elegans can experience bouts of feast or famine that no doubt affect their development and longevity. Sherwood’s colleague Ryan Baugh, an assistant professor of medicine at Duke, showed that hatching C. elegans eggs in a nutrient-free environment shut down their development completely. He asked Sherwood to investigate whether restricting diet to the point of starvation later in life would have the same effect.


Sherwood and his postdoctoral fellow Adam Schindler decided to focus on the last two stages of C. elegans larval development — known as L3 and L4 — when critical tissues and organs like the vulva are still developing. During these stages, the worm vulva develops from a speck of three cells to a slightly larger ball of 22 cells. The researchers found that when they took away food at various times throughout L3 and L4, development paused when the vulva was either at the three-cell stage or the 22-cell stage, but not in between.


When they investigated further, the researchers found that not just the vulva, but all the tissues and cells in the organism seemed to get stuck at two main checkpoints. These checkpoints are like toll booths along the developmental interstate. If the organism has enough nutrients, its development can pass through to the next toll booth. If it doesn’t have enough, it stays at the toll booth until it has built up the nutrients necessary to get it the rest of the way.


“Development isn’t a continuous nonstop process,” said Schindler, who is lead author of the study. “Organisms have to monitor their environment and decide whether or not it is amenable to their development. If it isn’t, they stop, if it is, they go. Those checkpoints seem to exist to allow the animal to make that decision. And the decision has implications, because the resources either go to development or to survival.”

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Anti-diabetic drug metformin slows aging and lengthens lifespan, worm study suggests

Anti-diabetic drug metformin slows aging and lengthens lifespan, worm study suggests | Amazing Science | Scoop.it
Researchers have provided new evidence that metformin, the world’s most widely used anti-diabetic drug, slows aging and increases lifespan. Scientists teased out the mechanism behind metformin's age-slowing effects: the drug causes an increase in the number of toxic oxygen molecules released in the cell and this, surprisingly, increases cell robustness and longevity in the long term.


In experiments reported in the journal Proceedings of the National Academy of Sciences, the researchers tease out the mechanism behind metformin's age-slowing effects: the drug causes an increase in the number of toxic oxygen molecules released in the cell and this, surprisingly, increases cell robustness and longevity in the long term. Mitochondria -- the energy factories in cells -- generate tiny electric currents to provide the body's cells with energy. Highly reactive oxygen molecules are produced as a by-product of this process.


While these molecules are harmful because they can damage proteins and DNA and disrupt normal cell functioning, a small dose can actually do the cell good, say the researchers: "As long as the amount of harmful oxygen molecules released in the cell remains small, it has a positive long-term effect on the cell. Cells use the reactive oxygen particles to their advantage before they can do any damage," explains Wouter De Haes. "Metformin causes a slight increase in the number of harmful oxygen molecules. We found that this makes cells stronger and extends their healthy lifespan."


It was long thought that harmful reactive oxygen molecules were the very cause of aging. The food and cosmetics industries are quick to emphasize the 'anti-aging' qualities of products containing antioxidants, such as skin creams, fruit and vegetable juices, red wine and dark chocolate.


But while antioxidants do in fact neutralize harmful reactive oxygen molecules in the cell, they actually negate metformin's anti-aging effects because the drug relies entirely on these molecules to work.


The researchers studied metformin's mechanism in the tiny roundworm Caenorhabditis elegans, an ideal species for studying aging because it has a lifespan of only three weeks. "As they age, the worms get smaller, wrinkle up and become less mobile. But worms treated with metformin show very limited size loss and no wrinkling. They not only age slower, but they also stay healthier longer," says Wouter De Haes. "While we should be careful not to over-extrapolate our findings to humans, the study is promising as a foundation for future research."


Other studies in humans have shown that metformin suppresses some cancers and heart disease. Metformin could even be an effective drug for counteracting the general effects of aging, say the researchers.

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GDF11 reverses signs of aging in mice and could be in clinical trials as early as 3 to 5 years

GDF11 reverses signs of aging in mice and could be in clinical trials as early as 3 to 5 years | Amazing Science | Scoop.it

Harvard Stem Cell Institute (HSCI) researchers have shown that a protein they previously demonstrated can make the failing hearts in aging mice appear more like those of young health mice, similarly improves brain and skeletal muscle function in aging mice.


In two separate papers given early online release today by the journal Science—which is publishing the papers this coming Friday, Professors Amy Wagers, PhD, and Lee Rubin, PhD, of Harvard’s Department of Stem Cell and Regenerative Biology (HSCRB), report that injections of a protein known as GDF11, which is found in humans as well as mice, improved the exercise capability of mice equivalent in age to that of about a 70-year-old human, and also improved the function of the olfactory region of the brains of the older mice—they could detect smell as younger mice do.


Rubin, and Wagers, who also has a laboratory at the Joslin Diabetes Center, each said that, baring unexpected developments, they expect to have GDF11 in initial human clinical trials within three to five years.

Postdoctoral fellow Lida Katsimpardi, PhD, is the lead author on the Rubin group’s paper, and postdocs Manisha Sinha, PhD, and Young Jang, PhD, are the lead authors on the paper from the Wagers group.


Both studies examined the effect of GDF11 in two ways. First, by using what is called a parabiotic system, in which two mice are surgically joined and the blood of the younger mouse circulates through the older mouse. And second, by injecting the older mice with GDF11, which in an earlier study by Wagers and Richard Lee, MD, of Brigham and Women’s Hospital who is also an author on the two papers released today, was shown to be sufficient to reverse characteristics of aging in the heart.


Doug Melton, PhD, co-chair of HSCRB and co-director of HSCI, reacted to the two papers by saying that he couldn’t “recall a more exciting finding to come from stem cell science and clever experiments. This should give us all hope for a healthier future. We all wonder why we were stronger and mentally more agile when young, and these two unusually exciting papers actually point to a possible answer: the higher levels of the protein GDF11 we have when young. There seems to be little question that, at least in animals, GDF11 has an amazing capacity to restore aging muscle and brain function,” he said.

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Over 400 acquired genetic mutations found in healthy blood of a supercentenarian

Over 400 acquired genetic mutations found in healthy blood of a supercentenarian | Amazing Science | Scoop.it

Genetic mutations are commonly studied because of links to diseases such as cancer; however, little is known about mutations occurring in healthy individuals. In a study published online in Genome Research, researchers detected over 400 mutations in healthy blood cells of a 115-year-old woman, suggesting that lesions at these sites are largely harmless over the course of a lifetime.


Our blood is continually replenished by hematopoietic stem cells that reside in the bone marrow and divide to generate different types of blood cells, including white blood cells. Cell division, however, is error-prone, and more frequently dividing cells, including the blood, are more likely to accumulate genetic mutations. Hundreds of mutations have been found in patients with blood cancers such as acute myeloid leukemia (AML), but it is unclear whether healthy white blood cells also harbor mutations.


In this new study, the authors used whole genome sequencing of white blood cells from a supercentenarian woman to determine if, over a long lifetime, mutations accumulate in healthy white blood cells. The scientists identified over 400 mutations in the white blood cells that were not found in her brain, which rarely undergoes cell division after birth. These mutations, known as somatic mutations because they are not passed on to offspring, appear to be tolerated by the body and do not lead to disease. The mutations reside primarily in non-coding regions of the genome not previously associated with disease, and include sites that are especially mutation-prone such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.


By examining the fraction of the white blood cells containing the mutations, the authors made a major discovery that may hint at the limits of human longevity. "To our great surprise we found that, at the time of her death, the peripheral blood was derived from only two active hematopoietic stem cells (in contrast to an estimated 1,300 simultaneously active stem cells), which were related to each other," said lead author of the study, Dr. Henne Holstege.


The authors also examined the length of the telomeres, or repetitive sequences at the ends of chromosomes that protects them from degradation. After birth, telomeres progressively shorten with each cell division. The supercentenarian's white blood cell telomeres were extremely short.

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Craig Venter Wants to Build the World’s Biggest Database for Genome Information

Craig Venter Wants to Build the World’s Biggest Database for Genome Information | Amazing Science | Scoop.it
Craig Venter’s new company wants to improve human longevity by creating the world’s largest, most comprehensive database of genetic and physiological information.


Human Longevity, based in San Diego, says it will sequence some 40,000 human genomes per year to start, using Illumina’s new high-throughput sequencing machines (Illumina Has the First $1,000 Genome).


Eventually, it plans to work its way up to 100,000 genomes per year. The company will also sequence the genomes of the body’s multitudes of microbial inhabitants, called the microbiome, and analyze the thousands of metabolites that can be found in blood and other patient samples.


By combining these disparate types of data, the new company hopes to make inroads into the enigmatic process of aging and the many diseases, including cancer and heart disease, that are strongly associated with it. “Aging is exerting a force on humans that is exposing us to diseases, and the diseases are idiosyncratic, partly based on genetics, partly on environment,” says Leonard Guarente, who researches aging at MIT and is not involved in the company. “The hope for many of us who study aging is that by having interventions that hit key pathways in aging, we can affect disease.”


To that end, Human Longevity will collaborate with Metabolon, a company based in Durham, North Carolina, to profile the metabolites circulating in the bloodstreams of study participants. Metabolon was an early pioneer in the field of metabolomics, which catalogues the amino acids, fats, and other small molecules in a blood or other sample to develop more accurate diagnostic tests for diseases (Metabolomics).


Metabolon uses mass spectrometry to identify small molecules in a sample. In a human blood sample, there are around 1,200 different types; Metabolon’s process can also determine the amount of each one present. While genome sequencing can provide information about inherited risk of disease and some hints of the likelihood that a person will have a long life, metabolic data provides information on how environment, diet, and other features of an individual’s life affect health.


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Predictable Lifespan: Worm Study Suggests that Mitochondrial Activity Determines Aging

Predictable Lifespan: Worm Study Suggests that Mitochondrial Activity Determines Aging | Amazing Science | Scoop.it

Scientists have a crystal ball on their hands: bursts of activity in the energy-producing mitochondria in a worm’s cells accurately predict how long it will live. The findings, published in Nature1, suggest that an organism’s lifespan is, for the most part, predictable in early adulthood. Unlike other biomarkers for aging, which work under limited conditions, these mitochondrial bursts are a stable predictor for a variety of genetic, environmental and developmental histories.


“Mitochondrial flashes have an amazing power to predict the remaining lifespan in animals,” says study lead Meng-Qiu Dong, a geneticist who studies aging in the Caenorhabditis elegans worm at the National Institute of Biological Sciences in Beijing. “There is truth in the mitochondrial theory of aging.”


The mitochondria are organelles that power the cells of plants, animals and other eukaryotic organisms. During energy production, they produce reactive oxygen molecules, such as free radicals, that can cause stress and damage the mitochondria. Although mitochondria break down over time, the mitochondrial theory of aging, first proposed2 in 1972, remains controversial and unproven. For instance, some long-lived organisms, such as naked mole rats, endure with high levels of oxidative damage. Nevertheless, many scientists think that mitochondria remain the primary drivers of aging.


Dong became interested in the 2008 discovery3 that mitochondria produce reactive oxygen molecules in 10-second pulses — ‘mitoflashes’ — every couple minutes. For the first time, scientists could observe individual mitochondria and their rates of activity through the course of an animal’s life. In this study, Dong initially compared mitoflash rates in short-lived C. elegans worms, which live an average of 21 days, to long-lived worms that live an average of 30 days or more. She found that, in all of the animals, there were two moments in life when mitoflashes bunched closely together: one burst during early adulthood and another during senescence.


At first, she expected that the burst later in life would be the important one. “It was a total failure,” she says. Instead, it was the early burst that revealed a correlation between flash frequency and lifespan: worms with an average lifespan of 21 days had more frequent flashes during this burst than their longer-lived brethren. The correlation held across 29 genetic mutants with various lifespans. Mitoflashes also proved to be a powerful record of a worm’s early life experiences. For instance, worms exposed to heat shock or starvation tend to have longer lives, and predictably, their mitoflashes occurred at longer intervals. Even genetically identical worms that had different lifespans due to chance events alone showed the same correlation between mitoflash frequency and longevity. The most striking finding came when Dong treated a long-lived worm to increase its production of reactive oxygen molecules. This shortened the worm’s life and increased the rate of mitoflashes.

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Genome of 11,000-year-old living dog cancer determined, revealing cancer's origin and evolution

Genome of 11,000-year-old living dog cancer determined, revealing cancer's origin and evolution | Amazing Science | Scoop.it

A cancer normally lives and dies with a person, however this is not the case with a sexually transmitted cancer in dogs. In a study published in Science, researchers have described the genome and evolution of this cancer that has continued living within the dog population for the past 11,000 years.


Scientists have sequenced the genome of the world's oldest continuously surviving cancer, a transmissible genital cancer that affects dogs. This cancer, which causes grotesque genital tumors in dogs around the world, first arose in a single dog that lived about 11,000 years ago. The cancer survived after the death of this dog by the transfer of its cancer cells to other dogs during mating.


The genome of this 11,000-year-old cancer carries about two million mutations -- many more mutations than are found in most human cancers, the majority of which have between 1,000 and 5,000 mutations. The team used one type of mutation, known to accumulate steadily over time as a "molecular clock," to estimate that the cancer first arose 11,000 years ago.


"The genome of this remarkable long-lived cancer has demonstrated that, given the right conditions, cancers can continue to survive for more than 10,000 years despite the accumulation of millions of mutations," says Dr Elizabeth Murchison, first author from the Wellcome Trust Sanger Institute and the University of Cambridge.


The genome of the transmissible dog cancer still harbors the genetic variants of the individual dog that first gave rise to the cancer 11,000 years ago. Analysis of these genetic variants revealed that this dog may have resembled an Alaskan Malamute or Husky. It probably had a short, straight coat that was colored either grey/brown or black. Its genetic sequence could not determine if this dog was a male or a female, but did indicate that it was a relatively inbred individual.


"We do not know why this particular individual gave rise to a transmissible cancer," says Dr Murchison, "But it is fascinating to look back in time and reconstruct the identity of this ancient dog whose genome is still alive today in the cells of the cancer that it spawned."

Transmissible dog cancer is a common disease found in dogs around the world today. The genome sequence has helped scientists to further understand how this disease has spread.


"The patterns of genetic variants in tumors from different continents suggested that the cancer existed in one isolated population of dogs for most of its history," says Dr Murchison. "It spread around the world within the last 500 years, possibly carried by dogs accompanying seafarers on their global explorations during the dawn of the age of exploration."


Transmissible cancers are extremely rare in nature. Cancers, in humans and animals, arise when a single cell in the body acquires mutations that cause it to produce more copies of itself. Cancer cells often spread to different parts of the body in a process known as metastasis. However, it is very rare for cancer cells to leave the bodies of their original hosts and to spread to other individuals. Apart from the dog transmissible cancer, the only other known naturally occurring transmissible cancer is an aggressive transmissible facial cancer in Tasmanian devils that is spread by biting.

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A naturally-produced compound rewinds aspects of age-related demise in mice

A naturally-produced compound rewinds aspects of age-related demise in mice | Amazing Science | Scoop.it

Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in.


Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA—and mutations cannot be reversed.


Sinclair and his group have been studying the fundamental science of aging—which is broadly defined as the gradual decline in function with time—for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.


Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which the SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced. “This was at odds with what the literature suggested,” said Gomes.


As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.


For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.


“This particular component of the aging process had never before been described,” said Gomes. While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough—prior to excessive mutation accumulation—within days, some aspects of the aging process could be reversed.


The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

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Not all species deteriorate with age, some buck trend in mortality and fertility

Not all species deteriorate with age, some buck trend in mortality and fertility | Amazing Science | Scoop.it

Water fleas live only days or under optimal conditions weeks, but their mortality increases sharply with age, as is the case in longer-lived animals such as humans. But other animals — such as the hermit crab, the red abalone and the hydra, a microscopic freshwater animal that can live centuries — buck that trend, enjoying near constant levels of fertility and mortality.


A comparison of standardized demographic patterns across 46 species, published in Nature, suggests that the vast diversity of ‘ageing strategies’ among them challenges the notion that evolution inevitably leads to senescence, or deterioration of mortality and fertility, with age, says Owen Jones, a biologist at the University of Southern Denmark in Odense, who led the study.

 

“By taking a grand view and doing a survey across species, we found plenty of violations of this underpinning theory,” says Jones.

To compare fertility and mortality patterns, the authors assembled published life-history data sets for 11 mammals, 12 other vertebrates, 10 invertebrates, 12 vascular plants and a green alga, and standardized the trajectories — dividing mortality rates at each point in the lifespan by the average mortality rate.

 

The researchers found no association between the length of life and the degree of senescence. Of the 24 species showing the most abrupt increase in mortality with age, 11 had relatively long lifespans and 13 had relatively short lifespans. A similar split in lifespan occurred in the species that had a less abrupt increase in mortality.


Laurence Mueller, an evolutionary biologist at the University of California at Irvine, agrees. “Organisms in the field die from a lot of causes — for example, predation or disease — other than ageing,” he says. “Unfortunately, the unknown source of mortality in field-data sets confounds the age-related patterns of senescence, which is what we’re all interested in,” he adds.

 


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Senescence is a developmental mechanism contributing to embryonic growth patterning and not only linked to aging

Senescence is a developmental mechanism contributing to embryonic growth patterning and not only linked to aging | Amazing Science | Scoop.it

Senescence is a form of cell-cycle arrest linked to tumor suppression and aging. However, it remains controversial and has not been documented in nonpathologic states.

 

Two studies published in Cell describe senescence as a normal and critical process during embryogenesis. They attribute a completely new and unexpected role to this process, which was always linked to aging and cancer.


“For the first time, these studies clearly show that senescence is a programmed developmental mechanism. This new description helps us to understand the role and significance of senescence as a normal cellular process”, explains Bill Keyes, head of the Mechanisms of Cancer and Aging laboratory at the CRG. “Our work demonstrates that in the embryo, the senescent cells are required, and through their normal secretory function, instruct tissue growth and patterning”, adds Dr. Keyes.


Keyes and collaborators describe senescence as a fundamental part of the biology of two major signalling centres in the embryo that helps to control normal limb and nervous system development. Likewise, the CNIO study led by Manuel Serrano, and postdoctoral researcher Daniel Munoz-Espin, identified identical processes in two other tissues, in the developing kidneys and ear.


Both studies show how the coordinated removal of senescent cells by macrophages plays a key role in the remodelling of the developing tissues, a process that is required for normal patterning. Interestingly, the tissues where the researchers describe the occurrence of senescence are among those most frequently affected by congenital birth defects, suggesting that an investigation of the mechanisms that regulate senescence in the embryo might help to explain the causes of some developmental abnormalities.

 

Thanks to this new perspective of senescence, the scientists suggest that senescence related to aging and cancer is an evolutionary adaptation of a developmental mechanism. “Hopefully, with the identification of senescence in a normal setting in the embryo, this will allow us to identify new mediators and biomarkers of senescence in future studies” says Mekayla Storer, a PhD student in the CRG and first author on the study, adding that “these findings change the way we understood senescence in the past, and give us novel important information to tackle cancer and aging”. 

 

Embryonic senescent cells are nonproliferative and share features with oncogene-induced senescence (OIS), including expression of p21, p15, and mediators of the senescence-associated secretory phenotype (SASP). Interestingly, mice deficient in p21 have defects in embryonic senescence, AER maintenance, and patterning. Surprisingly, the underlying mesenchyme was identified as a source for senescence instruction in the AER, whereas the ultimate fate of these senescent cells is apoptosis and macrophage-mediated clearance. We propose that senescence is a normal programmed mechanism that plays instructive roles in development, and that OIS is an evolutionarily adapted reactivation of a developmental process.

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Sirtuins work through Niacin to extend life span

Sirtuins work through Niacin to extend life span | Amazing Science | Scoop.it
The vitamin niacin has a life-prolonging effect, as Michael Ristow has demonstrated in roundworms.

 

Sirtuins, a family of histone deacetylases, have a fiercely debated role in regulating lifespan. In contrast with recent observations, a recent study finds that overexpression of sir-2.1, the ortholog of mammalian SirT1, does extend Caenorhabditis elegans lifespan.


Sirtuins mandatorily convert NAD+ into nicotinamide (NAM). NAM and its metabolite, 1-methylnicotinamide (MNA), extend C. elegans lifespan even in the absence of sir-2.1. The researchers identified a previously unknown C. elegans nicotinamide-N-methyltransferase, encoded by a gene now named anmt-1, to generate MNA from NAM. Disruption and overexpression of anmt-1 have opposing effects on lifespan independent of sirtuins, with loss of anmt-1 fully inhibiting sir-2.1–mediated lifespan extension.


MNA serves as a substrate for a newly identified aldehyde oxidase, GAD-3, to generate hydrogen peroxide, which acts as a mitohormetic reactive oxygen species signal to promote C. elegans longevity. Taken together, sirtuin-mediated lifespan extension depends on methylation of NAM, providing an unexpected mechanistic role for sirtuins beyond histone deacetylation.

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DNA damage may cause ALS (Lou Gehrig’s disease), involving SIRT1, HDAC1 and sarcoma breakpoint protein FUS

DNA damage may cause ALS (Lou Gehrig’s disease), involving SIRT1, HDAC1 and sarcoma breakpoint protein FUS | Amazing Science | Scoop.it

MIT neuroscientists have found new evidence that suggests that a failure to repair damaged DNA could underlie not only ALS, but also other neurodegenerative disorders such as Alzheimer’s disease. These findings imply that drugs that bolster neurons’ DNA-repair capacity could help ALS patients, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and senior author of a paper describing the ALS findings in the Sept. 15, 2013 issue of Nature Neuroscience.


Neurons are some of the longest-living cells in the human body. While other cells are frequently replaced, our neurons are generally retained throughout our lifetimes. Consequently, neurons can accrue a lot of DNA damage and are especially vulnerable to its effects. 

“Our genome is constantly under attack and DNA strand breaks are produced all the time. Fortunately, they are not a worry because we have the machinery to repair it right away. But if this repair machinery were to somehow become compromised, then it could be very devastating for neurons,” Tsai says.


Tsai’s group has been interested in understanding the importance of DNA repair in neurodegenerative processes for several years. In a study published in 2008, they reported that DNA double-strand breaks precede neuronal loss in a mouse model that undergoes Alzheimer’s disease-like neurodegeneration and identified a protein, HDAC1, which prevents neuronal loss under these conditions.  

HDAC1 is a histone deacetylase, an enzyme that regulates genes by modifying chromatin, which consists of DNA wrapped around a core of proteins called histones. HDAC1 activity normally causes DNA to wrap more tightly around histones, preventing gene expression. However, it turns out that cells, including neurons, also exploit HDAC1’s ability to tighten up chromatin to stabilize broken DNA ends and promote their repair. 


In a paper published earlier this year in Nature Neuroscience, Tsai’s team reported that HDAC1 works cooperatively with another deacetylase called SIRT1 to repair DNA and prevent the accumulation of damage that could promote neurodegeneration. 

When a neuron suffers double-strand breaks, SIRT1 migrates within seconds to the damaged sites, where it soon recruits HDAC1 and other repair factors. SIRT1 also stimulates the enzymatic activity of HDAC1, which allows the broken DNA ends to be resealed. 

SIRT1 itself has recently gained notoriety as the protein that promotes longevity and protects against diseases including diabetes and Alzheimer’s disease, and Tsai’s group believes that its role in DNA repair contributes significantly to the protective effects of SIRT1. 

In an attempt to further unveil other partners that work with HDAC1 to repair DNA, Tsai and colleagues stumbled upon a protein called Fused In Sarcoma (FUS). This finding was intriguing, Tsai says, because the FUS gene is one of the most common sites of mutations that cause inherited forms of ALS. 

The MIT team found that FUS appears at the scene of DNA damage very rapidly, suggesting that FUS is orchestrating the repair response. One of its roles is to recruit HDAC1 to the DNA damage site. Without it, HDAC1 does not appear and the necessary repair does not occur. Tsai believes that FUS may also be involved in sensing when DNA damage has occurred.


At least 50 mutations in the FUS gene have been found to cause ALS. The majority of these mutations occur in two sections of the FUS protein. The MIT team mapped the interactions between FUS and HDAC1 and found that these same two sections of the FUS protein bind to HDAC1. 

They also generated four FUS mutants that are most commonly seen in ALS patients. When they replaced the normal FUS with these mutants, they found that the interaction with HDAC1 was impaired and DNA damage was significantly increased. This suggests that those mutations prevent FUS from recruiting HDAC1 when DNA damage occurs, allowing damage to accumulate and eventually leading to ALS.

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Immortal jellyfish: Does it really live forever?

Immortal jellyfish: Does it really live forever? | Amazing Science | Scoop.it
The Turritopsis nutricula jellyfish has displayed a remarkable ability to regenerate its cells in times of crisis.


While it is often joked that cats have nine lives, a certain species of jellyfish has been deemed “immortal” by scientists who have observed its ability to, when in crisis, revert its cells to their earliest form and grow anew. That means that these tiny creatures, 4 mm to 5 mm long, potentially have infinite lives.
 
The creature, known scientifically as Turritopsis nutricula, was discovered in the Mediterranean Sea in 1883, but its unique regeneration was not known until the mid-1990s. How does the process work? If a mature Turritopsis is threatened — injured or starving, for example — it attaches itself to a surface in warm ocean waters and converts into a blob. From that state, its cells undergo transdifferentiation, in which the cells essentially transform into different types of cells. Muscle cells can become sperm or eggs, or nerve cells can change into muscle cells, “revealing a transformation potential unparalleled in the animal kingdom,” according to the original study of the species published in 1996.


But Turritopsis can — and do — die. Their regeneration only occurs after sexual maturation, therefore they can succumb to predators or disease in the polyp stage. But because the jellyfish are the only known animal with this “immortality,” scientists are studying them closely, with the hopes of applying what they learn to issues such as human aging and illness.

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Oxytocin helps old muscle work like new, study finds

Oxytocin helps old muscle work like new, study finds | Amazing Science | Scoop.it
UC Berkeley researchers have discovered that oxytocin — a hormone associated with maternal nurturing, social attachments, childbirth and sex — is indispensable for healthy muscle maintenance and repair. It is the latest target for development into a potential treatment for age-related muscle wasting.


A few other biochemical factors in blood have been connected to aging and disease in recent years, but oxytocin is the first anti-aging molecule identified that is approved by the Food and Drug Administration for clinical use in humans, the researchers said. Pitocin, a synthetic form of oxytocin, is already used to help with labor and to control bleeding after childbirth. Clinical trials of an oxytocin nasal spray are also underway to alleviate symptoms associated with mental disorders such as autism, schizophrenia and dementia.


“Unfortunately, most of the molecules discovered so far to boost tissue regeneration are also associated with cancer, limiting their potential as treatments for humans,” said study principal investigator Irina Conboy, associate professor of bioengineering. “Our quest is to find a molecule that not only rejuvenates old muscle and other tissue, but that can do so sustainably long-term without increasing the risk of cancer.”


Conboy and her research team say that oxytocin, secreted into the blood by the brain’s pituitary gland, is a good candidate because it is a broad range hormone that reaches every organ, and it is not known to be associated with tumors or to interfere with the immune system.


The new study determined that in mice, blood levels of oxytocin declined with age. They also showed that there are fewer receptors for oxytocin in muscle stem cells in old versus young mice.


To tease out oxytocin’s role in muscle repair, the researchers injected the hormone under the skin of old mice for four days, and then for five days more after the muscles were injured. After the nine-day treatment, they found that the muscles of the mice that had received oxytocin injections healed far better than those of a control group of mice without oxytocin.


“The action of oxytocin was fast,” said Elabd. “The repair of muscle in the old mice was at about 80 percent of what we saw in the young mice.”


Interestingly, giving young mice an extra boost of oxytocin did not seem to cause a significant change in muscle regeneration.

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M. Philip Oliver's curator insight, June 13, 2:11 PM

Muscle wasting reversal

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Added drug allows rapamycin to slow aging without risking to induce diabetes

Added drug allows rapamycin to slow aging without risking to induce diabetes | Amazing Science | Scoop.it

New research at the Linus Pauling Institute at Oregon State University suggests a fix for serious side effects of rapamycin(*), a drug that appears to mimic the ability of dietary restriction to slow the aging process.


Laboratory mice that have received rapamycin have reduced the age-dependent decline in spontaneous activity, demonstrated more fitness, improved cognition and cardiovascular health, had less cancer, and lived substantially longer than mice fed a normal diet.


However, rapamycin has some drawbacks, including an increase in insulin resistance that could set the stage for diabetes, observed in both humans and laboratory animals. The new findings, published in the Journals of Gerontology: Biological Sciences, help to explain why that happens, and what could be done to address it.


The new research study found that both dietary restriction and rapamycin inhibited lipid synthesis, but only dietary restriction increased the oxidation of those lipids in order to produce energy. Rapamycin, by contrast, allowed a buildup of fatty acids and eventually an increase in insulin resistance, which in humans can lead to diabetes.


However, the drug metformin can address that concern, and is already given to some diabetic patients to increase lipid oxidation. In lab tests, the combined use of rapamycin and metformin prevented the unwanted side effect.


“If proven true, then combined use of metformin and rapamycin for treating aging and age-associated diseases in humans may be possible,” the researchers wrote in their conclusion.


“This could be an important advance if it helps us find a way to gain the apparent benefits of rapamycin without increasing insulin resistance,” said Viviana Perez, an assistant professor in the Department of Biochemistry and Biophysics in the OSU College of Science.


“It could provide a way not only to increase lifespan but to address some age-related diseases and improve general health,” Perez said. “We might find a way for people not only to live longer, but to live better and with a higher quality of life.”


“There’s still substantial work to do, and it may not be realistic to expect with humans what we have been able to accomplish with laboratory animals,” Perez said. “People don’t live in a cage and eat only the exact diet they are given. Nonetheless, the potential of this work is exciting.”


(*) Rapamycin, first discovered from the soils of Easter Island, or Rapa Nui in the South Pacific Ocean, is primarily used as an immunosuppressant to prevent rejection of organs and tissues. In recent years it was also observed that it can function as a metabolic “signaler” that inhibits a biological pathway found in almost all higher life forms — the ability to sense when food has been eaten, energy is available and it’s okay for cell proliferation, protein synthesis and growth to proceed. Called mTOR in mammals, for the term “mammalian target of rapamycin,” this pathway has a critical evolutionary value — it helps an organism avoid too much cellular expansion and growth when energy supplies are insufficient. That helps explain why some form of the pathway has been conserved across such a multitude of species, from yeast to fish to humans.

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Experimental Drug TM5441 Prolongs Life Span in a Strain of Rapidly Aging Mice 4-fold

Experimental Drug TM5441 Prolongs Life Span in a Strain of Rapidly Aging Mice 4-fold | Amazing Science | Scoop.it

Rapidly aging mice fed an experimental drug lived more than four times longer than a control group, and their lungs and vascular system were protected from accelerated aging, according to a new study.


The reason is a protein's key role in cell and physiological aging. The experimental drug inhibits the protein's effect and prolonged the lifespan in a mouse model of accelerated aging. 

This is a completely different target and different drug than anything else being investigated for potential effects in prolonging life and the experimental drug is in the early stages of testing, they note in Proceedings of the National Academy of Sciences.


The experimental drug, TM5441, is one of only several chosen each year by the National Institute on Aging to be tested in its Interventions Testing Program, which investigates treatments with the potential to extend lifespan and delay disease in mice.


When cells or tissue age -- senescence -- they lose the ability to regenerate and secrete certain proteins, like a distinctive fingerprint. One of those proteins, PAI-1 (plasminogen activator inhibitor) has been the focus for Northwestern University's Douglas Vaughan, M.D., senior author of the study, originally as it relates to cardiovascular disease. 


"We made the intellectual leap between a marker of senescence and physiological aging," Vaughan said. "We asked is this marker for cell aging one of the drivers or mechanisms of rapid physiological aging?"


For the study, he and colleagues used mice bred to be deficient in a gene (Klotho) that suppresses aging. These mice exhibit accelerated aging in the form of arteriosclerosis, neurodegeneration, osteoporosis and emphysema and have much shorter life spans than regular mice. Vaughan determined that these rapidly aging mice produce increased levels of PAI-1 in their blood and tissue.


Then scientists fed the rapidly aging mice TM5441 -- the experimental drug -- in their food every day. The result was a decrease in PAI-1 activity (the aging protein Vaughan's team had identified), which quadrupled the mice's life span and kept their organs healthy and functioning.


Northwestern scientists also genetically produced the same life prolonging results when they crossed the mice deficient in the age-suppressing gene with mice deficient in PAI-1. Importantly, partial genetic deficiency of PAI-1 and the experimental PAI-1 antagonist produced provided similar benefits in the mice, Vaughan noted.

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Blood Of World’s Oldest Woman Shows Life Limit

Blood Of World’s Oldest Woman Shows Life Limit | Amazing Science | Scoop.it
Researchers say two-thirds of her blood at the time of death came from just two stem cells - yet humans are born with 20,000.


Scientists who examined the body of one of the world's oldest women say dying stem cells may be the "limit" on our lifespans. The findings imply that most or all of the blood stem cells she started life with had already burned out and died.


Ms Andel-Schipper was born in Holland in 1890, and at one point was the oldest woman in the world. When she died in 2005 she gave her body to science, and asked for the analysis to be made public. Henne Holstege, from the VU University Medical Center in Amsterdam, said: "Is there a limit to the number of stem cell divisions, and does that imply that there's a limit to human life? 


"It's estimated that we're born with around 20,000 blood stem cells, and at any one time, around 1,000 are simultaneously active to replenish blood."  The researchers also found that her blood cells had worn-down telomeres - the protective tips on chromosomes that burn down like candle wicks each time a cell divides.


On average, the telomeres on her white blood cells were 17 times shorter than those on brain cells, which hardly replicate at all throughout life.

Ms Holstege added the study could raise the possibility of extending life by reinjecting stem cells saved from birth or early life.


"If I took a sample now and gave it back to myself when I'm older, I would have long telomeres again - although it might only be possible with blood, not other tissues," Holstege explained.

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Simply become immortal: AI will talk to loved ones when you die and preserve your digital footprint

Simply become immortal: AI will talk to loved ones when you die and preserve your digital footprint | Amazing Science | Scoop.it

Eterni.me wants to build an AI from your digital footprint, so you can have virtual chats with loved ones from beyond the grave.


"We don't try to replace humans or give false hopes to people grieving." Romanian design consultant Marius Ursache, cofounder of Eterni.me, needs to clear this up quickly. Because when you're building a fledgling artificial intelligence company that promises to bring back the dead -- or at least, their memories and character, as preserved in their digital footprint -- for virtual chats with loved ones, expect a lot of flack.


The site launched with the look of any other Silicon Valley internet startup, but a definitively new take on an old message. While social media companies want you to share and create the story of you while you're alive, and lifelogging company Memoto promises to capture "meaningful [and shareable] moments", Eterni.me wants to wrap that all up for those you leave behind into a cohesive AI they can chat with.


Three thousand people registered to the service within the first four days of the site going live, despite there being zero product to make use of (a beta version is slated for 2015). So with a year to ponder your own mortality, why the excitement for a technology that is, at this moment, merely a proof of concept? 


The company's motto is "it's like a Skype chat from the past," but it's still very much about crafting how the world sees you -- or remembers you, in this case -- just as you might pause and ponder on hitting Facebook's post button, wondering till the last if your spaghetti dinner photo/comment really gets the right message across. On its more troubling side, the site plays on the fear that you can no longer control your identity after you're gone; that you are in fact a mere mortal. "The moments and emotions in our lifetime define how we are seen by our family and friends. All these slowly fade away after we die -- until one day… we are all forgotten," it says in its opening lines -- scroll down and it provides the answer to all your problems: "Simply Become Immortal". Part of the reason we might identify as being immortal -- at least unconsciously, as Freud describes it -- is because we craft a life we believe will be memorable, or have children we believe our legacy will live on in. Eterni.me's comment shatters that illusion and could be seen as opportunistic on the founders' part. The site also goes on to promise a "virtual YOU" that can "offer information and advice to your family and friends after you pass away", a comfort to anyone worried about leaving behind a spouse or children.


The ultimate stumbling block might be, however, the something that's worse than the fear of being forgotten. Admitting you're going to die one day. It's a tough sell, to persuade someone to confess to the secret of their heroism.

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Laura E. Mirian, PhD's curator insight, February 17, 10:47 AM

you can have virtual chats with loved ones from beyond the grave.

Laura E. Mirian, PhD's curator insight, February 23, 10:34 AM

DON'T KNOW IF I WANT TO LIVE FOREVER IN THIS UNIVERSE-WHAT ABOUT YOU?

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Why Do We Age? An animal that survives 1,400 years as part of a population

Why Do We Age? An animal that survives 1,400 years as part of a population | Amazing Science | Scoop.it
Why we age is a tricky evolutionary question. A full set of DNA resides in each of our cells, after all, allowing most of them to replicate again and again and again.


In our youth we are strong and healthy and then we weaken and die - that's probably how most would describe what aging is all about. But, in nature, the phenomenon of aging shows an unexpected diversity of patterns and is altogether rather strange, conclude researchers from The University of Southern Denmark.


Not all species weaken and become more likely to die as they age. Some species get stronger and less likely to die with age, while others are not affected by age at all. Increasing weakness with age is not a law of nature.


Researchers from the University of Southern Denmark have studied aging in 46 very different species including mammals, plants, fungi and algae, and they surprisingly find that there is a huge diversity in how different organisms age. Some become weaker with age – this applies to e.g. humans, other mammals, and birds; others become stronger with age – this applies to e.g. tortoises and certain trees, and others become neither weaker nor stronger – this applies to e.g. Hydra, a freshwater polyp.


"Many people, including scientists, tend to think that aging is inevitable and occurs in all organisms on Earth as it does for humans: that every species becomes weaker with age and more likely to die. But that is not the case", says evolutionary biologist and assistant professor Owen Jones from the Max-Planck Odense Center at the University of Southern Denmark .


He is the lead author of an article on the subject in the scientific journal Nature. Other authors are from the Max Planck Institute for Demographic Research in Rostock, Germany, the University of Queensland in Australia, University of Amsterdam in Holland and elsewhere.


Owen Jones and his colleagues studied aging in species ranging from oak trees, nematodes, baboons and lice to seaweed and lions. The species included 11 mammals, 12 other vertebrates, 10 invertebrates, 12 plants and one algae.


"The diversity of mortality and fertility patterns in these organisms surprised us, and there is clearly a need for more research before we fully understand the evolutionary causes of aging and become better able to address problems of aging in humans", says Owen Jones.


He points out that while there is plenty of scientific data on aging in mammals and birds, there is only sparse and incomplete data on aging in other groups of vertebrates, and most invertebrates, plants, algae, and fungi.


For several species mortality increases with age - as expected by evolutionary scientists. This pattern is seen in most mammal species including humans and killer whales, but also in invertebrates like water fleas. However, other species experience a decrease in mortality as they age, and in some cases mortality drops all the way up to death. This applies to species like the desert tortoise (Gopherus agassizii) which experiences the highest mortality early on in life and a steadily declining mortality as it ages. Many plant species, e.g. the white mangrove tree (Avicennia marina) follow the same pattern.


Amazingly, there are also species that have constant mortality and remain unaffected by the ageing process. This is most striking in the freshwater polyp Hydra magnipapillata which has constant low mortality. In fact, in lab conditions, it has such a low risk of dying at any time in its life that it is effectively immortal.


"Extrapolation from laboratory data show that even after 1400 years five per cent of a hydra population kept in these conditions would still be alive", says Owen Jones.


Several animal and plant species show remarkably little change in mortality throughout their life course. For example, these include rhododendron (Rhododendron maximum), great tit (Parus major), hermit crab (Pagurus longicarpus), common lizard (Lacerta vivapara), collared flycatcher (Ficedula albicollis), viburnum plants (Viburnum furcatum ), oarweed (Laminaria digitata), red abalone (Haliotis rufescens), the plant armed saltbush (Atriplex acanthocarpa), red-legged frog (Rana aurora) and the coral red gorgonian (Paramuricea clavata).


When you look at the fertility patterns of the 46 surveyed species, there is also a great diversity and some large departures from the common beliefs about ageing. Human fertility is characterized by being concentrated in a relatively short period of life, and by the fact that humans live for a rather long time both before and after the fertile period.


A similar pattern of a concentrated fertile period is also seen in other mammals like killer whales, chimpanzees, and chamois (Rupicapra rupicapra), and also in birds like sparrow hawks (Accipiter nisus).


However, there are also species that become more and more fertile with age, and this pattern is especially common in plants such as the agave (Agave marmorata) and the rare mountain plants hypericum (Hypericum cumulicola) and borderea (Borderea pyrenaica).


On the contrary fertility occurs very early in the nematode worm Caenorhabditis elegans. Actually this species starts its life with being fertile, then it quite quickly and quite suddenly loses the ability to produce offspring.


To sum up there is no strong correlation between the patterns of ageing and the typical life spans of the species. Species can have increasing mortality and still live a long time, or have declining mortality and still live a short time. "It makes no sense to consider ageing to be based on how old a species can become. Instead, it is more interesting to define ageing as being based on the shape of mortality trajectories: whether rates increase, decrease or remain constant with age", says Owen Jones.

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Great white sharks live much longer than previously thought — for over 70 years

Great white sharks live much longer than previously thought — for over 70 years | Amazing Science | Scoop.it

Using a new technique to age the tissues of these impressive creatures, scientists have identified a male great white that lived into its 70s. The researchers say the finding has important implications for the animals' protection.


Knowing the longevity of a species, how fast it grows and when it reaches sexual maturity is vital information for designing conservation programmes. "These creatures are amazing and it's fascinating to study them," said Li Ling Hamady, who is part of a joint programme between MIT and the Woods Hole Oceanographic Institution in the US.


"Everyone thinks they know these animals so well, and the public perception is that they're either loved or hated. But in terms of the science, we're only just now beginning to understand what they eat, where they go and how long they live."


Scientists have tried to age the spectacular predators by counting annual growth rings in their tissues, such as in their vertebrae. But the sharks' cartilage skeleton makes the division between these rings hard to discern even under the microscope. Now, Ms Hamady and colleagues tell the journal Plos One that they made these rings easier to read by looking for a known radioactive marker.

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What are the limits to longevity? Combining mutants lead to a 5-fold lifespan extension in C. elegans

What are the limits to longevity? Combining mutants lead to a 5-fold lifespan extension in C. elegans | Amazing Science | Scoop.it

New research in simple animals suggests that combining mutants can lead to radical lifespan extension. Scientists at the Buck Institute combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans. The research, done at the Buck Institute and published online in Cell Reports on December 12, 2013, introduces the possibility of combination therapy for aging and the maladies associated with it.


The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Lead scientist and Buck faculty Pankaj Kapahi, PhD, said single mutations in TOR (in this case RSKS-1) usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms -- added together they would be expected to extend longevity by 130 percent. "Instead, what we have here is a synergistic five-fold increase in lifespan," Kapahi said. "The two mutations set off a positive feedback loop in specific tissues that amplified lifespan. Basically these worms lived to the human equivalent of 400 to 500 years."


Kapahi said the research points to the possibility of using combination therapies for aging, similar to what is done for cancer and HIV. "In the early years, cancer researchers focused on mutations in single genes, but then it became apparent that different mutations in a class of genes were driving the disease process," he said. "The same thing is likely happening in aging." Kapahi said this research could help explain why scientists are having a difficult time identifying single genes responsible for the long lives experienced by human centenarians. "It's quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives."


Former Buck postdoctoral fellow Di Chen, PhD, now an associate professor at the Model Animal Research Center, Nanjing University, China, lead author of the study, said that the positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. "The germline was the key tissue for the synergistic gain in longevity -- we think it may be where the interactions between the two mutations are integrated," Chen said. "The finding has implications for similar synergy between the two pathways in more complex organisms."


Kapahi said ideally the research would move into mice as a way of determining if the lifespan-extending synergy extends into mammals. "The idea would be to use mice genetically engineered to have suppressed insulin signaling, and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway."


Reference:

  1. Pankaj Kapahi, PhD et al. Germline Signaling Mediates the Synergistically Prolonged Longevity by Double Mutations in daf-2 and rsks-1 in C. elegansCell Reports, December 2013


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Signs of Aging, Even in the Embryo

Signs of Aging, Even in the Embryo | Amazing Science | Scoop.it
New research indicates that senescent cells, those that stop dividing, play an important role at both the dawn and dusk of life.

 

In 1961, two biologists named Leonard Hayflick and Paul Moorehead discovered that old age is built into our cells. At the time, many scientists believed that if healthy human cells were put in a flask with a steady supply of nutrients, they would multiply forever. But when Dr. Hayflick and Dr. Moorehead reared fetal human cells, that’s not what they found. Time and again, their cells would divide about 50 times and then simply stop.


In fact, it turned out, senescent cells are involved in many of the ravages of old age. Wrinkled skin, cataracts and arthritic joints are rife with senescent cells. When researchers rid mice of senescent cells, the animals become rejuvenated.

 

Given all this research, the last place you would expect to find senescent cells would be at the very start of life. But now three teams of scientists are reporting doing just that. For the first time, they have found senescent cells in embryos, and they have offered evidence that senescence is crucial to proper development.

 

The discoveries raise the prospect that the dawn and dusk of life are intimately connected. For life to get off to the right start, in other words, youth needs a splash of old age.

 

Scott Lowe, an expert on senescence at Memorial Sloan-Kettering Cancer Center who was not involved in the research, praised the studies for pointing to an unexpected role for senescence. He predicted they would provoke a spirited debate among developmental biologists who study how embryos form. “They’re going to really love it or really hate it,” Dr. Lowe said.

 

While senescence may be a powerful defense against cancer, however, it comes at a steep cost. Even as we escape cancer, we accumulate a growing supply of senescent cells. The chronic inflammation they trigger can damage surrounding tissue and harm our health.

 

In the mid-2000s, William Keyes, a biologist then at Cold Spring Harbor Laboratory on Long Island, was studying how senescence leads to aging with experiments on mice. By shutting down a gene called P63, he could accelerate the rate at which the mice accumulated senescent cells — and accelerate their aging.

 

To observe the senescent cells, Dr. Keyes added a special stain to the bodies of these mice. To see the difference between these mice and normal ones, Dr. Keyes added the same stain to normal mouse embryos.

Naturally, he expected that none of the cells in the normal mouse embryos would turn dark. After all, senescent cells had been found only in old or damaged tissues. Much to his surprise, however, Dr. Keyes found patches of senescent cells in the normal mouse embryos. Dr. Keyes decided to look again at those peculiar senescent cells in normal embryos. He and his colleaguesconfirmed that cells became senescent in many parts of an embryo, such as along the developing tips of the legs.

 

The researchers, however, found no evidence that the senescent cells in embryos have damaged DNA. That discovery raises the question of how the cells were triggered to become senescent. Dr. Keyes hypothesizes they did so in response to a signal from neighboring cells.

 

Once an embryonic cell becomes senescent, it does the two things that all senescent cells do: it stops dividing and it releases a special cocktail. 

The new experiments suggest that this cocktail plays a different role in the embryo than in the adult body. It may act as a signal to other cells to become different tissues. It may also tell those tissues to grow at different rates into different shapes.

 

Dr. Keyes suspects that the sculpting that senescent cells carry out may be crucial to the proper development of an embryo. Consequently, any disruption to senescent cells may have dire consequences. “Where we see senescence in the embryo is where we see a lot of different birth defects,” he said.


For an embryo to develop properly, signals have to be sent to the right places at the right times. The peculiar behavior of senescent cells may help in both regards. If a cell stops growing, it won’t spread too far from a particular spot in an embryo. And by summoning immune cells to kill it, a senescent cell may ensure that its signals don’t last too long.

 

It’s possible, Dr. Keyes speculates, that senescence actually evolved first as a way to shape embryos; only later in evolution did it take on a new role, as a weapon against cancer. “I like the idea that it was a simple process that was then modified,” Dr. Keyes said.

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PatrickHance's comment, December 17, 2013 10:06 PM
Senescent cells are cells that stop dividing. These cells are one of the main causes of medical conditions caused by old age. However, they also defend against cancer because they can no longer divide. Scientists recently discovered that senescent cells also exist in embryos. These senescent cells in embryos help development by telling other cells what to grow. However, if they are disrupted they can easily cause birth defects. Zimmer, Carl. "Signs of Aging, Even in the Embryo." New York Times [New York] 21 11 2013, n. pag. Web. 17 Dec. 2013. <http://www.nytimes.com/2013/11/21/science/signs-of-aging-even-in-the-embryo.html?src=recg&_r=0>.
Joseph Perrone's comment, January 12, 11:34 AM
In 1961 two biologist discovered that old age is built into our cells. Senescent cells are responsible for the ageing of our body's, when scientist removed the cells from mice body's they where rejuvenated. The strange part about it all is that the cells are found in the very beginning of life, three teams of scientist have found that these cells help the process of life happen. They also found that when a cell divides too much it becomes too damaged and becomes senescent. They also discovered that these cells help defend us from cancer, they secrete a cocktail of chemicals that help make sure the cell does not go out of control.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I found this article to be very interesting, scientist found something really cool. who would have thought that the ageing of our body is a built in process that has all of that stuff happen. These Senescent cells are very different, they even defend us from cancer, i would have thought the opposite. Very interesting article!
Madison Punch's comment, March 24, 7:14 PM
I found this article to be among the coolest I've read from scoop.it. I figured that aging came with the weakening, or rather aging, of the body. Who knew it was basically "installed" into our cells? The end of cell division basically stops the flourishing of the peak of life and begins to fall into aging. Very cool.
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World's oldest living animal was 507 years old when scientists accidentally killed it

World's oldest living animal was 507 years old when scientists accidentally killed it | Amazing Science | Scoop.it

World's oldest creature - known as Ming the mollusc - is proven even older than previously thought. When scientists inadvertently killed what turned out to be the world’s oldest living creature, it was bad enough. Now, their mistake has been compounded after further research found it was even older – at 507 years.


The ocean quahog - a type of deep-sea clam - was dredged alive from the bottom of the North Atlantic near Iceland in 2006 by researchers. They then put it in a freezer, as is normal practice, unaware of its age.

 

It was only when it was taken to a laboratory that scientists from Bangor University studied it and concluded it was 400 years old.

The discovery made it into the Guinness Book of World Records however by this time, it was too late for Ming the Mollusc – named after the Chinese dynasty on the throne when its life began.

 

Now, after examining the ocean quahog more closely, using more refined methods, the researchers have found the animal was actually 100 years older than they first thought.

 

Dr. Paul Butler, from the University’s School of Ocean Sciences, said: “We got it wrong the first time and maybe we were a bit hasty publishing our findings back then. But we are absolutely certain that we’ve got the right age now.”

 

A quahog’s shell grows by a layer every year, in the summer when the water is warmer and food is plentiful. It means that when its shell is cut in half, scientists can count the lines in a similar way trees can be dated by rings in their trunks.

 

The growth rings can be seen in two places; on the outside of the shell and at the hinge where the two halves meet. The hinge is generally considered by scientists as the best place to count the rings, as it is protected from outside elements.

 

When researchers originally dated Ming, they counted the rings at the hinge. However because it was so old, many had become compressed. When they looked again at the outside of the shell, they found more rings. It means the mollusc was born in 1499 – just seven years after Columbus discovered America and before Henry VIII had even married his first wife, Catherine of Aragon in 1509.

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Connor Keesee's curator insight, December 5, 2013 12:30 PM

Oldest animal in history accidentally killed by scientists. The age of the shell is found by counting the rings on the outside just like a tree. The shell was found in the North Atlantic near Iceland in 2006 by researchers. The clam is called the Ming Mollusc. 

Nancy jodoin's curator insight, July 29, 5:00 PM

This about the Ming dynasty with a twist.

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Is increased protein synthesis fidelity the secret weapon against aging?

Is increased protein synthesis fidelity the secret weapon against aging? | Amazing Science | Scoop.it

The naked mole-rat (Heterocephalus glaber) is a subterranean eusocial rodent with a markedly long lifespan and resistance to tumorigenesis. Multiple data implicate modulation of protein translation in longevity.

 

The 28S ribosomal RNA (rRNA) of the naked mole-rat is processed into two smaller fragments of unequal size. The two breakpoints are located in the 28S rRNA divergent region 6 and excise a fragment of 263 nt. The excised fragment is unique to the naked mole-rat rRNA and does not show homology to other genomic regions. Because this hidden break site could alter ribosome structure, scientists investigated whether translation rate and amino acid incorporation fidelity were altered. They found that naked mole-rat fibroblasts have significantly increased translational fidelity despite having comparable translation rates with mouse fibroblasts. Although they didn't directly test whether the unique 28S rRNA structure contributes to the increased fidelity of translation, they speculated that it may change the folding or dynamics of the large ribosomal subunit, altering the rate of GTP hydrolysis and/or interaction of the large subunit with tRNA during accommodation, thus affecting the fidelity of protein synthesis. These results suggest that naked mole-rat cells produce fewer aberrant proteins, supporting the hypothesis that the more stable proteome of the naked mole-rat contributes to its longevity.

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