Sleep Position Affects Brain Health

side sleeping

Sleeping in the lateral, or side position, as compared to sleeping on one’s back or stomach, may more effectively remove brain waste and prove to be an important practice to help reduce the chances of developing Alzheimer’s, Parkinson’s and other neurological diseases, according to researchers at Stony Brook University.

By using dynamic contrast magnetic resonance imaging (MRI) to image the brain’s glymphatic pathway, a complex system that clears wastes and other harmful chemical solutes from the brain, Stony Brook University researchers Hedok Lee, PhD, Helene Benveniste, MD, PhD, and colleagues, discovered that a lateral sleeping position is the best position to most efficiently remove waste from the brain. In humans and many animals the lateral sleeping position is the most common one. The buildup of brain waste chemicals may contribute to the development of Alzheimer’s disease and other neurological conditions. Their finding is published in the Journal of Neuroscience.

Dr. Benveniste, Principal Investigator and a Professor in the Departments of Anesthesiology and Radiology at Stony Brook University School of Medicine, has used dynamic contrast MRI for several years to examine the glymphatic pathway in rodent models. The method enables researchers to identify and define the glymphatic pathway, where cerebrospinal fluid (CSF) filters through the brain and exchanges with interstitial fluid (ISF) to clear waste, similar to the way the body’s lymphatic system clears waste from organs. It is during sleep that the glymphatic pathway is most efficient. Brain waste includes amyloid ? (amyloid) and tau proteins, chemicals that negatively affect brain processes if they build up.

In the paper, “The Effect of Body Posture on Brain Glymphatic Transport,” Dr. Benveniste and colleagues used a dynamic contrast MRI method along with kinetic modeling to quantify the CSF-ISF exchange rates in anesthetized rodents’ brains in three positions ? lateral (side), prone (down), and supine (up).

“The analysis showed us consistently that glymphatic transport was most efficient in the lateral position when compared to the supine or prone positions,” said Dr. Benveniste. “Because of this finding, we propose that the body posture and sleep quality should be considered when standardizing future diagnostic imaging procedures to assess CSF-ISF transport in humans and therefore the assessment of the clearance of damaging brain proteins that may contribute to or cause brain diseases.”

Dr. Benveniste and first-author Dr. Hedok Lee, Assistant Professor in the Departments of Anesthesiology and Radiology at Stony Brook developed the safe posture positions for the experiments. Their colleagues at the University of Rochester, including Lulu Xie, Rashid Deane and Maiken Nedergaard, PhD, used fluorescence microscopy and radioactive tracers to validate the MRI data and to assess the influence of body posture on the clearance of amyloid from the brains.

“It is interesting that the lateral sleep position is already the most popular in human and most animals ? even in the wild ? and it appears that we have adapted the lateral sleep position to most efficiently clear our brain of the metabolic waste products that built up while we are awake,” says Dr. Nedergaard. “The study therefore adds further support to the concept that sleep subserves a distinct biological function of sleep and that is to ‘clean up’ the mess that accumulates while we are awake. Many types of dementia are linked to sleep disturbances, including difficulties in falling asleep. It is increasing acknowledged that these sleep disturbances may accelerate memory loss in Alzheimer’s disease. Our finding brings new insight into this topic by showing it is also important what position you sleep in,” she explained.

Dr. Benveniste cautioned that while the research team speculates that the human glymphatic pathway will clear brain waste most efficiency when sleeping in the lateral position as compared to other positions, testing with MRI or other imaging methods in humans are a necessary first step.

Reference: “The Effect of Body Posture on Brain Glymphatic Transport” The Journal of Neuroscience, 5 August 2015, 35(31): 11034-11044; DOI: 10.1523/JNEUROSCI.1625-15.2015

Weight Loss on a Low Fat vs. Low Carbohydrate Diet

A study from the US National Institutes of Health presents some of the most precise human data yet on whether cutting carbs or fat has the most benefits for losing body fat. In a paper published August 13 in Cell Metabolism, the researchers show how, contrary to popular claims, restricting dietary fat can lead to greater body fat loss than carb restriction, even though a low-carb diet reduces insulin and increases fat burning.

Since 2003, Kevin Hall, Ph.D. is a physicist turned metabolism researcher at the National Institute of Diabetes and Digestive and Kidney Diseases who has been using data from dozens of controlled feeding studies conducted over decades of nutrition research to build mathematical models of how different nutrients affect human metabolism and body weight.

He noticed that despite claims about carbohydrate versus fat restriction for weight loss, nobody had ever measured what would happen if carbs were selectively cut from the diet while fat remained at a baseline or vice versa. His model simulations showed that only the carb-restricted diet would lead to changes in the amount of fat burned by the body, whereas the reduced-fat diet would lead to greater overall body fat loss, but he needed the human data to back it up.

“A lot of people have very strong opinions about what matters for weight loss, and the physiological data upon which those beliefs are based are sometimes lacking,” Hall says. “I wanted to rigorously test the theory that carbohydrate restriction is particularly effective for losing body fat since this idea has been influencing many people’s decisions about their diets.”

Studying the effects of diet on weight loss is often confounded by the difficulty in measuring what people actually eat since participants may not adhere to meal plans, misjudge amounts, or are not truthful in follow-up surveys. To counter this, Hall and colleagues confined 19 consenting adults with obesity to a metabolic ward for a pair of 2-week periods, over the course of which every morsel of food eaten was closely monitored and controlled.

To keep the variables simple, the two observation periods were like two sides of a balance scale: during the first period, 30% of baseline calories were cut through carb restriction alone, while fat intake remained the same. During the second period the conditions were reversed. Each day, the researchers measured how much fat each participant ate and burned and used this information to calculate the rate of body fat loss.

At the end of the two dieting periods, the mathematical model proved to be correct. Body fat lost with dietary fat restriction was greater compared with carbohydrate restriction, even though more fat was burned with the low-carb diet. However, over prolonged periods the model predicted that the body acts to minimize body fat differences between diets that are equal in calories but varying widely in their ratio of carbohydrate to fat.

“There is one set of beliefs that says all calories are exactly equal when it comes to body fat loss and there’s another that says carbohydrate calories are particularly fattening, so cutting those should lead to more fat loss,” Hall says. “Our results showed that, actually, not all calories are created equal when it comes to body fat loss, but over the long term, it’s pretty close.”

Hall does caution against making sweeping conclusions about how to diet from this study. The study’s purpose was to explore the physiology of how equal calorie reductions of fat versus carbs affect the human body. The research is limited by its sample size; only 19 people could be enrolled due to the expense of such research and the restrictiveness of the carefully controlled protocol. However, this study clearly reaches statistical significance. In addition,, the menu that the participants followed does not emulate normal dieting and does not account for what diet would be easier to eat over extended periods.

“We are trying to do very careful studies in humans to better understand the underlying physiology that will one day be able to help generate better recommendations about day to day dieting,” Hall says. “But there is currently a gap between our understanding of the physiology and our ability to make effective diet recommendations for lasting weight loss.”

Hall recommends that for now, the best diet is the one that you can stick to. His lab will next investigate how reduced-carbohydrate and reduced-fat diets affect the brain’s reward circuitry, as well as its response to food stimuli. He hopes these results might inform why people respond differently to different diets.

Cellular Rejuvenation Factors Suppress Old Mitochondria

Scientists from A*STAR’s Genome Institute of Singapore (GIS) have discovered metabolic rejuvenation factors in eggs. This critical finding furthers our understanding of how cellular metabolism changes during aging, and during rejuvenation after egg fertilization.

When a sperm fertilizes an egg to create a baby, two adult cells combine to form a new embryo. A similar process of combining an egg’s cytoplasm with an adult cell nucleus led to the cloning of Dolly the sheep. However, the metabolic factors underlying this fascinating process had remained unclear.

A new study from GIS suggests that old mitochondria — the oxygen-consuming metabolic engines in cells — are roadblocks to cellular rejuvenation. By tuning up a gene called Tcl1, which is highly abundant in eggs, researchers were able to suppress old mitochondria to enhance a process known as somatic reprogramming, which turn adult cells into embryonic-like stem cells.

GIS researchers found that Tcl1 does its job by suppressing mitochondrial polynucleotide phosphorylase, thereby inhibiting mitochondrial growth and metabolism.

Findings from the study were published in the scientific journal Cell Reports.

Stem cell researchers had known that egg (or oocyte) cytoplasm contains some special unknown factors that can reprogram adult cells into embryonic-like stem cells, either during egg-sperm fertilization or during artificial cloning procedures like those that created Dolly the sheep. While the Nobel Prize winner Dr. Shinya Yamanaka had invented a technology called induced pluripotent stem cell (iPSC) reprogramming to replace the ethically controversial oocyte-based reprogramming technique, oocyte-based reprogramming was still deemed superior in complete cellular reprogramming efficiency.

To address this shortfall, the GIS team led by Dr Khaw Swea-Ling, Dr Lim Bing and Dr. Ng Shyh-Chang combined oocyte factors with the iPSC reprogramming system. Their bioinformatics-driven screening efforts led to two genes: Tcl1 and its cousin Tcl1b1. After a deeper investigation, the team found that the Tcl1 genes were acting via the mitochondrial enzyme, PnPase.

“We were quite surprised, because nobody would have thought that the key to the oocyte’s reprogramming powers would be a mitochondrial enzyme. The stem cell field’s conventional wisdom suggests that it should have been some other signaling genes instead,” said corresponding author of the research, Dr Ng Shyh-Chang.

Tcl1 is a cytoplasmic protein that binds to the mitochondrial enzyme PnPase. By locking PnPase in the cytoplasm, Tcl1 prevents PnPase from entering mitochondria, thereby suppressing its ability to promote mitochondrial growth and metabolism. Thus, an increase in Tcl1 suppresses old mitochondria’s growth and metabolism in adult cells, to enhance the somatic reprogramming of adult cells into embryonic-like stem cells.

Cracking the mystery of reprogramming factors in oocytes is an important milestone. These new insights could boost efficacy of the alternative, non-oocyte-based iPSC techniques for stem cell banking, organ and tissue regeneration, as well as further our understanding of how cellular metabolism rejuvenates after egg-sperm fertilization. This could help address both the aging and the fertility problems of modern societies.

GIS Executive Director Prof Ng Huck Hui said, “This is an exciting step forward in the study of cellular aging. Although accumulated defects in mitochondrial metabolism were known to cause cellular aging, no solutions were available. Shyh-Chang’s team has uncovered a molecular pathway to solve this problem.”

The above post is reprinted from materials provided by The Agency for Science, Technology and Research (A*STAR).

Skin Cell Reprogrammed into Neurons Without Genetic Engineering

Two labs in China have independently succeeded in transforming skin cells into neurons using only a cocktail of chemicals, with one group using human cells from humans and the other group using cells from mice. The two studies reinforce the idea that a purely chemical approach is a promising way to scale up cell reprogramming research that may avoid the technical challenges and safety concerns associated with the more popular method of using transcription factors. Both papers appear on August 6 in the journal Cell Stem Cell.

The importance of these studies is that they were able to change skin cells into neurons without using genetic engineering. This has already been done many times by adding new genes to cells, however that approach creates significant risks if they are used for actual human therapy since the DNA has been changed in ways that may have unknown consequences in the long run.

One of the challenges of forcing cells to change identity is that the cells you end up with may look normal but have different internal activities than their naturally forming counterparts. The two papers provide evidence that similar gene expression, action potentials, and synapse formation can be detected in transcription-factor-induced neurons as those generated from the chemical cocktails. (Both groups used mixtures of seven small molecules, but different recipes–outlined in detail in the supplemental information section of each paper–because they focused on different species.)

“We found that the conversion process induced by our chemical strategy is accompanied by the down-regulation of [skin-cell] specific genes and the increased expression of neuronal transcription factors,” said human study co-author Jian Zhao, of the Shanghai Institutes for Biological Sciences and Tongji University. “By coordinating multiple signaling pathways, these small molecules modulate neuronal transcription factor gene expression and thereby promote the neuronal cell transition.” The authors add that the direct conversion bypasses a proliferative intermediate progenitor stage, which circumvents safety issues posed by other reprogramming methods.

Zhao’s paper, co-led with cell biologist Gang Pei, also shows that the pure chemical protocol can be used to make neurons from the skins cells of Alzheimer’s patients. Most of the work using patient stem cells has been done by using transcription factors–molecules that affect which genes are expressed in a cell–to create induced pluripotent stem cells. Chemical cell reprogramming is seen as an alternative for disease modeling or even potential cell replacement therapy of neurological disorders, but the “proof-of-concept” is still emerging.

“In comparison with using transgenic reprogramming factors, the small molecules that are used in this chemical approach are cell permeable; cost-effective; and easy to synthesize, preserve, and standardize; and their effects can be reversible,” says mouse study co-author Hongkui Deng of the Peking University Stem Cell Research Center. “In addition, the use of small molecules can be fine-tuned by adjusting their concentrations and duration, and the approach bypasses the technical challenges and safety concerns of genetic manipulations, which may be promising in their future applications.”

Deng worked for four years with Zhen Chai and Yang Zhao, also of Peking University, to identify the small molecules that could create chemically induced mouse neurons. Researchers had been close for years, but a transcription factor was always necessary to complete the transformation. Through many chemical screens they identified the key ingredient, I-BET151, which works to suppress transcription in skin cells. They then found the right steps and conditions to mature the neurons post-transformation.

The authors of both papers aim to learn more about the biology behind chemically induced reprogramming and to make the protocols more efficient. While their success is promising, there are still a number of hurdles to overcome.

“We hope in the future that the chemical approaches would be more robust in inducing functional mature neurons,” Deng says. “In addition, we are attempting to generate specific neuronal subtypes and patient-specific functional neurons for translational medicine by using pure chemicals.”

Jian Zhao, of the human study, says: “It should be possible to generate different subtypes of neurons with a similar chemical approach but using slightly modified chemical cocktails.” She adds: “It also needs to be explored whether functional neurons could be induced by chemical cocktails in living organisms with neurological diseases or injury.”

References:

1.Wenxiang Hu, Binlong Qiu, Wuqiang Guan, Qinying Wang, Min Wang, Wei Li, Longfei Gao, Lu Shen, Yin Huang, Gangcai Xie, Hanzhi Zhao, Ying Jin, Beisha Tang, Yongchun Yu, Jian Zhao, Gang Pei. Direct Conversion of Normal and Alzheimer?s Disease Human Fibroblasts into Neuronal Cells by Small Molecules. Cell Stem Cell, 2015; 17 (2): 204 DOI: 10.1016/j.stem.2015.07.006

2.Xiang Li, Xiaohan Zuo, Junzhan Jing, Yantao Ma, Jiaming Wang, Defang Liu, Jialiang Zhu, Xiaomin Du, Liang Xiong, Yuanyuan Du, Jun Xu, Xiong Xiao, Jinlin Wang, Zhen Chai, Yang Zhao, Hongkui Deng. Small-Molecule-Driven Direct Reprogramming of Mouse Fibroblasts into Functional Neurons. Cell Stem Cell, 2015; 17 (2): 195 DOI: 10.1016/j.stem.2015.06.003

Higher Carotenoid Intake Associated With Lower Lipid Oxidation and DNA Damage

Lending fruits and vegetables their bright orange, red, and yellow colors, carotenoids are abundant in antioxidants, for which previous studies have associated a lower risk of premature death. A recent study assessed the potential relationships of carotenoid intake with lipid and oxidative stress markers in middle-aged men. Data analysis revealed that higher total carotenoid intake was associated with lower lipid and oxidative stress markers, and in middle-aged men higher beta-carotene intake was also associated with five of the six lower lipid stress markers.

If you decide to obtain beta-carotene from a nutritional supplement be sure and use one that is derived from carrots, algae and other natural sources rather than synthetic beta-carotene which has been associated with some negative effects in a previous study.

A total of 296 apparently healthy middle-aged men with a mean age of 50.5 years and a mean BMI of 25.8 kg/m2 were recruited to participate in the study. Dietary intake, anthropometry, blood pressure, lifestyle features, blood and urine biomarkers were assessed using validated procedures. The lipid markers included NEFA, Castelli index, and TAG:HDL ratio; oxidative stress markers included urinary 8-hydroxy-2-deoxyguanosine (8-OHdG), 8-iso-PGF2 and plasma oxidised-LDL (ox-LDL). The scientists observed a significant inverse association (P< 0?05) between NEFA concentrations and consumption of lutein plus zeaxanthin, alpha-carotene, beta-carotene and total carotenoid, while the Castelli index was negatively associated with daily intake of lycopene, beta-carotene and total carotenoids. Regarding oxidative stress biomarkers, urinary 8-OHdG and ox-LDL concentrations were also inversely associated (P< 0?05) with consumption of lycopene, lutein plus zeaxanthin, alpha-carotene, beta-carotene and total carotenoids, regardless of confounding variables. Moreover, there was a negative association of urinary 8-iso-PGF2 concentration with dietary lutein plus zeaxanthin and with the sum of all carotenoids. In conclusion, higher total daily carotenoid intake based on five investigated carotenoid types (beta-cryptoxanthin, lycopene, lutein plus zeaxanthin, alpha-carotene and beta-carotene) was associated with lower relevant lipid and oxidative stress markers in middle-aged men, with emphasis on beta-carotene that was negatively associated with five of the six lipid and oxidative stress markers evaluated in the present study.

Mystery of Liver Stem Cells Solved

Howard Hughes Medical Institute (HHMI) scientists have identified stem cells in the liver that give rise to functional liver cells. The work solves a long-standing mystery about the origin of new cells in the liver, which must constantly be replenished as cells die off, even in a healthy organ.

“We’ve solved a very old problem,” says Roel Nusse, an HHMI investigator at Stanford University who led the research. “We’ve shown that like other tissues that need to replace lost cells, the liver has stem cells that both proliferate and give rise to mature cells, even in the absence of injury or disease.” Nusse and his colleagues reported their findings August 5, 2015, in the journal Nature.

The liver is made up mostly of hepatocytes, highly specialized cells that carry out the organ’s many tasks, including storing vitamins and minerals, removing toxins, and helping regulate fats and sugars in the bloodstream. As these cells die off, they are replaced by healthy new hepatocytes. The source of those new cells had never been identified, Nusse says.

Stem cells, which replenish their own populations and maintain the ability to develop into more specialized cells, provide new cells in the skin, blood, and other tissues where cells are naturally lost over time. But no stem cells had been found in the liver. Some scientists speculated that mature hepatocytes might maintain their populations by dividing. But Nusse says the mature cells have become so specialized to carry out the work of the liver, they have likely lost the ability to divide.

“Differentiated hepatocytes have amplified their chromosomes,” he explains. That is, the cells have more than the usual two copies of every chromosome. “This enables the cells to make more proteins, but it really compromises their ability to divide.”

Nusse’s lab at Stanford focuses on a family of proteins of called Wnts, which are key regulators of stem cell fate. To find and follow stem cells in a variety of tissues, they have developed mice in which cells that respond to the Wnt signal are labeled with a fluorescent protein. Several years ago, they decided to use the mice to search for stem cells in the liver.

Bruce Wang, a gastroenterologist at the Liver Center at the University of California, San Francisco, led the experiments as a visiting scholar in Nusse’s lab. Wang began by searching for fluorescently labeled, Wnt-responsive cells in the livers of the engineered mice, and he ultimately found them clustered around the liver’s central vein.

Once they knew which cells to focus on, the scientists tracked the fluorescently labeled cells’ behavior. Over time, they noticed that the cells they were tracking divided rapidly, steadily replenishing their own population. This was possible because unlike mature hepatocytes, the labeled cells had only two copies of each chromosome. By following the descendents of the stem cells for up to a year, the scientists discovered that these had changed, taking on the specialized features and amplified genomes of mature hepatocytes. “This fits the definition of stem cells,” Nusse says.

As expected, the liver stem cells required Wnt signals to maintain their stem cell identity. Nusse’s team discovered that endothelial cells lining the central vein, the blood vessel around which the stem cells were clustered, released Wnt molecules into the tissue. Stem cells that migrated out of reach of that signal quickly lost their ability to divide into new stem cells and began to develop into mature hepatocytes. Nusse says this is consistent with how stem cells are known to behave in other tissues.

The lab is now investigating how the newly identified stem cells might contribute to regeneration of liver tissue after injury. It will also be important to explore whether liver cancers tend to originate in these replicating cells, as opposed to more mature hepatocytes, Nusse says.

The above post is reprinted from materials provided by Howard Hughes Medical Institute. Note: Materials may be edited for content and length.

Better to Avoid Melamine Tableware

melamine tableware

With their vibrant colors and breakage resistance, melamine plates, bowls, and cups are becoming popular. A number of previous studies suggest that heat and acid can cause melamine from dinnerware to seep into food ? leading to increased risks of urinary stones and kidney problems. Ming-Tsang Wu, from Kaohsiung Medical University (Taiwan), and colleagues propose that a substitution can dramatically reduce this potential exposure problem. The researchers first measured melamine levels in the urine of study subjects and then substituted stainless steel boxes and silverware for their hot meals. The melamine levels in their urine decreased after using the containers by as much as 92%. The study authors write that:” Regular use of stainless steel-made meals boxes can mitigate melamine exposure from melamine tableware.”

In 2008, the health effects of acute melamine exposure became widely known when a scandal erupted in China over the material’s use in milk powder. About 300,000 people were sickened, and more than 50,000 babies were hospitalized. Although officials largely stamped out the practice of adding melamine to food, most people continue to be exposed to the substance, an industrial chemical also used in other plastics, flooring and whiteboards. Some research has suggested that even small amounts could increase the risk of urinary stones or kidney problems, and one major source of the material is tableware. Ming-Tsang Wu and colleagues wanted to see what kinds of practices could lower people’s exposure.

The researchers first measured melamine levels in the urine of study subjects and then gave them stainless steel boxes and silverware for their hot meals. The melamine levels in their urine decreased after using the containers by 41 to 92 percent. The wide range could be due to subjects’ exposure to other uncontrolled sources of the substance, the researchers say.

Automating the Production of IPS Cells

Ten years ago there was a lot of controversy about the use of human embryonic stem cells in scientific research. The problem was solved with the creation of IPS Cells (induced pluripotent stem cells) which are made by turning adult skin or other cells back into embryonic like stem cells. The process has been time consuming and manual so robotic equipment has now been produced to make it much faster and more efficient.

The New York Stem Cell Foundation designed and has built a revolutionary, high-throughput robotic platform that automates and standardizes the process of transforming patient samples into stem cells. This one-of-a-kind system addresses challenges that face the entire field, and is now an essential resource that NYSCF provides in collaborations with leading academic and industry partners around the world.

In the paper published in Nature Methods, NYSCF scientists demonstrated how the NYSCF Global Stem Cell Array?, for the first time ever, gives researchers the scale to look at diverse populations and draw meaningful conclusions. This breakthrough technology will allow researchers to better understand the underlying causes of disease and, ultimately, create individually tailored treatments for patients.

Induced pluripotent stem cells (iPSCs) are an essential tool for modeling how causal genetic variants impact cellular function in disease, as well as an emerging source of tissue for regenerative medicine. The preparation of somatic cells, their reprogramming and the subsequent verification of iPSC pluripotency are laborious, manual processes limiting the scale and reproducibility of this technology. This process can not be automated using a modular, robotic platform for iPSC reprogramming, high-throughput conversion of skin biopsies into iPSCs and differentiated cells with minimal manual intervention. Automated reprogramming and the pooled selection of polyclonal pluripotent cells results in high-quality, stable iPSCs. These lines display less line-to-line variation than either manually produced lines or lines produced through automation followed by single-colony subcloning. The robotic platform will enable the application of iPSCs to population-scale biomedical problems including the study of complex genetic diseases and the development of personalized medicines.

Scientists Say They Will Soon Extend Human Lifespan Well Beyond 120 Years

Each new paradigm goes through three stages. The first is outright rejection, the second is discussion and the third is when it is accepted as self evident. For development of significant life extension technologies we are now in the second stage. Even five years ago the scientific consensus was that aging research was interesting but unlikely to lead to anything practical. Now Google is funding it’s Calico life extension startup with hundreds of millions of dollars and a number of other billonaires and Silicon Valley startups are also seriously funding or working on anti-aging research.

At Life Code we have taken the approach of using the scientific knowledge that is already available to develop nutraceutical supplements to help extend both the quality and quantity of life now. Combining these with a healthy diet and exercise program will yield even better results. We want to enjoy life as we get older and not end up shuffling around a nursing home with a walker. We also want to be alive when even more effective anti-aging therapies become available whether from our parent biotechnology companies or from others.

An excellent article with the title Live for ever: Scientists say they?ll soon extend life ?well beyond 120? appeared in the Guardian earlier this year. It gives an overview of some of the high profile people involved with life extension research.

Scientists Discover When Aging Begins

When does aging really begin? Two Northwestern University scientists now have a molecular clue. In a study of the transparent roundworm C. elegans, they found that adult cells abruptly begin their downhill slide when an animal reaches reproductive maturity.

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. The switch is thrown by germline stem cells in early adulthood, after the animal starts to reproduce, ensuring its line will live on.

While the studies were conducted in worms, the findings have implications for humans, the researchers report. The genetic switch and other components identified by the scientists as playing a role in aging are conserved in all animals, including humans, offering targets for future study. (C. elegans has a biochemical environment similar to that of humans and is a popular research tool for the study of the biology of aging and as a model of human disease.)

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases.

“Wouldn’t it be better for society if people could be healthy and productive for a longer period during their lifetime?” said Richard I. Morimoto, the senior author of the study. “I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress.”

Morimoto is the Bill and Gayle Cook Professor of Molecular Biosciences and director of the Rice Institute for Biomedical Research in Northwestern’s Weinberg College of Arts and Sciences.

The study, built on a decade of research, will be published in the July 23 issue of the journal Molecular Cell. Johnathan Labbadia, a postdoctoral fellow in Morimoto’s lab, is the first author of the paper.

In C. elegans, the decline begins eight hours into adulthood — all the switches get thrown to shut off an animal’s cell stress protective mechanisms. Morimoto and Labbadia found it is the germline stem cells responsible for making eggs and sperm that control the switch.

In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so Morimoto and Labbadia looked specifically at the heat shock response in the life of C. elegans.

“We saw a dramatic collapse of the protective heat shock response beginning in early adulthood,” Morimoto said.

Morimoto and Labbadia found the genetic switch occurs between two major tissues in an organism that determine the future of the species: the germline and the soma (the body tissues of the animal, such as muscle cells and neurons). Once the germline has completed its job and produced eggs and sperm — necessary for the next generation of animals — it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal.

“C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was,” Morimoto said.

“In a system where we can actually do the experiments, we discover a switch that is very precise for aging,” he said. “All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses.”

Using a combination of genetic and biochemical approaches, Morimoto and Labbadia found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. The animals still appear normal in behavior, but the scientists can see molecular changes and the decline of protein quality control.

In one experiment, the researchers blocked the germline from sending the signal to turn off cellular quality control. They found the somatic tissues remained robust and stress resistant in the adult animals.

“This was fascinating to see,” Morimoto said. “We had, in a sense, a super stress-resistant animal that is robust against all kinds of cellular stress and protein damage. This genetic switch gives us a target for future research.”

Reference: Johnathan Labbadia, Richard I. Morimoto. Repression of the Heat Shock Response Is a Programmed Event at the Onset of Reproduction. Molecular Cell, 2015; DOI: 10.1016/j.molcel.2015.06.027