It has to be said, it is pretty rare for researchers to find a genetic effect as large as a halving of disease risk in human studies. We'll have to see if this particular case holds up in replication studies, but for the moment researchers are claiming that a mutation in the angiopoietin-like 4 (ANGPTL4) gene reduces risk of heart attack by 50%, and that to initial inspection this mutation doesn't seem to bear any detrimental side-effects. If this is in fact the case, we can add this to the growing list of potentially desirable gene therapies that are now well within the technical capabilities of most laboratories in this new age of CRISPR and low-cost, reliable genetic editing. At this point there are probably a score or more speculative changes that may be worth carrying out on the basis of animal studies or the existence of healthy human mutants, but only two or three, such as myostatin knockout, that are backed by sufficient evidence and experience to seem viable and low risk for immediate clinical translation.

Somewhere out there, right now, people with an interest, people with scientific knowledge, and people with money are exchanging missives and chewing over business plans that involve producing and selling packages of gene therapies for human enhancement. Some of these will include viable compensatory treatments for specific aspects of age-related degeneration; myostatin knockout to reduce loss of muscle mass and strength in aging, for example, or adding lysosomal receptors to increase cellular maintenance and slow loss of organ function. As the cost of gene therapy continues to fall, even as its reliability and capabilities increase by leaps and bounds, we're going to see the same thing happen for this field as happened for stem cell research fifteen years ago. Many groups and clinics will choose to circumvent the more restrictive regulatory systems of the US and Europe. They will offer therapies in other regions based on the technical ability to do so, and where there is a reasonable expectation of success and benefit. My prediction is that this process of commercial and medical exploration will be well underway five years from now.

Mutated gene safeguards against heart attacks

For the large-scale study at hand, the scientists analyzed 13,000 different genes from a pool of 200,000 participants - both heart attack patients and healthy control persons. They were on the lookout for correlations between gene mutations and coronary artery disease. For a number of genes, the researchers registered a correlation, including the ANGPTL4 (angiopoietin-like 4) gene. In addition, subjects with the mutated ANGPTL4 gene had significantly lower triglyceride values in their blood. "The blood fat triglyceride serves as an energy store for the body. However, as with LDL cholesterol, elevated values lead to an increased risk of cardiovascular disease. Low values, by contrast, lower the risk. For most patients the focus still lies on cholesterol. A differentiation is always made between the healthy HDL and the harmful LDL cholesterol variants. However, in the mean time we know that the HDL values always run inversely proportional to those of the triglycerides and that HDL itself actually tends to behave in a neutral manner. The triglycerides, on the other hand, are the second important blood fat, alongside the harmful LDL cholesterol. The only reason HDL blood values are still measured is because, together with HDL and triglyceride values, they can be used to derive the LDL values, which cannot be measured directly."

The current study now shows that the concentration of triglycerides in the blood are influenced not only by nutrition and predisposition, but also by the ANGPTL4 gene. "At the core of our data is the lipoprotein lipase (LPL) enzyme. It causes the decomposition of triglycerides in the blood." Normally, ANGPTL4 hems the LPL enzyme, causing blood fat values to rise. The mutations identified by the researchers disable the function of this gene and thereby ensure that the triglyceride value drops significantly. "At the same time, we discovered that the body does not even need the ANGPTL4 gene and manages wonderfully without it. It seems to be superfluous." Shutting down the gene or inhibiting the LPL enzyme in another manner may ultimately protect against coronary disease. "Based on our results, medications now need to be developed that neutralize the effect of the ANGPTL4 gene, thereby reducing the risk of a heart attack. Other researchers have already done this successfully in animal tests. They drastically reduced the blood fat levels in monkeys that received a neutralizing antibody against ANGPTL4. This feeds the hope that antibody preparations with a similar effect can soon be used successfully in humans."

Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease

Through large-scale exomewide screening, we identified a low-frequency coding variant in ANGPTL4 that was associated with protection against coronary artery disease and a low-frequency coding variant in SVEP1 that was associated with an increased risk of the disease. Moreover, our results highlight LPL as a significant contributor to the risk of coronary artery disease and support the hypothesis that a gain of LPL function or loss of ANGPTL4 inhibition protects against the disease.

ANGPTL4 has previously been found to be involved in cancer pathogenesis and wound healing. Previous functional studies also revealed that ANGPTL4 regulates plasma triglyceride concentration by inhibiting LPL. The minor allele at p.E40K has previously been associated with lower levels of triglycerides and higher levels of HDL cholesterol. We now provide independent confirmation of these lipid effects. In vitro and in vivo experimental evidence suggests that the lysine allele at p.E40K results in destabilization of ANGPTL4 after its secretion from the cell in which it was synthesized. It may be that the p.E40K variant leads to increases in the enzymatic activity of LPL because of this destabilization. Previous, smaller studies produced conflicting results regarding p.E40K and the risk of coronary artery disease; we now provide robust support for an association between p.E40K and a reduced risk of coronary artery disease.

To provide confirmatory orthogonal evidence that a loss of ANGPTL4 function is associated with a decreased risk of coronary artery disease, we searched for loss-of-function mutations in this gene. We found that ANGPTL4 loss-of-function mutations were associated with substantially lower triglyceride levels (35% lower than in persons who were not carriers of a loss-of-function mutation), and we also found that these loss-of-function alleles were associated with a 53% lower risk of coronary artery disease. The identification of additional ANGPTL4 inactivating mutation carriers provides further evidence of the association between a loss of ANGPTL4 function and lower triglyceride levels and a reduced risk of coronary artery disease.

Researchers have developed a means of reversing periodontitis, inflammation of the gums, in an animal model. This is of interest in the context of aging as periodontitis is widespread in the population, and inflammation in the gums doesn't remain isolated: it spreads to contribute to the progression of much more dangerous conditions such as atherosclerosis. A clinical therapy that eliminates periodontitis entirely would be a very positive advance.

Periodontitis, a gum disease present in nearly half of all adults in the United States, involves inflammation, bleeding and bone loss. In its severe form, it is associated with systemic inflammatory conditions such as atherosclerosis and rheumatoid arthritis. Few treatment options exist beyond dental scaling and root planing, done in an attempt to reduce plaque and inflammation. Now, however, researchers have employed an inhibitor of a protein called C3, a component of the body's complement system, which is involved in immunity and inflammatory responses. Delivering this inhibitor, Cp40, to the periodontal tissue just once a week reversed naturally occurring chronic periodontitis inflammation in a preclinical model. "Even after one treatment, you could see a big difference in inflammation. After six weeks, we saw reversals in inflammation, both clinically and by looking at cellular and molecular measures of osteoclast formation and inflammatory cytokines. The results were so clean, so impressive. The next step is to pursue Phase 1 trials in humans."

This study builds on earlier work which identified C3 as a promising target for treating periodontal disease. C3, or the third component of the complement system, is a key part of signaling cascades that trigger inflammation and activate the innate immune system. Their previous research, which used an inducible model of periodontal disease, found that Cp40 could reduce signs of the disease. To get closer to a natural scenario, however, the current work was conducted on animals that naturally had developed chronic periodontitis. Initially the research team tried administering Cp40 three times a week, but after seeing significant reductions in inflammation, they tried giving it only once a week to a different group and saw the same good results. This study delivered the drug via a local injection to avoid any potential systemic effects from inhibiting a component of the immune system. There were no adverse effects reported. "Some people have been concerned that blocking complement would lead to more infections but that is not the case here. We're stopping the inflammation in the gums and thereby killing the bacteria that need inflammatory tissue breakdown proteins to survive."

Link: https://news.upenn.edu/news/penn-team-reverses-signs-naturally-occurring-chronic-periodontitis

Neurogenesis, the creation of new neurons in the brain, slows with age. This is most likely an important contributing factor in the age-related loss of neural plasticity, the ability of the central nervous system to change, adapt, and to a limited degree repair itself. Here researchers show that they can increase the pace of neurogenesis in old mice by raising the level of fibroblast growth factor (FGF) signaling:

The mechanisms regulating hippocampal neurogenesis remain poorly understood. Particularly unclear is the extent to which age-related declines in hippocampal neurogenesis are due to an innate decrease in precursor cell performance or to changes in the environment of these cells. Several extracellular signaling factors that regulate hippocampal neurogenesis have been identified. However, the role of one important family, FGFs, remains uncertain. Although a body of literature suggests that FGFs can promote the proliferation of cultured adult hippocampal precursor cells, their requirement for adult hippocampal neurogenesis in vivo and the cell types within the neurogenic lineage that might depend on FGFs remain unclear.

Here, specifically targeting adult neural precursor cells, we conditionally express an activated form of an FGF receptor or delete the FGF receptors that are expressed in these cells. We find that FGF receptors are required for neural stem-cell maintenance and that an activated receptor expressed in all precursors can increase the number of neurons produced. Moreover, in older mice, an activated FGF receptor can rescue the age-related decline in neurogenesis to a level found in young adults. These results suggest that the decrease in neurogenesis with age is not simply due to fewer stem cells, but also to declining signals in their niche. Thus, enhancing FGF signaling in precursors can be used to reverse age-related declines in hippocampal neurogenesis.

Link: http://dx.doi.org/10.1523/JNEUROSCI.1469-15.2015

Researchers have found that, unusually, entering a senescent state actually improves some measures of performance in the beta cells of the pancreas responsible for producing insulin. Senescent cells are those that have removed themselves from the cycle of replication, either because they have reached the Hayflick limit, or prior to that point in reaction to molecular damage or a toxic local environment. A senescent cell may destroy itself via programmed cell death mechanisms or it may be destroyed by the immune system, but while it remains in place it behaves badly, secreting a harmful mix of molecules that change surrounding cellular behavior and remodel tissue structures. Aging brings a growing number of these senescent cells in all tissues, lingering long past the point at which they should have been destroyed. Their harmful effects grow sizable and contribute to the pathology of most age-related conditions. Thus cellular senescence is a cause of aging, age-related disease, and death. Even if all of the other mechanisms that cause aging were hand-waved away, increasing numbers of senescent cells alone would be enough to kill us eventually.

Biology is complex, however, and it is rare for any given process to do just one thing, or for any mechanism to be important in just one way. Evolution likes reuse, and cellular senescence has a variety of forms and has evolved into a variety of roles. It may have started as a process of embryonic development, a way to halt growth in order to define the shape of extremities such as fingers. The transient creation of senescent cells is also involved in wound healing, however, and senescence in response to damage and toxins likely serves to reduce the risk of cancer, or at least initially. Large numbers of senescent cells cause significant chronic inflammation, among other issues, and that eventually overwhelms any cancer-prevention benefit resulting from preventing replication in cells at a greater risk of suffering cancerous mutations.

Given all of this, it shouldn't be completely surprising to find more places and circumstances in the body in which cellular senescence produces benefits along the way towards ultimately helping to kill us. That we find such benefits isn't a good reason to pull back from efforts to produce therapies that can clear senescent cells from the body, and thereby prevent their contribution to aging, of course, but they do serve to remind us that nothing is ever simple when it comes to living organisms.

Cellular Aging Process Unexpectedly Enhances Insulin Secretion

New research shows that a cellular program that causes aging can also bring unexpected benefits in the function of pancreatic beta cells and the production of insulin in mice and humans. The researchers examined the activity of a gene named p16, which is known to activate a program called senescence in cells. Senescence prevents cells from dividing, and is therefore important in preventing cancer. The activity of the p16 gene increases in human and mouse pancreatic beta cells during aging and limits their potential to divide. This activity is thus seen as having a negative effect - the lack of ability of these cells to divide can contribute to diabetes, since beta cells are the cells responsible for secreting insulin when blood glucose levels are high, and their loss causes diabetes. However, it was unknown whether senescent beta cells could continue functioning at all.

To their surprise, the researchers discovered that during normal aging, p16 and cellular senescence actually improve the primary function of beta cells: the secretion of insulin upon glucose stimulation. Because insulin secretion increases during the normal aging of mice and is driven by elevated p16 activity, some of these cells actually start to function better. The researchers further found that activation of p16 and senescence in beta cells of mice that suffer from diabetes enhanced insulin secretion, thereby partly reversing the disease and improving the health of the mice. Similar experiments conducted in human cells strongly suggest that senescence-induced enhancement of insulin secretion is conserved between mice and humans, and point to the p16 gene as its main driver in both organisms.

p16Ink4a-induced senescence of pancreatic beta cells enhances insulin secretion

Cellular senescence is thought to contribute to age-associated deterioration of tissue physiology. The senescence effector p16Ink4a is expressed in pancreatic beta cells during aging and limits their proliferative potential; however, its effects on beta cell function are poorly characterized. We found that beta cell-specific activation of p16Ink4a in transgenic mice enhances glucose-stimulated insulin secretion (GSIS). In mice with diabetes, this leads to improved glucose homeostasis, providing an unexpected functional benefit.

Expression of p16Ink4a in beta cells induces hallmarks of senescence - including cell enlargement, and greater glucose uptake and mitochondrial activity - which promote increased insulin secretion. GSIS increases during the normal aging of mice and is driven by elevated p16Ink4a activity. We found that islets from human adults contain p16Ink4a-expressing senescent beta cells and that senescence induced by p16Ink4a in a human beta cell line increases insulin secretion in a manner dependent, in part, on the activity of the mechanistic target of rapamycin (mTOR) and the peroxisome proliferator-activated receptor (PPAR)-γ proteins. Our findings reveal a novel role for p16Ink4a and cellular senescence in promoting insulin secretion by beta cells and in regulating normal functional tissue maturation with age.

Specialized components of the immune system present in the brain, such as microglia, are integral to many of the processes involved in or degraded by neurodegenerative conditions. For example, microglia may be a primary cause of the chronic inflammation found in older brain tissue, and which contributes to the pathology of a range of conditions, including Alzheimer's disease. The study noted here focuses on a different aspect of the role of microglia, a way in which they participate in the normal operation of the brain in conjunction with neurons: the researchers involved show that microglia play a necessary role in altering the connections between neurons. This will no doubt be of interest to the field of aging research, as the plasticity of neural connections diminishes with age, and it will be interesting and potentially useful to know the degree to which this is a problem of neurons versus a problem of the immune system.

A new study shows that cells normally associated with protecting the brain from infection and injury also play an important role in rewiring the connections between nerve cells. While this discovery sheds new light on the mechanics of neuroplasticity, it could also help explain diseases like dementia, which may arise when this process breaks down and connections between brain cells are not formed or removed correctly. "We have long considered the reorganization of the brain's network of connections as solely the domain of neurons. These findings show that a precisely choreographed interaction between multiple cells types is necessary to carry out the formation and destruction of connections that allow proper signaling in the brain."

The study is another example of a dramatic shift in scientists' understanding of the role that the immune system, specifically cells called microglia, plays in maintaining brain function. Microglia have been long understood to be the sentinels of the central nervous system, patrolling the brain and spinal cord and springing into action to stamp out infections or gobble up dead cell tissue. However, scientists are now beginning to appreciate that, in addition to serving as the brain's first line of defense, these cells also have a nurturing side, particularly as it relates to the connections between neurons. The formation and removal of the physical connections between neurons is a critical part of maintaining a healthy brain and the process of creating new pathways and networks among brain cells enables us to absorb, learn, and memorize new information.

While this constant reorganization of neural networks - called neuroplasticity - has been well understood for some time, the basic mechanisms by which connections between brain cells are made and broken has eluded scientists. Performing experiments in mice, the researchers employed a well-established model of measuring neuroplasticity by observing how cells reorganize their connections when visual information received by the brain is reduced from two eyes to one. The researchers found that in the mice's brains microglia responded rapidly to changes in neuronal activity as the brain adapted to processing information from only one eye. They observed that the microglia targeted the synaptic cleft - the business end of the connection that transmits signals between neurons. The microglia "pulled up" the appropriate connections, physically disconnecting one neuron from another, while leaving other important connections intact. "These findings demonstrate that microglia are a dynamic and integral component of the complex machinery that allows neurons to reorganize their connections in the healthy mature brain. While more work needs to be done to fully understand this process, this study may help us understand how genetics or disruption of the immune system contributes to neurological disorders."

Link: https://www.urmc.rochester.edu/news/story/4516/the-brains-gardeners-immune-cells-prune-connections-between-neurons.aspx

Researchers are working on a method of targeting stellate cells in the liver to prevent them from causing fibrosis when overactivated in response to infections, autoimmunity, and other causes of liver disease:

Liver fibrosis and its more severe form, cirrhosis, are caused by scar tissue that forms in the liver. The progressive stiffening of the liver, a hallmark of the disorders, occurs when a type of liver cell known as the hepatic stellate cell is "activated" and overproduces the stringy network of proteins called the extracellular matrix that binds cells together. Being able to turn cirrhosis around, especially in its late stages, would be a great boon, because liver fibrosis and cirrhosis can be asymptomatic for decades. Many patients only seek treatment when their disease becomes very advanced, at which point liver transplant is their only option.

Scientists have known for more than a decade that a protein called tumor necrosis factor-related apoptosis-inducing ligand - TRAIL, for short - can specifically kill activated hepatic stellate cells that overproduce the extracellular matrix, sparing healthy cells in the liver. However, TRAIL has thus far proven unsuccessful for clinical use because in animal studies, enzymes in the bloodstream quickly degrade it before it has time to work. Seeking a way to extend TRAIL's half-life, or the time that it remains intact in the bloodstream, researchers coated TRAIL with polyethylene glycol (PEG), a synthetic polymer. Initial experiments showed that this "PEGylated" TRAIL had a half-life of between eight and nine hours in monkeys, compared to less than 30 minutes for the unmodified protein. When the scientists intravenously dosed rats that had liver fibrosis with the modified TRAIL for 10 days, the animals' activated hepatic stellate cells died off. By fighting these bad cells, signs of fibrosis began to diminish. Further investigation showed that multiple genes associated with fibrosis had reduced activity, and the proteins produced by these genes faded away.

Findings were similar in rats with advanced cirrhosis. Additionally, when the researchers examined the rodents' liver tissue under a microscope, they found that animals treated with PEGylated TRAIL had fewer deposits of collagen and other extracellular matrix proteins, offering some evidence that the disease had actually been reversed. The research team hopes to develop PEGylated TRAIL for clinical trials in human patients in the next two years. Some preliminary data suggest that the modified protein could also treat other fibrotic diseases as well, such as pancreatic or lung fibrosis, which also have no effective treatment.

Link: http://www.eurekalert.org/pub_releases/2016-03/jhm-mpr030216.php

Cells use the bloodstream as a way to communicate with one another, and blood in an old individual has many differences when compared to that of a young individual. The amounts of numerous important signal molecules are different, for example. By the evidence to date, obtained from parabiosis studies in which the circulatory systems of an old and a young individual are linked, this appears to be connected to the age-related decline in stem cell activity, and probably to many other systems as well. These signal molecules are just one class of change in the blood over the course of aging, however. Here is another: fragments of DNA sequences, the nucleic acids that make up DNA, are another type of molecule found in the bloodstream in greater amounts in old individuals. Researchers are presently debating whether and how this molecular debris might cause harm.

These circulating nucleic acids are thought to arise from the destruction of cells, though given that cells are capable of creating and releasing quite complex structures into the surrounding tissues - consider extracellular vesicles for example - it is perhaps plausible that dysfunctional cells could be exporting nucleic acids while still intact. The theorized problem caused by extracellular nucleic acids is that cells will take them up and integrate them into their DNA, and that this could be a significant source of stochastic mutational damage.

This might be considered a part of the broader argument as to whether nuclear DNA damage is significant in aging over a normal human life span in any way other than generating an increased risk of cancer. It is indisputably the case that mutational damage occurs, and is a distinguishing feature of old tissues, each cell with its own unique pattern of damage. What is hard to prove is that this actually causes significant problems in and of itself, absent any of the other changes of aging. A large enough level of mutation will definitely change the behavior of cells in ways that degrade tissue function, but is the present mutation rate in aging anywhere near high enough to get to that point? The studies needed to definitively answer that question have yet to take place.

The dark side of circulating nucleic acids

Billions of cells in the adult human body are eliminated daily through cell death processes, such as apoptosis and necrosis; especially necrotic cells, which unlike apoptotic cells are not generally removed cleanly by phagocytosis, are thought to be a source of degraded DNA fragments released to the blood plasma or serum as cell-free DNA or circulating free DNA (cfDNA). Some aspects of the biology of cfDNA are still unexplored and several key questions remain. One question with high relevance to aging is whether or not cfDNA fragments can behave as mobile genetic elements, illegitimately integrating in the chromosomal DNA of healthy cells in its own host, thereby contributing to genome instability and possibly causing age-related functional decline and age-related pathophysiological processes.

Recently evidence was provided that the integration of cell-free nucleic acid with host cells occurs in vivo as well as in vitro. Mice were injected intravenously with human cfDNA and Cfs and analysis of heart, lung, liver, and brain of the mice sacrificed 7 days after injection revealed genomic localization of nucleic acids, with Cfs localizing more efficiently than cfDNA. Of note, genomic integration of Cfs in the mouse brain indicated that chromatin particles are able to cross the blood-brain barrier. This recent work offers a fascinating new mechanism of age-related mutagenesis, highlighting the fate and effects of free nucleic acids within our body. However, many questions remain. Probably the most interesting question is whether cfDNA truly behaves as mobile genetic elements under normal conditions. That is, rather than extracting concentrated cfDNA from heterogenic serum samples and intravenously injecting that in the mouse, integration of its own cfDNA should be studied, for example, as a function of age. Because integrated DNA fragments can then no longer be uniquely aligned as foreign DNA to a reference sequence, single cells or clones should be studied for insertion events as compared to the germline sequence, which is considerably more difficult than screening for reads containing human sequences.

While still lacking in important details, this recent work opens up the intriguing prospect of a new, endogenous source of genome instability that could well contribute to increased genome mosaicism with age. In this respect, cfDNA could act similarly to the previously described age-related derepression of endogenous retrotransposons in the somatic genome during aging. In this respect, there is evidence that cfDNA becomes increasingly frequent in the circulation as a function of age, for example, due to increased vulnerability of aged and damaged cells to cell death. Its activation of the DNA damage response could increase the level of genome instability considerably, contributing to aging-related degenerative processes, such as cellular senescence, cancer, and inflammation. Further research on the biological and pathological roles of cell-free nucleic acids will help to elucidate its importance as an intrinsic mechanism of aging.

The cryonics industry offers low-temperature preservation of the body and brain on death, and this is presently the only alternative to the grave and oblivion for those who will age to death prior to the advent of rejuvenation therapies. Preservation of the structures holding the data of the mind provides a chance at life again in a future in which technology has advanced to the point at which restoration of a preserved individual becomes practical. The media these days treats cryonics with a lot more respect than used to be the case, though they still tend to dumb things down by talking about freezing rather than vitrification with cryoprotectants - a very important distinction when talking about tissue preservation. I think that this change in attitudes is in part because the development of vitrification techniques for use in the organ preservation and transplant industry is much more evidently making progress and gathering support in the research community. Since that is an accepted field of research, and meanwhile researchers are demonstrating preservation of fine structure in vitrified brain tissue, it becomes hard for journalists to dismiss cryonics out of hand.

In a nondescript industrial office park in San Leandro, a little city on the outskirts of Oakland, sits the headquarters of a business named Trans Time. The walls in the foyer of the building are filled with posters about anti-aging research. There's a lab with microscopes and beakers that look like they've been around since Trans Time opened in 1974, and a white room with an operating table. In the very back of the office, you'll find a large canister of liquid nitrogen, and a handful of 10-foot-tall metal vats that look like huge coffee Thermoses. Visitors aren't allowed to look inside these vats, but if you could, you'd see that one of them contains three human corpses - or, as the facility refers to them, "patients."

With just three patients frozen in its tanks, Trans Time is a scrappy little cryonics competitor. (The last person to enter one of Trans Time's vats was the company's founder, Paul Segall, a Berkeley Ph.D who co-founded the publicly-traded medical company BioTime. He died of a brain aneurism in 2003.) The two largest cryonics facilities are Alcor, in Arizona, and the Cryonics Institute, in Michigan; that's where you'll find most of the 300 or so people who are currently frozen. There's also KrioRus in Russia, which has 45 people on ice. And there are over 2,000 people worldwide who have signed up to be frozen, but haven't died yet.

Greg Fahy is a cryobiologist at 21st Century Medicine, a scientific institution based in southern California that has received funding from the National Institutes of Health to work on cryonically preserving organs. And he thinks the sci-fi fantasy of bringing frozen bodies back to life may not be as far-fetched as we think. "We're getting pretty good at this. We can load a kidney up with cryoprotectant and save it. We now know we can remove a piece of the brain and preserve it with perfection, and then put it back and it will still operate." Fahy, who has experimented successfully with cryonic preservation in rabbits and rats, thinks it may one day work in humans, too. "There's nothing about brain tissue that prevents it from being cryonically preserved."

In fact, Fahy said, the biggest obstacle to successful cryonic reanimation might be the law, not science. Most cryonics experts agree that cryonic preservation would work best on bodies that aren't yet dead, and haven't begun to decompose. But under current law, cryonics facilities are prohibited from freezing their patients while they're alive. (Doing so would be considered assisted suicide, or possibly murder.) "There may need to be legal changes that need to be made to allow cryonic preservation before deterioration begins."

Cryonics, itself, represents a kind of faith - a faith that scientific progress will continue unabated, and will eventually be able to solve even death itself. Cryonicists believe so strongly in our scientific future that many think that people who bury, cremate or compost their bodies instead of freezing them are, essentially, committing suicide.

Link: http://fusion.net/video/256864/real-future-episode-9-cryonics/

Mitochondrially targeted antioxidant compound SkQ1, a plastinquinone, has at this point been moving through the commercial development pipeline for a decade or so. This is par for the course in medicine, sad to say. Engaging with the regulatory system is a slow, slow process, and requires such a large amount of money that organizing the funding itself often requires years of groundwork and initiatives.

SkQ1 has been shown to modestly extend life in laboratory animals, and along the way have also proven to be a useful therapy for a range of inflammatory conditions of the eye. They work by soaking up damaging oxidative molecules where they are produced, in the mitochondria, before they can cause harm to cell structures, particular the nearby mitochondrial DNA. That said, any significant alteration to the net rate of production of oxidative molecules affects the regulation of many cellular activities. A lot of unrelated methods of slowing aging in laboratory species involve either reducing or raising the rate of production of oxidative molecules by mitochondria, for example. So it isn't just a matter of preventing damage, but also of changing cellular behavior. Since it has a demonstrated ability to reduce inflammation, it is probably useful as a treatment for a range of conditions in which inflammation is an important contributing cause.

In any case, it looks like work is progressing past the initial availability of therapies for eye conditions towards formulations of SkQ1 in pill form. A lot of people in the broader longevity advocacy community will be interested in this, but bear in mind that, like all approaches so far shown to slow aging in short-lived animals, it will probably have only much smaller effects in long-lived species such as our own. Reducing the rate of mitochondrial damage caused by oxidative molecules isn't in the same class of expected outcome as repairing that damage or completely preventing its consequences, as is the goal of SENS strategies such as allotopic expression of mitochondrial DNA.

Mitotech S.A., a Luxembourg based clinical stage biotechnology company, announced a successful completion of its pre-clinical program and a start of clinical development for systemic drug Plastomitin based on Mitotech's lead compound SkQ1. SkQ1 is a small molecule engineered specifically for reducing oxidative stress inside mitochondria. Previously, SkQ1 demonstrated efficacy and safety in a double-masked placebo-controlled Phase 2 study of an eye drop formulation - Visomitin - in the U.S.

"This is a very exciting new step for our company. Our strategy assumes parallel development of a variety of formulations for our lead compound SkQ1 targeting a spectrum of age-related disorders. Visomitin had been the most advanced drug in our pipeline and already reached Phase III stage for dry eye indication in the U.S. Ophthalmic field, where we have been pursuing uveitis in addition to dry eye syndrome, remains the forefront area of development for Mitotech. At the same time, this new milestone brings us to clinical level of development for a variety of indications outside ophthalmic field. Mitotech is now in a great position to tackle critical disorders associated with aging such as neurodegenerative and metabolic diseases. Here at Mitotech we feel that we are approaching a major clinical breakthrough that could help many patients around the world."

"SkQ1 has demonstrated efficacy when administered systemically in a whole spectrum of preclinical studies. The very unique mechanism of action of the molecule has proved its benefit in models of rare genetic diseases as well as in models of more common age-related disorders. We see enormous potential in this novel mode of action and our clinical team worked very diligently on getting Plastomitin to its first clinical trial. Mitotech's goal is to progress with this new clinical program as efficiently as we did with the ophthalmic program and to deliver Plastomitin to patients within the next few years."

Link: http://www.mitotechpharma.com/news/Mitotech-SA-to%20initiate-its-first-clinical-study-of-a-systemic-formulation-of-SkQ1

Calorie restriction is a growing area of research these days, linked to diverse fields ranging from aging to diabetes to pharmaceutical development, and above all to the overarching quest to produce a grand map of cellular metabolism. Calorie restriction is of greatest interest outside the scientific community for the fact that it reliably slows aging and extends healthy life in most species and lineages tested to date. This effect, like all methods of slowing aging through altered metabolic state, is much more pronounced in short-lived species. The additional life gained as a proportion of life span falls as the species life span increases: we all know that calorie restriction in humans, while it produces impressive short-term benefits for basically healthy individuals that have yet to be matched by medical science, doesn't extend human life span by 40% or more as it does in mice. We would have noticed by now.

Messing with metabolism, however it is done, isn't a great approach to life extension. It has a limited upside, and has proven very hard and very expensive to achieve successfully via drug development. Calorie restriction itself already exists, however, is reliable, and even though it has a limited upside, it is free. Just as for exercise, it seems silly not to take advantage. The cost-benefit analysis for metabolic alteration via drugs is terrible because it will cost an enormous amount of time and money to produce results, and those resources would be better devoted to SENS rejuvenation research. The cost-benefit analysis for calorie restriction is completely different because it costs nothing and is here now - something for nothing, even if it is not much of a benefit in the grand scheme of things.

Moving away from considerations of enhanced longevity, inside the scientific community calorie restriction is perhaps of greatest interest as a reliable tool with which to interrogate the operation of cellular metabolism. The ability to reliably adjust that operation into a different stable state is very useful if the aim is to try to understand the function of this complex system. Two operating states provides points of comparison and analysis that don't exist for one state. This is of particular interest in aging research, and calorie restriction is used by some groups in much the same way as comparisons between species with different life spans: to try to identify important mechanisms relevant to aging and understand how the operation of metabolism determines natural variations in life span.

Nevertheless, some research groups are attempting to refine the application of calorie restriction as a formal treatment, largely to augment existing approaches to diabetes and cancer, as that is where the ability to raise funding best overlaps with potential benefits for patients. This involves a lot more careful categorization of short-term results for human calorie restriction, and a classification of different types of calorie restriction, some of which don't involve a reduction in overall calorie intake at all, but rather focus on timing and dietary content, such as intermittent fasting or protein restriction. The first of the papers linked here is a review along these lines:

Dietary restriction with and without caloric restriction for healthy aging

Caloric restriction is the most effective and reproducible dietary intervention known to regulate aging and increase the healthy lifespan in various model organisms, ranging from the unicellular yeast to worms, flies, rodents, and primates. However, caloric restriction, which in most cases entails a 20-40% reduction of food consumption relative to normal intake, is a severe intervention that results in both beneficial and detrimental effects. Specific types of chronic, intermittent, or periodic dietary restrictions without chronic caloric restriction have instead the potential to provide a significant healthspan increase while minimizing adverse effects. Improved periodic or targeted dietary restriction regimens that uncouple the challenge of food deprivation from the beneficial effects will allow a safe intervention feasible for a major portion of the population. Here we focus on healthspan interventions that are not chronic or do not require calorie restriction.

Newer antidiabetic drugs and calorie restriction mimicry

In rhesus monkeys unsurprisingly one of the most potent mechanisms of longevity was the reduction of cardiovascular risk factors and glucose intolerance in calorie-restricted monkeys. In the University of Wisconsin cohort, none of the individual calories restricted animals developed any degree of glucose impairment at the time of the interim analysis in contrast with the control monkeys who developed diabetes in a fairly good number. The animal data suggests the long-term CR in adult animals is a potent way to prevent the development of glucose impairment.

There are no comparable human studies with CR. Type 2 diabetes mellitus in humans is currently described as a progressive disease with a pathophysiology that involves over eight different organ systems. However, this understanding of disease does not really give a valid explanation to the reversibility and induction of normal glucose tolerance in patients with type 2 diabetes who undergo bariatric surgery. The improvements in glucose control happen within a few days after surgery much before there is any significant reduction in body weight. There are many explanations offered for early improvement in glucose tolerance like changes in gut hormone profile, changes in gut bacteria, etc., Both these overlook the most logical explanation for the phenomenon which is an acute profound decrease in calorie intake.

However, considering the difficulties in getting healthy adults to limit food intake science has focused on understanding the biochemical processes that accompany calorie restriction (CR) to formulate drugs that would mimic the effects of CR without the need to actually restrict calories. Drugs in this emerging therapeutic field are called CR mimetics. Some of the currently used anti-diabetic agents may have some CR mimetic like effects. This review focuses on the CR mimetic properties of the currently available anti-diabetic agents.

Sex difference in pathology of the ageing gut mediates the greater response of female lifespan to dietary restriction

Women live on average longer than men, but have greater levels of late-life morbidity. We have uncovered a substantial sex difference in the pathology of the ageing gut in Drosophila. The intestinal epithelium of the ageing female undergoes major deterioration, driven by intestinal stem cell (ISC) division, while lower ISC activity in males associates with delay or absence of pathology, and better barrier function, even at old ages. Males succumb to intestinal challenges to which females are resistant, associated with fewer proliferating ISCs, suggesting a trade-off between highly active repair mechanisms and late-life pathology in females. Dietary restriction reduces gut pathology in ageing females, and extends female lifespan more than male. By genetic sex reversal of a specific gut region, we induced female-like ageing pathologies in males, associated with decreased lifespan, but also with a greater increase in longevity in response to dietary restriction.

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways

Food intake and circadian rhythms are regulated by hypothalamic neuropeptides and circulating hormones, which could mediate the anti-ageing effect of calorie restriction (CR). We tested whether these two signaling pathways mediate CR by quantifying hypothalamic transcripts of male C57BL/6 mice exposed to graded levels of CR (10 % to 40 %) for 3 months. Hunger signaling, circadian rhythms and their downstream effects are far more complex than the results described here. Although limited by using a knowledge based signaling network, we were able to gain insights into the potential mechanisms underpinning the action of CR. Associations between gene expression and physiological outcomes such as body temperature and food anticipatory activity established by linear models and correlations are obviously only descriptive and causality cannot be assumed. Nevertheless these individual mice have been subjected to an unprecedented level of phenotyping allowing us to tie together the complex transcriptomic changes to alterations in body composition, circulating hormones and physiological outcomes.

Overall, our study has demonstrated that increasing levels of CR lead to a graded expression of genes involved in both hunger signaling and circadian rhythms. The expression of genes in these pathways wwere correlated with circulating levels of leptin, insulin, TNF-α and IGF-1, but not resistin or IL-6. We also demonstrated the phenotypic responses to CR (body temperature and physical activity) were significantly associated with the key hunger and core clock genes. Our results suggest that under CR modulation of the hunger and circadian signaling pathways, in response to altered levels of circulating hormones, drive some of the key phenotypic outcomes, such as activity and body temperature, which are probably important components of the longevity effects of CR.

There are many ways to extend life in short-lived nematode worms, but most overlap, being different ways to manipulate the same few core mechanisms. Everything in cellular biology connects to everything else, so isn't at all unexpected for there to be a dozen indirect ways to alter levels of any one particular protein, or alter the behavior of any one particular pathway. Much of the present focus in the aging research community involves mapping all of these methods so as to pin down the list of those core mechanisms, the most important ways in which metabolism determines variations in longevity between individuals and species. This actually has very little relevance to the future of human longevity and the development of rejuvenation treatments: those will emerge from efforts to repair the cell and tissue damage known to cause aging, an approach that will produce rejuvenation, not from altering the operation of metabolism to merely slightly slow down aging.

"We found that longevity can be extended by increasing the amount of a protein called arginine kinase-1 (ARGK-1). ARGK-1 maintains ATP availability within cells, and we suspect that increased levels trigger a fuel sensor, regulating energy homeostasis and extending lifespan." The research team identified ARGK-1 by comparing protein levels in normal worms to those in worms lacking S6 kinase (S6K), a genetic change that extends worm lifespan by at least 25%. Reduction of S6K proteins also extends lifespan significantly in several other organisms, including laboratory mice, showing that this pathway that controls aging is evolutionarily conserved. "ARGK-1 caught our attention because levels in S6K mutant worms were more than 30 times higher compared to normal worms. When we created normal worms that overexpressed ARGK-1, they also lived significantly longer, meaning that ARGK-1 on its own can extend life."

ARGK-1 and its mammalian equivalent, creatine kinase, are enzymes that transport energy in the form of phosphoarginine or phosphocreatine to various locations within cells. The research team found that, as in worms, creatine kinase levels are increased in the brains of mice lacking a similar S6K protein. "Our main goal in studying aging is not to find ways to extend human lifespan, but to understand the processes by which our cells and tissues become less functional over time. Such insight might allow us to develop better preventive care that improves overall health at advanced ages, or interventions that can slow or perhaps even prevent the progression of diseases associated with aging. For example, in cancer, some tumors highly activate S6K to feed tumor growth. Further work to understand the relationship between creatine kinase and S6K may lead to new avenues to pursue novel drugs for age-related diseases, including cancer."

Link: http://beaker.sbpdiscovery.org/2016/02/fine-tuning-cellular-energy-increases-longevity/

This is an illustrative example of the continued exploration of modest life extension via metabolic manipulation in short-lived animals. A lot of effort is spent on sifting through the existing catalog of known and approved drugs for those that might impact life span, something I consider to be a waste of time and effort from the point of view of producing therapies to extend life in humans. It is an important part of purely scientific efforts to map the interaction of metabolism and aging, however:

To identify drugs that delay age-related degeneration, we used the powerful Caenorhabdtitis elegans model system to screen for FDA-approved drugs that can extend the adult lifespan of worms. Here we show that captopril extended mean lifespan. Captopril is an angiotensin-converting enzyme (ACE) inhibitor used to treat high blood pressure in humans. To explore the mechanism of captopril, we analyzed the acn-1 gene that encodes the C. elegans homolog of ACE. Reducing the activity of acn-1 extended the mean life span. Furthermore, reducing the activity of acn-1 delayed age-related degenerative changes and increased stress resistance, indicating that acn-1 influences aging. Captopril could not further extend the lifespan of animals with reduced acn-1, suggesting they function in the same pathway; we propose that captopril inhibits acn-1 to extend lifespan.

To define the relationship with previously characterized longevity pathways, we analyzed mutant animals. The lifespan extension caused by reducing the activity of acn-1 was additive with caloric restriction and mitochondrial insufficiency, and did not require sir-2.1, hsf-1 or rict-1, suggesting that acn-1 functions by a distinct mechanism. The interactions with the insulin/IGF-1 pathway were complex, since the lifespan extensions caused by captopril and reducing acn-1 activity were additive with daf-2 and age-1 but required daf-16. Captopril treatment and reducing acn-1 activity caused similar effects in a wide range of genetic backgrounds, consistent with the model that they act by the same mechanism. These results identify a new drug and a new gene that can extend the lifespan of worms and suggest new therapeutic strategies for addressing age-related degenerative changes.

Link: http://dx.plos.org/10.1371/journal.pgen.1005866

In the open access paper I'll point out today, a group of researchers who focus on the phenomenon of cellular senescence present their argument for cellular senescence to be the central process in aging. It has to be said that I'm bullish on the clearance of senescent cells as a strong first step towards a toolkit of therapies for human rejuvenation, especially now that startup companies are working on it, but it is important to recognize that the accumulation of senescent cells is just one of a number of fairly independent mechanisms that contribute to aging. Yes, the damage caused by these mechanisms interacts, but the sources of that damage are very different. Removing one only helps to the degree that you have removed one. The others will still get you, because all of them are associated with at least one fatal age-related disease. You can take a look at the introduction to the SENS vision for rejuvenation therapies for a list of the forms of cell and tissue damage that contribute to degenerative aging.

I think we've all heard the fable of the blind men and the elephant deployed in connection with aging research. The life sciences are overwhelmingly populated by specialists, as biochemistry and medicine are both so very complex that productive work requires a narrow focus. Investigating one tiny area of cellular biochemistry can be the focus of an entire career. Even when you can see what you are doing, when poised two centimeters from an elephant's face, the creature is essentially a trunk - and maybe some other stuff back there that obviously can't be as important as the giant trunk occupying your field of vision. The elephant of aging is surrounded by hundreds of researchers, each of whom is focused intently upon a small piece of the whole. There are far too few generalists working to link parts of the field and make otherwise disconnected researchers aware that they are looking at the same biochemistry through different lenses.

In any case, this is a very long-winded way of saying that one should be cautious about any analysis that places one particular mechanism at the center of aging. It isn't at all clear to me that aging has a center, and the research community is still unable to say with confidence that any one of the the forms of cell and tissue damage listed in the SENS view of aging is more or less important than the others. The way we will find out which of the forms of age-related damage is the most important is by firstly developing the means to repair that damage and then secondly watching the results of repair therapies in animal models - which is exactly what is happening at the moment for senescent cell clearance. The try it and see approach will get to answers a lot faster than any of the much more analytical alternatives.

Cellular Senescence as the Causal Nexus of Aging

In 1881 the evolutionary biologist August Weismann proposed that "Death takes place because a worn-out tissue cannot forever renew itself, and because a capacity for increase by means of cell division is not everlasting but finite." How did he arrive at such a bold conclusion? Weismann observed that during evolution, simple multicellular organisms such as Pandorina Morum, which were immortal, gradually evolved into mortal organisms such as Volvox Minor. The absolutely crucial difference between these two organisms is that while Pandorina's cells were undifferentiated and divided without limit, Volvox's cells had differentiated into two very different types: the Somatic (body) cells, and the Germ (reproductive) cells. Thus, while the germ line has retained the capacity for infinite renewal, the body cells have not; they age and expire. While Weismann's hypotheses were remarkably prescient, at that time neither DNA nor cultured cells were sufficiently understood to allow his theory to be adequately tested. In fact, it was not until nearly one hundred years later, following the development of sophisticated animal cell culture protocols, that he was proven correct: it was shown that somatic cells grown in culture have limited growth potential. After approximately forty passages, human cells stop proliferating and undergo cellular senescence.

Besides Weismann's evolutionary theory, many additional theories have been proposed to explain the complexity of aging. These include the antagonistic pleiotropy theory, the free radical theory, age-associated shortening of telomeres, development of insulin resistance, decreased immune function, the mitochondrial theory, as well as deregulation of the circadian clock. While these theories indicate functional diversity in the etiology of aging, it must be stressed that each one relies on the concept of internal alterations in individual cells, and does not explain how the microscopic cellular damage manifests as macroscopic aging and tissue breakdown in the organism (with a few exceptions, such as changes in hormone function and declines in immune function). Theories of mutation accumulation and antagonistic pleiotropy address the genetic causes of aging, and environmental stress or lack of it contributes to modulation of the epigenome as well as physiological alterations in different tissues of the whole organism, but each theory revolves around the functional competence of different components of cells and again does not explain how this manifests as macroscopic organismal aging. Experimental evidence unifying the interactions of some components has started to emerge, but we propose that all of the changes described by diverse theories ultimately converge on the cellular senescence theory.

Since aging is a progressive condition that steadily advances from invisible to visible and localized to ubiquitous, the central question as to the direct cause of the entire process is key. The answer has been elusive due to its complex nature. Our model proposes that the process of aging results from a sequential passage through three distinct phases and can be described by the following blueprint: (1) molecular damage which results in (2) cessation of proliferation leading to cellular senescence followed by (3) body-wide aging of the organism. The first step occurs when localized, microscopic damage accumulates to a point where the burden to repair overwhelms the system. Despite the tissue source or broad input of molecular damage, crossing of this threshold results in the second phase, the crux of the entire process - arrest of cellular proliferation, acquisition of the senescence-associated secretory phenotype (SASP), and imminent cellular senescence. Once this occurs, the third phase of aging begins. This final phase is marked by tissue dysfunction and breakdown that results in the visible signs of comprehensive organismal aging.

The incremental advance proposed by our model is that while there are many undisputed factors that trigger the onset of cellular senescence and result in cessation of proliferation and SASP, the first phase in the model (cumulative molecular damage) is a precursor, rather than a final cause of aging. The complexity normally imposed by countless variables (i.e., age of onset, site of damage, affected cell type, mechanism of damage, and even species) that need to be overcome is rendered manageable by eliminating the first phase in the aging schematic. And since organismal aging can be artificially and reversibly induced by blocking and restarting cellular proliferation, this indicates that the second phase in the model - cessation of proliferation followed by cellular senescence - clearly represents the essential cause of aging. Placing cellular senescence in the pivotal junction between cause and effect, the causal nexus, to yield an integrated model of aging will serve to advance identification of crucial targets for future therapeutic investigation. By identifying cellular senescence as the causal nexus of aging, the process of treating, reversing and possibly even eventually eliminating this once inevitable outcome draws closer to reality.

Researchers here investigate one of the mechanisms by which the immune system recognizes senescent cells, targeting them for destruction. Accumulating numbers of senescent cells are one of the contributing causes of aging, and the age-related decline of the immune system probably accelerates this process in later life. In theory, given a good enough understanding of the biochemistry involved, it should be possible to greatly increase the efficiency with which the immune system destroys senescent cells. This is not the direction taken by the first companies to work on senescent cell clearance technologies, however, so this approach may never be developed, as it will prove to be unnecessary.

Senescent cells are specifically recognized and eliminated by natural killer (NK) cells. In this study we investigated the mechanisms which control the recognition of senescent cells by NK cells. We found that senescent cells up-regulate the expression of NKG2D ligands MICA and ULBP2 regardless of the senescence-inducing stimuli. The mechanisms regulating the expression of NKG2D ligands in senescent cells are partly attributed to a DNA damage response and activation of ERK activity. MICA and ULBP2 were found to be localized at the cell membrane where they can interact with NK cells to mediate efficient killing of senescent cells. Interaction of the ligands with the NKG2D receptor on the NK cells is necessary for the recognition of senescent cells by the NK cells in vitro. Importantly, NKG2D receptor-ligand interaction is essential for efficient elimination of senescent cells in vivo and thus for restraining fibrosis development. Overall, our findings demonstrate that NKG2D ligands on senescent cells are necessary for efficient recognition and elimination of senescent cells in vitro and during tissue damage in vivo.

The increase in expression of NKG2D ligands, particularly MICA and ULBP2, is likely a general feature of human senescent cells. A number of other studies have demonstrated the expression of MICA and/or ULBP2 in senescent cells derived from different cell types. Furthermore, senescent cells also acquire unique NKG2D ligand expression profiles consisting of several additional NKG2D ligands that result from differences between cell types (or cell-strains) and the mechanism by which senescence was induced. The repertoire of NKG2D ligands in mice is vast and similar to human cells, however based on sequence comparisons, mouse ligands are not homologous to the human ligands. Of note, NKG2D ligands are present on mouse cells that become senescent following p53 reactivation, and participate in the interaction of these cells with NK cells. In addition to their expression in senescent cells, NKG2D ligands are upregulated in other cell contexts related to cellular stress, including cancer, virally infected cells or following DNA damage. Therefore, the expression of these ligands might be part of a general stress response of cells that is utilized by senescent cells.

Our findings add to the emerging conceptual idea that the senescent program might represent a change in cell state that is associated with conversion to an immunogenic phenotype, functioning to remove damaged cells by immune clearance rather than through apoptosis. In addition to the upregulation of NKG2D ligands, the secretion of chemoattractants or the expression of adhesion molecules are further examples by which senescent cells become immunogenic. Immune clearance of senescent cells is likely beneficial in complex organisms where the regenerative capacity is dependent on non-resident stem cell populations and therefore temporal preservation of tissue architecture is necessary. Elimination of senescent cells following short-term insults, mediated by immune clearance, has physiological functions in tumor suppression and wound healing. Moreover, inefficient clearance might lead to the long-term persistence of senescent cells in tissues that has been associated with promotion of cancer development, ageing and age-related disease. Therefore, understanding the normal processes and mechanisms by which senescent cells are eliminated by the immune system will enable the formulation of conjectures concerning the mechanism responsible for impaired senescent cells elimination in later life. Such an understanding could lead to novel therapeutic strategies that enhance elimination of senescent cells by the immune system to improve tissue repair, cancer therapy and prevent deleterious effects of accumulation of senescent cells.

Link: http://www.impactaging.com/papers/v8/n2/full/100897.html

One of the interesting results that has emerged from the growing use of accelerometers in studies of exercise is that even small differences in activity levels have an noticeable correlation with mortality rates and life expectancy:

Even for people who already exercised, swapping out just a few minutes of sedentary time with some sort of movement was associated with reduced mortality. Researchers looked at data from approximately 3,000 people aged 50 to 79 who participated in the National Health and Nutrition Examination Survey (NHANES). For the study, subjects wore ultra-sensitive activity trackers, called accelerometers, for seven days. For these same people, the agency then tracked mortality for the next eight years. The results were striking. The least active people were five times more likely to die during that period than the most active people and three times more likely than those in the middle range for activity. "When we compare people who exercise the same amount, those who sit less and move around more tend to live longer. The folks who were walking around, washing the dishes, sweeping the floor tended to live longer than the people who were sitting at a desk."

Previous activity-tracking studies have drawn similar conclusions. But such studies usually ask participants to monitor their own exercise frequency and quantity, numbers they notoriously over-report. Also, the trackers used for NHANES have a higher level of precision than what's typically employed. "Because the device captures the intensity of activity so frequently, every minute, we can actually make a distinction between people who spent two hours a day doing those activities versus people who spent an hour and a half." To account for chronic conditions or illness influencing mortality rates, researchers statistically controlled for factors like diagnosed medical conditions, smoking, age and gender. They also completed a secondary examination from which they entirely excluded participants with chronic conditions. Though the scientists didn't discover any magic threshold for the amount a person needs to move to improve mortality, they did learn that even adding just 10 minutes per day of light activity could make a difference. Replacing 30 minutes of sedentary time with light or moderate-to-vigorous physical activity produced even better results.

Link: https://news.upenn.edu/news/new-penn-study-links-moving-more-decreased-mortality