How African turquoise killifish press the pause button on aging

 African turquoise killifish embryos put organ development on hold during a state of suspended growth called diapause. Organs like the brain, eyes and ears (pictured in a developmentally suspended embryo) enter diapause with multiple cell types, such as precursor nerve cells (pink), glial cells (blue) and mature nerve cells (green).

CHI-KUO HU

The fish can double their life span by temporarily halting cell and organ growth while embryos

By Erin Garcia de Jesus

When the ponds where one African fish lives dry up, its offspring put their lives on pause. And now researchers have a sense for how the creatures do it.  

African turquoise killifish embryos can halt their development during a state of suspended activity called diapause. Now a study shows that the embryos effectively don’t age while in that state. Genetic analyses reveal that, to stay frozen in time, the embryos put functions such as cell growth and organ development on hold, researchers report in the Feb. 21 Science.

“Nature has identified ways to pause the clock,” says Anne Brunet, a geneticist Stanford University. Knowing how killifish pause their lives could help scientists figure out how to treat aging-related diseases or learn how to preserve human organs long-term, she says.

Nematode worm larvae (Caenorhabditis elegans) can also halt development and aging when faced with a lack of food or if their environment is overcrowded. Invertebrates like nematodes, however, lack many of the features that make other animals age, such as an adaptive immune system. More than 130 species of mammals from mice to bears also have some form of diapause.

The killifish (Nothobranchius furzeri) live in ponds in Mozambique and Zimbabwe that disappear for months during the dry season, leaving the fish without a home until the rain returns (SN: 8/6/18). For adults that typically live only four to six months anyway, vanishing ponds don’t pose much of a threat. But some killifish embryos press pause on their development during dry months, until ponds fill up again. 

Killifish advance from colorful, young fish to pale, old fish within a few months, making them a good animal for scientists to use to study aging.CHI-KUO HU

Killifish embryos can put their growth on hold from five months up to two years, matching or even greatly exceeding their typical adult life span. If humans could do something similar, an 80-year-old person might instead have a life span from 160 to more than 400 years, Brunet says. But if, or how, these animals protect themselves from aging while in this limbo was unknown.

In the study, Brunet and her colleagues compared killifish embryos that halted their growth with those that bypassed diapause and hatched into adults. Diapause didn’t decrease an adult fish’s growth, life span or ability to reproduce — a sign that the animal didn’t age, even if it paused its development for longer than its typical lifetime, the researchers found.

The team then analyzed the genetic blueprint of embryos suspended in diapause to determine which genes were active. Although the young killifish had developing muscles, hearts and brains before diapause, genes involved in organ development and cell proliferation were subsequently turned off. But other genes were cranked up, such as some crucial for turning other sets of genes on or off.

Killifish embryos (one pictured) can pause their development for a few months or up to two years during a state of suspended activity called diapause.CHI-KUO HU

One gene, the chromobox 7 gene, or CBX7, repressed genes involved in metabolism, but turned on those important for maintaining muscle and staying in diapause, the researchers found. Embryos without CBX7 came out of diapause sooner, and their muscles began to deteriorate after one month.

The new study shows that the embryos aren’t passively waiting for better environmental conditions — their cells coordinate responses during diapause that protect killifish from the passage of time. “We have always looked at this diapause state as more passive — nothing happens there,” says Christoph Englert, a molecular geneticist at the Leibniz Institute on Aging in Jena, Germany, who wasn’t involved in the work. But the new research “shifts the paradigm of diapause as a passive, boring state to an active state of embryonic nondevelopment.”

Researchers aren’t sure how things like temperature might spark a developing killifish to begin or end diapause. But understanding what’s going on inside an embryo is a step toward pinpointing how external signals might control when the animals suspend time, Englert says.      

CITATIONS

C.K. Hu et al. Vertebrate diapause preserves organisms long term through Polycomb complex members. Science. Vol 367, February 21, 2020, p. 870. doi:10.1126/science.aaw2601.

About Erin Garcia de Jesus

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Erin I. Garcia de Jesus is the Winter 2019 science writing intern at Science News. She holds a PhD in microbiology from the University of Washington and went on to earn a master’s in science communication from the University of California, Santa Cruz.

FAVORITE IMAGES OF THE WEEK - 10

Kevin Hand (JPL/Caltech), Jack Cook (Woods Hole Oceanographic Institution), Howard Perlman (USGS)

Europa's Water

Here's what Earth (right) and Jupiter's moon Europa (left) would look like if all the water was removed and shaped into a lovely blue sphere. Europa's ocean is two to three times larger than our own. Read more here.

Libero Rutilo

The Green Wheel

This hydroponic wheel was actually, according to FastCoDesign, thought up by NASA back in the 1980s as a way to grow plants in space. It was never actually made, for some reason, but designer Libero Rutilo brought it back in this mockup. Seems like it's work well in apartments as well!

RayFish Footwear

Stingray Leather

We're pretty sure this isn't possible for a few reasons--like, we haven't sequenced the stingray's genome, and it seems unlikely that we'd have this level of control anyway--but a company called RayFish is attempting to offer a customized shoe made of genetically modified stingray leather. You pick what you want the stingray to look like, RayFish creates said stingray, then kills it, skins it, and makes shoes out of it. Just for you! It's weird. Read more here.

EPFL/Grégoire Courtine via Reuters

Run Rat Run

This rat may be running a little oddly, but remember what happened to it--this rat was previously paralyzed, and a combination of drugs actually enabled it to walk again. Read more about it here, and don't forget to check out American Photo Mag for more amazing photojournalism like this.

X-ray: NASA/CXC/SAO; IR & UV: NASA/JPL-Caltech; Optical: NASA/STScI

Pinwheel Galaxy

The Pinwheel Galaxy, located in Ursa Major, is about 21 million light-years from Earth--but we can still enjoy its cheerfulness. Read more here.

Jennifer R.S. Gordon and Joaquin C. Brieva

Half Aged

This guy is a truck driver, 69 years old, who's been exposed to 25 years of direct sunlight thanks to his job--but only on the left side of his face. So we get a first-hand view at how much more aged human skin looks when bombarded with sunlight over the years. Crazy. [via Gizmodo]

What Causes Waking Up Too Early Among Older People?

Disrupted Sleep and Insomnia May Occur Due to Sleep Apnea, Circadian Changes

If you are an older person who wakes up too early in the morning, you may wonder what causes you to do so.

Aging may contribute to multiple unique conditions that worsen sleep in the retirement years and among the elderly. Discover some of the potential causes of early morning awakenings, including contributors to insomnia such as circadian rhythm and melatonin production changes, advanced sleep phase syndrome, dementia, untreated sleep apnea, mood disorders like depression, and even going to bed too early.

Understanding the Nature of Insomnia

Not everyone who wakes up too early suffers from insomnia. Insomnia is defined as difficulty falling asleep or returning to sleep after an awakening. It may lead to prolonged periods of wakefulness and may make sleep less refreshing. It may cause impairment during the daytime, including symptoms of fatigue as well as worsening mood, concentration, short-term memory, and pain complaints. There are many potential causes of insomnia.

It is normal to wake up at night. If the awakening is brief, it may be easy to return to sleep. Unfortunately, awakenings towards morning may come at a time when it is difficult to get back to sleep. This is because the sleep drive, a desire for sleep dependent on the levels of a chemical called adenosine in the brain, has been greatly diminished. Many times an awakening toward morning results in the affected person simply staying awake the rest of the night.

What causes early morning awakenings to occur? To better answer this question, it may be helpful to explore the corresponding system that enhances our ability to sleep overnight.

The Role of Circadian Rhythms and Melatonin in Aging

Beyond sleep drive, the circadian alerting signal is imperative to determining the patterns of sleep and wakefulness.

In particular, it helps to coordinate the timing of sleep to occur during the natural period of darkness. An area of the brain called the suprachiasmatic nucleus (SCN) in the hypothalamus directs this rhythm. It lies close to the optic nerves that extend from the eyes to the brain. As such, it is heavily influenced by light input.

Light, especially morning sunlight, has a strong influence on the circadian rhythm. It reinforces waking. If an organism lives in an exposed environment, it may not be safe to remain asleep when it is daytime. Light helps to adjust the timing of sleep. This also seasonally impacts sleep and mood. In the winter, many people have a desire to sleep in as darkness persists, and inadequate light may contribute to seasonal affective disorder.

In older people, it is common for the brain to produce less melatonin. This sleep signal may reinforce the ability to sleep. This decrease in production may be due to changes in the pineal gland. It is also possible that decreased light perception, such as the discoloration that often occurs in the lenses of the eyes among older people, may play a role. Some people take melatonin as a sleep aid in an attempt to normalize these levels, but this may be of limited benefit.

Older adults are more likely to experience two circadian rhythm sleep disorders: advanced sleep phase syndrome (ASPS) and irregular sleep-wake rhythm. Each of these may cause early morning awakenings. ASPS is characterized by a desire to fall asleep and wake early. Those affected may doze in the late evening hours and then wake by 4AM with an inability to get back to sleep. This condition is relatively uncommon, affecting about 1 percent of people. It may have a genetic predisposition.

Irregular sleep-wake rhythm occurs more often among people who are institutionalized, especially among those with dementia like Alzheimer’s disease.

This may be due to reduced exposure to the natural patterns of light and darkness. It may also occur due to damage or degeneration of areas of the brain that are important for circadian regulation. The incidence is not well studied, but it is believed to be relatively rare among healthy populations.

Blaming Sleep Needs and Sleep Apnea in Older People

There are perhaps two reasons older people wake up too early that account for most of these awakenings: sleep needs and sleep apnea. Beyond the age of 65, it is estimated that the average sleep need decreases from 7 to 9 hours to 7 to 8 hours. This may seem like a modest difference, but it may still be significant. Retirementitself may contribute to its impact.

Often as people retire, they relish the opportunity to permanently silence their alarm clocks. Such folks might say, “I am retired: I don’t have to get up at a specific time any more.” Although this may be true in reference to work demands, it may neglect a bodily need. By allowing the wake time to vary—rather than getting up at the same time every day—the circadian rhythm and sleep drive are both impacted. The restricted lifestyle in retirement may also contribute to boredom and social isolation, prompting some to even go to bed earlier.

Moreover, due to the diminished need for sleep among this age group, the quality of rest can be compromised by spending more time in bed. If someone now needs 7 hours of sleep, but goes to bed at 9 PM and tries to sleep until 7 AM (even after an earlier awakening), the 10 hours in bed will include 3 hours of insomnia. This can occur even among those who previously slept well, as the time in bed exceeds the ability to sleep. Reducing the time in bed to reflect current sleep needs may enhance the quality of sleep and reduce these awakenings.

In addition, obstructive sleep apnea often contributes to early morning awakenings. This condition occurs more often among older people, with the frequency increasing 10-fold in women beyond menopause. Sleep apnea may be associated with snoring, daytime sleepiness, teeth grinding (bruxism), waking often to urinate (nocturia), and unwanted awakenings that lead to insomnia.

Sleep apnea may be worsened during periods of REM sleep, when the muscles of the body are relaxed so that dream-enactment does not occur. REM sleep occurs at 90-minute to 2-hour intervals and is concentrated in the last third of the night. (These regular sleep cycles also prompt a brief awakening as each cycle is completed.)

Perhaps not coincidentally, this timing often corresponds to regular early morning awakenings. Sleep apnea may cause a person to wake, and insomnia may make it harder to get back to sleep. Treatment of sleep apnea with continuous positive airway pressure (CPAP) or an oral appliance may help to reduce these events.

Considering Mood and Other Environmental Causes of Waking Too Early

Finally, it may be important to consider the role of mood disorders contributing to early morning awakenings in older people. Depression is often associated with these events. It should be noted that depression is also strongly linked to sleep apnea, so this might be more evidence of an underlying sleep-related breathing disorder.

In addition, anxiety may exacerbate insomnia. No matter the cause, if the awakening elicits an anxious or frustrated response, it will become more difficult to return to sleep. This might be improved with cognitive behavioral therapy for insomnia (CBTI).

Treatment of these mood disorders may help to improve sleep. There seems to be a bidirectional relationship, with one inevitably affecting the other. By improving both mood and sleep simultaneously, both can improve.

It might also be important to consider the influence of environmental factors. Noise, light, and temperature may prompt awakenings. Consider whether changes in the sleep environment are necessary to optimize the quality of early morning sleep.

If you continue to wake too early, and feel that you are overly tired with poor quality sleep, consider speaking with a board-certified sleep physician. By reviewing your history, it may be possible to identify causes and conditions that may respond well to treatment.

Sources:

Brzezinski, A et al. "Effects of exogenous melatonin on sleep: a meta-analysis." Sleep Med Rev 2005;9:41.

Kryger MH et al. "Principles and Practice of Sleep Medicine." Elsevier, 6th edition, 2016.

Moore-Ede, MC et al. “A physiological system measuring time,“ in The Clocks That Time Us. Cambridge, Massachusetts, Harvard University Press, 1984, p. 3.

Peters, BR. “Irregular Bedtimes and Awakenings,” in Evaluation of Sleep Complaints. Sleep Med Clinic. 2014;9:481-489.

Scientists Say the Clock of Aging May Be Reversible

mpaired muscle repair in mice, left, compared with improved muscle regeneration seen after reprogramming. CreditThe Salk Institute for Biological Studies

By NICHOLAS WADE

At the Salk Institute in La Jolla, Calif., scientists are trying to get time to run backward.

Biological time, that is. In the first attempt to reverse aging by reprogramming the genome, they have rejuvenated the organs of mice and lengthened their life spans by 30 percent. The technique, which requires genetic engineering, cannot be applied directly to people, but the achievement points toward better understanding of human aging and the possibility of rejuvenating human tissues by other means.

The Salk team’s discovery, reported in the Thursday issue of the journal Cell, is “novel and exciting,” said Jan Vijg, an expert on aging at the Albert Einstein College of Medicine in New York.

Leonard Guarente, who studies the biology of aging at M.I.T., said, “This is huge,” citing the novelty of the finding and the opportunity it creates to slow down, if not reverse, aging. “It’s a pretty remarkable finding, and if it holds up it could be quite important in the history of aging research,” Dr. Guarente said.

The finding is based on the heterodox idea that aging is not irreversible and that an animal’s biological clock can in principle be wound back to a more youthful state.

Continue reading the main story

The aging process is clocklike in the sense that a steady accumulation of changes eventually degrades the efficiency of the body’s cells. In one of the deepest mysteries of biology, the clock’s hands are always set back to zero at conception: However old the parents and their reproductive cells, a fertilized egg is free of all marks of age.

Ten years ago, the Japanese biologist Shinya Yamanaka amazed researchers by identifying four critical genes that reset the clock of the fertilized egg. The four genes are so powerful that they will reprogram even the genome of skin or intestinal cells back to the embryonic state. Dr. Yamanaka’s method is now routinely used to change adult tissue cells into cells very similar to the embryonic stem cells produced in the first few divisions of a fertilized egg.

Scientists next began to wonder if the four Yamanaka genes could be applied not just to cells in glassware but to a whole animal. The results were disastrous. As two groups of researchers reported in 2013 and 2014, the animals all died, some because their adult tissue cells had lost their identity and others from cancer. Embryonic cells are primed for rapid growth, which easily becomes uncontrolled.

But at the Salk Institute, Juan Carlos Izpisua Belmonte had been contemplating a different approach. He has long been interested in regeneration, the phenomenon in which certain animals, like lizards and fish, can regenerate lost tails or limbs. The cells near the lost appendage revert to a stage midway between an embryonic cell, which is open to all fates, and an adult cell, which is committed to being a particular type of cell, before rebuilding the missing limb.

This partial reprogramming suggested to him that reprogramming is a stepwise process, and that a small dose of the Yamanaka factors might rejuvenate cells without the total reprogramming that converts cells to the embryonic state.

With Alejandro Ocampo and other Salk researchers, Dr. Izpisua Belmonte has spent five years devising ways to deliver a nonlethal dose of Yamanaka factors to mice. The solution his team developed was to genetically engineer mice with extra copies of the four Yamanaka genes, and to have the genes activated only when the mice received a certain drug in their drinking water, applied just two days a week.

The Salk team worked first with mice that age prematurely, so as to get quick results. “What we saw is that the animal has fewer signs of aging, healthier organs, and at the end of the experiment we could see they had lived 30 percent longer than control mice,” Dr. Izpisua Belmonte said.

Juan Carlos Izpisua Belmonte of the Salk Institute in La Jolla, Calif., has long been interested in regeneration, the phenomenon in which certain animals, like lizards and fish, can regenerate lost tails or limbs.CreditConcepcion Rodriguez Esteban/The Salk Institute for Biological Studies

The team also saw improved organ health in normal mice but, because the mice are still living, could not yet say if longevity was extended.

Dr. Izpisua Belmonte believes these beneficial effects have been obtained by resetting the clock of the aging process. The clock is created by the epigenome, the system of proteins that clads the cell’s DNA and controls which genes are active and which are suppressed.

When an egg develops into a whole animal, the epigenome plays a critical role by letting a heart cell, say, activate just the genes specific to its role but switching off all the genes used by other types of cells. This process lets the embryo’s cells differentiate into all the various types of cells required by the adult body.

The epigenome is also involved throughout life in maintaining each cell and letting it switch genes on and off as required for its housekeeping duties. The epigenome itself is controlled by agents that add or subtract chemical groups, known as marks, to its proteins.

Only in the last few years have biologists come to realize that the state of the epigenome may be a major cause of aging. If the epigenome is damaged, perhaps by accumulating too many marks, the cell’s efficiency is degraded.

Dr. Izpisua Belmonte sees the epigenome as being like a manuscript that is continually edited. “At the end of life there are many marks and it is difficult for the cell to read them,” he said.

What the Yamanaka genes are doing in his mice, he believes, is eliminating the extra marks, thus reverting the cell to a more youthful state.

The Salk biologists “do indeed provide what I believe to be the first evidence that partial reprogramming of the genome ameliorated symptoms of tissue degeneration and improved regenerative capacity,” Dr. Vijg said.

But he cautioned the fast-aging mice used in the study might not be fully representative of ordinary aging.

Dr. Guarente said it was more likely that the Yamanaka genes were not erasing the epigenomic marks directly, but rather were activating the genes which are responsible for the immense health and vitality of embryonic cells. This gene activation is a natural function of the Yamanaka factors. It is these embryonic pro-health genes that are rejuvenating the tissues in the mice, Dr. Guarente suggested, and causing changes in the epigenome through their activity.

Thomas A. Rando, an expert on stem cells and aging at Stanford, said that it should be possible in theory to uncouple the differentiation program and the aging process, and that “if that’s what’s happening, this is the first demonstration of that.”

Dr. Izpisua Belmonte said he was testing drugs to see if he could achieve the same rejuvenation as with the Yamanaka factors. The use of chemicals “will be more translatable to human therapies and clinical applications,” he said.

First gene therapy successful against human aging

Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

In September 2015, then 44 year-old CEO of BioViva USA Inc. Elizabeth Parrish received two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities.

The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world's first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient.

In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish's telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life.

In March 2016, the same tests taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb, implying that Parrish's white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.

Bioviva will continue to monitor Parrish's blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, 'patient zero' of restorative gene therapy.

Since her first gene therapy injections BioViva has received global interest from both the scientific and investment communities. Earlier this month BioViva became a portfolio company of Deep Knowledge Life Sciences (DKLS), a London-based investment fund which aims to accelerate the development of biotechnologies for healthy longevity.

http://bg-rf.org.uk/

Gene Linked To Age Perception Discovered

photo credit: Aging is thought to be a mixture of genetic and environmental factors. Evgeny Atamanenko/Shutterstock

by Josh L Davis

We all know that even when people are exactly the same age, some of us look older than we actually are, and some of us younger. Many of these differences can be attributed to lifestyle choices and behavior, from smoking to sitting in the sunshine for too long, but what about the role of genetics? A new study, published in Current Biology, claims to have found a single gene that can influence whether or not someone is perceived to be older by up to two years.

The study, carried out by scientists in the Netherlands, involved looking at photographs of close to 2,700 people and estimating their ages, before then trawling through the subjects' genetics to search for any similarities. Surprisingly, they found that those carrying two copies of a variant of the gene in question, MC1R, were perceived to be up to two years older, while those carrying a single copy were seen as being one year older than they actually were, as opposed to those not carrying this variant. Interestingly, this gene is more commonly known for being involved in giving people ginger hair and pale skin. 

“Discovering this first gene involved in perceived age is important, because it opens the door for identifying more, which we know exist, and we now know are possible to find,” said Professor Manfred Kayser from the Erasmus Medical Center in Rotterdam, and co-author of the study, in a statement. “Our finding marks another step in understanding aging differences between people and provides new leads to identify the molecular links between perceived age, chronological age, and biological age.”

The MC1R gene is already known to be involved with the making of melanin and skin protection from UV, which would seem to be the mechanism that could potentially make anyone who has it appear older. But the researchers write that for the study they took into account the aging effects of skin color, wrinkles, and sun exposure, which would imply that the gene is acting in some other, currently unknown fashion.

While many other experts have commented that this finding may not be the fountain of youth, they have also conceded that the findings are of interest. “MC1R has been genetically associated with UV-induced skin damage, skin features like pigmentation, freckles and age spots, and with skin cancer,” João Pedro de Magalhães, a researcher of aging at Liverpool University, told The Guardian. “So it is perhaps not surprising that this gene plays a role in perceived age.”

The main question now is whether or not MC1R genuinely does affect aging, or just how pale someone’s skin is, and thus their perceived age. In addition to that, another expert not involved with the research has suggested that perhaps the study was measuring not the perceived age of the subjects, but the psychology and bias of the people doing the judging.

Whether or not the finding could be of significance is still unknown, with Professor Tim Frayling from the University of Exeter telling BBC News that, “whilst interesting, the authors admit that they need to find more genetic variation to have any chance of predicting someone’s appearance from DNA alone.”