Tag Archives: #ageing

You Cannot Live Forever: Ageing is Unstoppable (Biology)

We probably cannot slow the rate at which we get older, because of biological constraints, an unprecedented study of lifespan statistics in human and non-human primates has confirmed.  

The study set out to test the ‘invariant rate of ageing’ hypothesis, which says that a species has a relatively fixed rate of ageing from adulthood. Aninternational collaboration of scientists from 14 different countries, including José Manuel Aburto from Oxford’s Leverhulme Centre for Demographic Science, analysed age-specific birth and death data spanning centuries and continents. 

Led by Fernando Colchero, University of Southern DenmarkandSusan Alberts, Duke University, North Carolina, the study was a huge endeavour requiring monitoring wild populations of primates over several decades.

Our findings support the theory that, rather than slowing down death, more people are living much longer due to a reduction in mortality at younger ages…This suggests that biological, rather than environmental factors, ultimately control longevity…a steep rise in death rates, as years advance into old age, is clear to see in all species

José Manuel Aburto

José Manuel Aburto says, ‘Our findings support the theory that, rather than slowing down death, more people are living much longer due to a reduction in mortality at younger ages. We compared birth and death data from humans and non-human primates and found this general pattern of mortality was the same in all of them. This suggests that biological, rather than environmental factors, ultimately control longevity.

‘The statistics confirmed, individuals live longer as health and living conditions improve which leads to increasing longevity across an entire population. Nevertheless, a steep rise in death rates, as years advance into old age, is clear to see in all species.’

He continues, ‘The debate over how long we can live has divided the academic community for decades. Some scholars argue human lifespan has no limit, while others say the opposite. But what has been missing is research comparing lifespans of multiple animal populations with humans, to work out what is driving mortality.  Our study plugs that gap. This extraordinarily diverse collection of data enabled us to compare mortality differences both within and between species.’

The team analysed data from primates, since they are our closest genetic relatives, and therefore most likely to shed light on our biology. The research team analysed information from 30 primate species, 17 in the wild and 13 in zoos, including gorillas, baboons, chimpanzees and guenons. And it examined birth and death records from nine diverse human populations in 17th to 20th century Europe, the Caribbean and Ukraine, and two hunter gatherer groups between 1900 and 2000.

The research team analysed information from 30 primate species…including gorillas, baboons, chimpanzees and guenons. And it examined records from diverse human populations 

All the datasets examined by the team revealed the same general pattern of mortality: A high risk of death in infancy which rapidly declines in the immature and teenage years, remains low until early adulthood, and then continually rises in advancing age.

José Manuel Aburto says, ‘Our findings confirm that, in historical populations, life expectancy was low because many people died young. But as medical, social, and environmental improvements continued, life expectancy increased.  More and more people get to live much longer now. However, the trajectory towards death in old age has not changed. This study suggests evolutionally biology trumps everything and, so far, medical advances have been unable to beat these biological constraints.’

The team hopes its findings will lead to greater understanding of the ecology and evolution of a wide range of animal species worldwide, and their conservation.

Featured image: You can’t live forever: The team analysed data from primates, including gorillas. All the datasets revealed the same general pattern…and suggests evolutionally biology trumps everything and, so far, medical advances have been unable to beat biological constraints. © University of Oxford

Reference: Colchero, F., Aburto, J.M., Archie, E.A. et al. The long lives of primates and the ‘invariant rate of ageing’ hypothesis. Nat Commun 12, 3666 (2021). https://doi.org/10.1038/s41467-021-23894-3

Provided by University of Oxford

Convergent Mechanism Of Ageing Discovered (Biology)

Fundamental signalling pathway is crucial for longevity

Several different causes of ageing have been discovered, but the question remains whether there are common underlying mechanisms that determine ageing and lifespan. Researchers from the Max Planck Institute for Biology of Ageing and the CECAD Cluster of Excellence in Ageing research at the University Cologne have now come across folate metabolism in their search for such basic mechanisms. Its regulation underlies many known ageing signalling pathways and leads to longevity.  This may provide a new possibility to broadly improve human health during ageing.

In recent decades, several cellular signalling pathways have been discovered that regulate the lifespan of an organism and are thus of enormous importance for ageing research. When researchers altered these signalling pathways, this extended the lifespan of diverse organisms. However, the question arises whether these different signalling pathways converge on common metabolic pathways that are causal for longevity.

The search begins in the roundworm

The scientists started their search in the roundworm Caenorhabditis elegans, a well-known model organism for ageing research. “We studied the metabolic products of several, long-lived worm lines. Our analyses revealed that, among other things, we observed clear changes in the metabolites and enzymes of the folate cycle in all worm lines. Since folate metabolism plays a major role in human health, we wanted to further pursue its role in longevity”, explains Andrea Annibal, lead author of the study.

A common mechanism for longevity

Folates are essential vitamins important for the synthesis of amino acids and nucleotides – the building blocks of our proteins and DNA. “We tuned down the activity of specific enzymes of folate metabolism in the worms. Excitingly, the result was an increase in lifespan of up to 30 percent”, says Annibal. “We also saw that in long-lived strains of mice, folate metabolism is similarly tuned down. Thus, the regulation of folate metabolism may underlie not only the various longevity signalling pathways in worms, but also in mammals.”

”We are very excited by these findings because they reveal the regulation of folate metabolism as a common shared mechanism that affects several different pathways of longevity and is conserved in evolution”, adds Adam Antebi, director at the Max Planck Institute for Biology of Ageing. “Thus, the precise manipulation of folate metabolism may provide a new possibility to broadly improve human health during ageing.” In future experiments, the group aims to find out the mechanism by which the folate metabolism affects longevity.

Featured image: Andrea Annibal uses the mass spectrometer to investigate various metabolites in long-lived worms and mice. © Link/Max Planck Institute for Biology of Ageing

Reference: Andrea Annibal, Rebecca George Tharyan, Maribel Fides Schonewolff, Hannah Tam, Christian Latza, Markus Max Karl Auler, Adam Antebi, “Regulation of the one carbon folate cycle as a shared metabolic signature of longevity” , Nature Communications, June 9th, 2021 Source

Provided by Max Planck Gesellschaft

We Cannot Cheat Ageing and Death (Physiology)

New study finds fresh evidence for our inevitable death

A study led by Fernando Colchero, University of Southern Denmark and Susan Alberts, Duke University, North Carolina, that included researchers from 42 institutions across 14 countries, provides new insights into the aging theory “the invariant rate of ageing hypothesis”, which states that every species has a relatively fixed rate of aging.

– Human death is inevitable. No matter how many vitamins we take, how healthy our environment is or how much we exercise, we will eventually age and die, said Fernando Colchero.

He is an expert in applying statistics and mathematics to population biology and an associate professor at Department of Mathematics and Computer Science, University of Southern Denmark.

“We were able to shed light on the invariant rate of ageing hypothesis by combining an unpresented wealth of data and comparing births and deaths patterns on nine human populations with information from 30 non-human primate populations, including gorillas, chimpanzees and baboons living in the wild and in zoos” said Fernando Colchero.

In order to explore this hypothesis, the researchers analyzed the relationship between life expectancy, this is the average age at which individuals die in a population, and lifespan equality, which measures how concentrated deaths are around older ages.

Their results show that, as life expectancy increases, so does lifespan equality. So, lifespan equality is very high when most of the individuals in a population tend to die at around the same age such as observed in modern Japan or Sweden – which is around their 70s or 80s. However, in the 1800s lifespan equality was very low in those same countries, since deaths were less concentrated at old ages, resulting also in lower life expectancy.

– Life expectancy has increased dramatically and still does in many parts of the world. But this is not because we have slowed our rate of aging; the reason is that more and more infants, children and young people survive and this brings up the average life expectancy, said Fernando Colchero.

Previous research from some of the authors of the study has unraveled the striking regularity between life expectancy and lifespan equality among human populations, from pre-industrial European countries, hunter gatherers, to modern industrialize countries.

However, by exploring these patterns among our closest relatives, this study shows that this pattern might be universal among primates, while it provides unique insights into the mechanisms that produce it.

“We observe that not only humans, but also other primate species exposed to different environments, succeed in living longer by reducing infant and juvenile mortality. However, this relationship only holds if we reduce early mortality, and not by reducing the rate of ageing” said Fernando Colchero.

Using statistics and mathematics the authors show that even small changes in the rate of ageing would make a population of, say, baboons, to demographically behave as a population of chimpanzees or even humans.

‘Not all is lost’, says Fernando Colchero, ‘medical science has advanced at an unprecedented pace, so maybe science might succeed in achieving what evolution could not: to reduce the rate of ageing’.

This work was supported by NIA P01AG031719, with additional support provided by the Max Planck Institute of Demographic Research and the Duke University Population Research Institute.

Reference: “The Long Lives of Primates and the ‘Invariant Rate of Ageing’ Hypothesis,” F. Colchero, J.M. Aburto, E.A. Archie, C. Boesch, T. Breuer, F.A. Campos, A. Collins, D.A. Conde, M. Cords, C. Crockford, M.E. Thompson, L.M. Fedigan, C. Fichtel, M. Groenenberg, C. Hobaiter, P.M. Kappeler, R.R. Lawler, R.J. Lewis, Z.P. Machanda, M.L. Manguette, M.N. Muller, C. Packer, R.J. Parnell, S. Perry, A.E. Pusey, M.M. Robbins, R.M. Seyfarth, J.B. Silk, J. Staerk, T.S. Stoinski, E.J. Stokes, K.B. Strier, S.C. Strum, J. Tung, F. Villavicencio, R.M. Wittig, R.W. Wrangham, K. Zuberbühler, J.W. Vaupel, S.C. Alberts. Nature Communications, DOI: 10.1038/s41467-021-23894-3.

Provided by University of Southern Denmark

Changes in Mouth Bacteria After Drinking Beetroot Juice May Promote Healthy Ageing (Food)

Drinking beetroot juice promotes a mix of mouth bacteria associated with healthier blood vessels and brain function, according to a new study of people aged 70-80.

Beetroot – and other foods including lettuce, spinach and celery – are rich in inorganic nitrate, and many oral bacteria play a role in turning nitrate to nitric oxide, which helps to regulate blood vessels and neurotransmission (chemical messages in the brain).

Older people tend to have lower nitric oxide production, and this is associated with poorer vascular (blood vessel) and cognitive (brain) health.

In the new study, by the University of Exeter, 26 healthy older people took part in two ten-day supplementation periods: one with nitrate-rich beetroot juice and another with nitrate-free placebo juice, which they drank twice a day.

The results showed higher levels of bacteria associated with good vascular and cognitive health, and lower levels of bacteria linked to disease and inflammation.

Systolic blood pressure dropped on average by five points (mmHg) after drinking the beetroot juice.

“We are really excited about these findings, which have important implications for healthy ageing,” said lead author Professor Anni Vanhatalo, of the University of Exeter.

“Previous studies have compared the oral bacteria of young and older people, and healthy people compared to those with diseases, but ours is the first to test nitrate-rich diet in this way.

“Our findings suggest that adding nitrate-rich foods to the diet – in this case via beetroot juice – for just ten days can substantially alter the oral microbiome (mix of bacteria) for the better.

“Maintaining this healthy oral microbiome in the long term might slow down the negative vascular and cognitive changes associated with ageing.”

The researchers ran tests to identify clusters (or “modules”) of oral bacteria that tend to thrive together in similar conditions.

A module (Prevotella-Veillonella) that has been associated with inflammation was reduced after nitrate supplementation, including a decrease of Clostridium difficile (which can infect the bowel and cause diarrhoea).

Professor Vanhatalo stressed that more research is needed to confirm the findings and see whether similar effects are found in other groups.

“Our participants were healthy, active older people with generally good blood pressure,” she said.

“Dietary nitrate reduced their blood pressure on average, and we are keen to find out whether the same would happen in other age groups and among people in poorer health.

“We are working with colleagues in the University of Exeter Medical School to investigate interactions between the oral bacteria and cognition to better understand the how diet could be used to delay cognitive decline in older age.”

Much research has been conducted into the benefits of a healthy gut microbiome, but far less is known about the oral microbial community, which plays a crucial role in “activating” the nitrate from a vegetable-rich diet.

The study was funded by the Dunhill Medical Trust, and the research team included Cardiff University.

The paper, published in the journal Redox Biology, is entitled: “Network analysis of nitrate-sensitive oral microbiome reveals interactions with cognitive function and cardiovascular health across dietary interventions.”

Featured image: Foods including beetroot are rich in inorganic nitrate © University of Exeter

Reference: Anni Vanhatalo, Joanna E. L’Heureux, James Kelly, Jamie R. Blackwell, Lee J. Wylie, Jonathan Fulford, Paul G. Winyard, David W. Williams, Mark van der Giezen, Andrew M. Jones, Network analysis of nitrate-sensitive oral microbiome reveals interactions with cognitive function and cardiovascular health across dietary interventions, Redox Biology, Volume 41, 2021, 101933, ISSN 2213-2317, https://doi.org/10.1016/j.redox.2021.101933. (https://www.sciencedirect.com/science/article/pii/S2213231721000811)

Provided by University of Exeter

Could Playing Host to Hookworms Help Prevent Ageing? (Biology)

Evidence is mounting to suggest that some helminth worms are ‘old friend’ commensals that can help us fight inflammation and prevent age-related disease.

Parasitic worms could hold the key to living longer and free of chronic disease, according to a review article published today in the open-access eLife journal.

The review looks at the growing evidence to suggest that losing our ‘old friend’ helminth parasites, which used to live relatively harmlessly in our bodies, can cause ageing-associated inflammation. It raises the possibility that carefully controlled, restorative helminth treatments could prevent ageing and protect against diseases such as heart disease and dementia.

“A decline in exposure to commensal microbes and gut helminths in developed countries has been linked to increased prevalence of allergic and autoimmune inflammatory disorders – the so-called ‘old friends hypothesis’,” explains author Bruce Zhang, Undergraduate Assistant at the UCL Institute of Healthy Ageing, London, UK. “A further possibility is that this loss of ‘old friend’ microbes and helminths increases the sterile, ageing-associated inflammation known as inflammageing.”

Inflammageing is increasingly thought to be a contributory factor to the major diseases of later life, including heart disease, dementia, cancer, chronic obstructive pulmonary disease, osteoporosis, age-related eye disease and – more recently – symptom severity during SARS-CoV-2 (COVID-19) infections.

One theory is that changes in the gut microbiome might cause inflammageing, but until now little consideration has been given to the role of organisms comprising the macrobiome – the ecosystem of macro-organisms – including helminth parasites such as flukes, tapeworms and nematodes.

Helminths have infected humans throughout our evolutionary history, and as a result have become master manipulators of our immune response. Humans, in turn, have evolved levels of tolerance to their presence.

In their article, Zhang and co-author David Gems, Professor of Biogerontology and Research Director at the UCL Institute of Healthy Ageing, review the evidence for helminth therapy in two areas: treating known inflammatory disorders, such as coeliac disease, and stopping or reversing inflammageing as part of the ageing process.

They reveal how the loss of helminths has so far been linked to a range of inflammatory diseases, including asthma, atopic eczema, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis and diabetes. Some studies have shown that natural infection with helminths can alleviate disease symptoms, for example in multiple sclerosis and eczema, while other studies in animal models suggest that intentional infection with helminths could have benefits against disease.

The safer, and perhaps more palatable, option is the concept of using helminth-derived proteins to achieve the same therapeutic benefits. This was tested recently in mice and shown to prevent the age-related decline in gut barrier integrity usually seen with a high-calorie diet. It also had beneficial effects on fat tissue, which is known to be a major source of inflammageing.

The authors speculate that if helminths have anti-inflammageing properties, you would expect to see lower rates of inflammageing-related disease in areas where helminth infection is more common. There is some evidence to support this. For example, in a region in Eastern India endemic for lymphatic filariasis caused by filarial worms, not a single person with rheumatoid arthritis (RA) tested positive for circulating filarial antigens, whereas a much higher proportion (40%) of people without RA tested positive for the nematode. Other epidemiological studies have shown protection from helminths against type 2 diabetes and blocked arteries.

“It goes without saying that improvements in hygiene and elimination of helminth parasites have been of incalculable benefit to humanity, but a cost coupled to this benefit is abnormalities of immune function,” Gems concludes. “In the wake of successes during the last century in eliminating the evil of helminths, the time now seems right to further explore their possible benefits, particularly for our ageing population – strange as this may sound.”

This study will be published as part of eLife’s special issue on evolutionary medicine. For more information, visit https://elifesciences.org/inside-elife/bb34a238/special-issue-call-for-papers-in-evolutionary-medicine.

Provided by Elife

Scientists Discover a New Type of Brain Cell That Could Help Detect Distance (Neuroscience)

The existence of GPS-like brain cells, which can store maps of the places we’ve been, like our kitchen or holiday destination, was already widely known, but this discovery shows there is also a type of brain cell sensitive to the distance and direction of objects that can store their locations on these maps.

Dr. Steven Poulter and Dr. Colin Lever in the lab discovering the cells. © Dr. Steven Poulter and Dr. Colin Lever

The research, led by Dr Steven Poulter and Dr Colin Lever from Durham University, and co-directed by Dr Thomas Wills from the University of Central London (UCL), found that Vector Trace cells can track how far we have travelled and remember where things are, which are added to our memory map of the places we have been.

Dr Steven Poulter said: “The discovery of Vector Trace cells is particularly important as the area of the brain they are found in is one of the first to be attacked by brain disorders such as Alzheimer’s disease, which could explain why a common symptom and key early ‘warning sign’ is the losing or misplacement of objects.”

Dr Lever added: “It looks like Vector Trace cells connect to creative brain networks which help us to plan our actions and imagine complex scenarios in our mind’s eye. Vector trace cells acting together likely allow us to recreate the spatial relationships between ourselves and objects, and between the objects in a scene, even when those objects are not directly visible to us.”

Brain cells that make up the biological equivalent of a satellite-navigation system were first discovered <> by Professors John O’Keefe, Edvard Moser, May-Britt Moser. Their discovery shed light on one of neurosciences great mysteries – how we know where we are in space – and won them the 2014 Nobel Prize in Medicine.

Speaking about the discovery, Professor John O’Keefe said: “I’m very impressed. Not only have they discovered a new type of brain cell, the Vector Trace cell, but their analysis of its properties is exhaustive and compelling. This discovery sheds considerable light on this important but enigmatic structure of the brain, supporting the idea that it is indeed the memory system we have always believed it to be.”

Professor Lord Robert Winston added: “This fascinating work on Vector Trace cells uncovers further levels of our memory, so often lost with brain damage and ageing. This discovery gives a possible insight into certain kinds of dementia which are now of massive importance.

He added: “The idea that loss or change of such cells might be an early biomarker of disease could lead to earlier diagnosis and more effective therapies for one of the most intractable medical conditions.”

Provided by Durham University

Cell Ageing Can Be Slowed By Oxidants (Biology)

At high concentrations, reactive oxygen species – known as oxidants – are harmful to cells in all organisms and have been linked to ageing. But a study from Chalmers University of Technology, Sweden, has now shown that low levels of the oxidant hydrogen peroxide can stimulate an enzyme that helps slow down the ageing of yeast cells.

Yeast can be grown on both solid and liquid nutrition medium and is a good model system for studying ageing. Yeast cells share many molecular mechanisms with cells in more complex organisms, yet it is easy to change their DNA and study different genes’ functions. Yeast also produces many generations in a short time. ©Martina Butorac/Chalmers University of Technology

One benefit of antioxidants, such as vitamins C and E, is that they neutralise reactive oxygen species – known as oxidants – which may otherwise react with important molecules in the body and destroy their biological functions. Larger amounts of oxidants can cause serious damage to DNA, cell membranes and proteins for example. Our cells have therefore developed powerful defence mechanisms to get rid of these oxidants, which are formed in our normal metabolism.

It was previously believed that oxidants were only harmful, but recently we have begun to understand that they also have positive functions. Now, the new research from Chalmers University of Technology shows that the well-known oxidant hydrogen peroxide can actually slow down the ageing of yeast cells. Hydrogen peroxide is a chemical used for hair and tooth whitening, among other things. It is also one of the oxidants formed in our metabolism that is harmful at higher concentrations.

The Chalmers researchers studied the enzyme Tsa1, which is part of a group of antioxidants called peroxiredoxins.

“Previous studies of these enzymes have shown that they participate in yeast cells’ defences against harmful oxidants,” says Mikael Molin, who leads the research group at Chalmers’ Department of Biology and Biological Engineering. “But the peroxiredoxins also help extend the life span of cells when they are subjected to calorie restriction. The mechanisms behind these functions have not yet been fully understood.”

It is already known that reduced calorie intake can significantly extend the life span of a variety of organisms, from yeast to monkeys. Several research groups, including Mikael Molin’s, have also shown that stimulation of peroxiredoxin activity in particular is what slows down the ageing of cells, in organisms such as yeast, flies and worms, when they receive fewer calories than normal through their food.

Yeast is a good model system for studying ageing. The researchers can easily determine the age of the cells by counting the bud scars, formed when they divide and form new cells by budding (left). As the yeast cells age, you can examine, for example, how proteins are damaged and aggregate (light spots in the image to the right), a process that in higher organisms can be linked to the degeneration of nerve or brain cells in, for example, Alzheimer’s or Parkinson’s disease. ©Mikael Molin/Chalmers University of Technology

“Now we have found a new function of Tsa1,” says Cecilia Picazo, postdoctoral researcher at the Division of Systems and Synthetic Biology at Chalmers. “Previously, we thought that this enzyme simply neutralises reactive oxygen species. But now we have shown that Tsa1 actually requires a certain amount of hydrogen peroxide to be triggered in order to participate in the process of slowing down the ageing of yeast cells.”

Surprisingly, the study shows that Tsa1 does not affect the levels of hydrogen peroxide in aged yeast cells. On the contrary, Tsa1 uses small amounts of hydrogen peroxide to reduce the activity of a central signalling pathway when cells are getting fewer calories. The effects of this ultimately lead to a slowdown in cell division and processes linked to the formation of the cells’ building blocks. The cells’ defences against stress are also stimulated – which causes them to age more slowly.

“Signal pathways which are affected by calorie intake may play a central role in ageing by sensing the status of many cellular processes and controlling them,” says Mikael Molin. “By studying this, we hope to understand the molecular causes behind why the occurrence of many common diseases such as cancer, Alzheimer’s disease, and diabetes shows a sharp increase with age.”

The fact that researchers have now come a step closer to understanding the mechanisms behind how oxidants can actually slow down the ageing process could lead to new studies, for example looking for peroxiredoxin-stimulating drugs, or testing whether age-related diseases can be slowed by other drugs that enhance the positive effects of oxidants in the body.

More about: The mechanism of slowed ageing by the enzyme Tsa1:

The Chalmers researchers have shown a mechanism for how the peroxiredoxin enzyme Tsa1 directly controls a central signalling pathway. It slows down ageing by oxidising an amino acid in another enzyme, protein kinase A, which is important for metabolic regulation. The oxidation reduces the activity of protein kinase A by destabilising a portion of the enzyme that binds to other molecules. Thus, nutrient signalling via protein kinase A is reduced, which in turn downregulates the division of cells and stimulates their defence against stress.

More about: Related results from other research groups:

Other studies have also shown that low levels of reactive oxygen species can be linked to several positive health effects. These oxidants are formed in the mitochondria, the ‘powerhouse’ of a cell, and the process, called mitohormesis, can be observed in many organisms, from yeast to mice. In mice, tumour growth is slowed by mitohormesis, while in roundworms it has been possible to link both peroxiredoxins and mitohormesis to the ability of the type 2 diabetes drug metformin to slow cellular ageing.

Metformin is also relevant in the hunt for drugs that can reduce the risk of older people being severely affected by Covid-19. Studies in China and the United States have yielded some promising results, and one theory is that metformin may counteract the deterioration of the immune system caused by ageing.

Reference: Friederike Roger, Cecilia Picazo, Wolfgang Reiter, Marouane Libiad, Chikako Asami, Sarah Hanzén, Chunxia Gao, Gilles Lagniel, Niek Welkenhuysen, Jean Labarre, Thomas Nyström, Morten Grøtli, Markus Hartl, Michel B Toledano, Mikael Molin, “Peroxiredoxin promotes longevity and H2O2-resistance in yeast through redox-modulation of protein kinase A”, Biochemistry and Chemical Biology, 2020. Doi: https://doi.org/10.7554/eLife.60346 link: https://elifesciences.org/articles/60346

Provided by Chalmers University Of Technology

Why Motivation To Learn Declines With Age? (Psychology)

Research on mice suggests aging affects a brain circuit critical for learning to make some types of decisions.

As people age, they often lose their motivation to learn new things or engage in everyday activities. In a study of mice, MIT neuroscientists have now identified a brain circuit that is critical for maintaining this kind of motivation.

©friedman et al.

This circuit is particularly important for learning to make decisions that require evaluating the cost and reward that come with a particular action. The researchers showed that they could boost older mice’s motivation to engage in this type of learning by reactivating this circuit, and they could also decrease motivation by suppressing the circuit.

“As we age, it’s harder to have a get-up-and-go attitude toward things,” says Ann Graybiel, an Institute Professor at MIT and member of the McGovern Institute for Brain Research. “This get-up-and-go, or engagement, is important for our social well-being and for learning — it’s tough to learn if you aren’t attending and engaged.”

Graybiel is the senior author of the study, which appears today in Cell. The paper’s lead authors are Alexander Friedman, a former MIT research scientist who is now an assistant professor at the University of Texas at El Paso, and Emily Hueske, an MIT research scientist.

Evaluating cost and benefit

The striatum is part of the basal ganglia — a collection of brain centers linked to habit formation, control of voluntary movement, emotion, and addiction. For several decades, Graybiel’s lab has been studying clusters of cells called striosomes, which are distributed throughout the striatum. Graybiel discovered striosomes many years ago, but their function had remained mysterious, in part because they are so small and deep within the brain that it is difficult to image them with functional magnetic resonance imaging (fMRI).

In recent years, Friedman, Graybiel, and colleagues including MIT research fellow Ken-ichi Amemori have discovered that striosomes play an important role in a type of decision-making known as approach-avoidance conflict. These decisions involve choosing whether to take the good with the bad — or to avoid both — when given options that have both positive and negative elements. An example of this kind of decision is having to choose whether to take a job that pays more but forces a move away from family and friends. Such decisions often provoke great anxiety.

In a related study, Graybiel’s lab found that striosomes connect to cells of the substantia nigra, one of the brain’s major dopamine-producing centers. These studies led the researchers to hypothesize that striosomes may be acting as a gatekeeper that absorbs sensory and emotional information coming from the cortex and integrates it to produce a decision on how to act. These actions can then be invigorated by the dopamine-producing cells.

The researchers later discovered that chronic stress has a major impact on this circuit and on this kind of emotional decision-making. In a 2017 study performed in rats and mice, they showed that stressed animals were far more likely to choose high-risk, high-payoff options, but that they could block this effect by manipulating the circuit.

In the new Cell study, the researchers set out to investigate what happens in striosomes as mice learn how to make these kinds of decisions. To do that, they measured and analyzed the activity of striosomes as mice learned to choose between positive and negative outcomes.

During the experiments, the mice heard two different tones, one of which was accompanied by a reward (sugar water), and another that was paired with a mildly aversive stimulus (bright light). The mice gradually learned that if they licked a spout more when they heard the first tone, they would get more of the sugar water, and if they licked less during the second, the light would not be as bright.

Learning to perform this kind of task requires assigning value to each cost and each reward. The researchers found that as the mice learned the task, striosomes showed higher activity than other parts of the striatum, and that this activity correlated with the mice’s behavioral responses to both of the tones. This suggests that striosomes could be critical for assigning subjective value to a particular outcome.

“In order to survive, in order to do whatever you are doing, you constantly need to be able to learn. You need to learn what is good for you, and what is bad for you,” Friedman says.

“A person, or this case a mouse, may value a reward so highly that the risk of experiencing a possible cost is overwhelmed, while another may wish to avoid the cost to the exclusion of all rewards. And these may result in reward-driven learning in some and cost-driven learning in others,” Hueske says.

The researchers found that inhibitory neurons that relay signals from the prefrontal cortex help striosomes to enhance their signal-to-noise ratio, which helps to generate the strong signals that are seen when the mice evaluate a high-cost or high-reward option.

Loss of motivation

Next, the researchers found that in older mice (between 13 and 21 months, roughly equivalent to people in their 60s and older), the mice’s engagement in learning this type of cost-benefit analysis went down. At the same time, their striosomal activity declined compared to that of younger mice. The researchers found a similar loss of motivation in a mouse model of Huntington’s disease, a neurodegenerative disorder that affects the striatum and its striosomes.

When the researchers used genetically targeted drugs to boost activity in the striosomes, they found that the mice became more engaged in performance of the task. Conversely, suppressing striosomal activity led to disengagement.

In addition to normal age-related decline, many mental health disorders can skew the ability to evaluate the costs and rewards of an action, from anxiety and depression to conditions such as PTSD. For example, a depressed person may undervalue potentially rewarding experiences, while someone suffering from addiction may overvalue drugs but undervalue things like their job or their family.

The researchers are now working on possible drug treatments that could stimulate this circuit, and they suggest that training patients to enhance activity in this circuit through biofeedback could offer another potential way to improve their cost-benefit evaluations.

“If you could pinpoint a mechanism which is underlying the subjective evaluation of reward and cost, and use a modern technique that could manipulate it, either psychiatrically or with biofeedback, patients may be able to activate their circuits correctly,” Friedman says.

References: Alexander Friedman, Emily Hueske, Sabrina M. Drammis, Charu Ramakrishnan, Karl Deisseroth, Ann M. Graybiel, “Striosomes Mediate Value-Based Learning Vulnerable in Age and a Huntington’s Disease Model”, October 27, 202. DOI: https://doi.org/10.1016/j.cell.2020.09.060 link: https://www.cell.com/cell/fulltext/S0092-8674(20)31301-5?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS0092867420313015%3Fshowall%3Dtrue

Provided by MIT

Identified A Subgroup Of Stem Cells That Resists Ageing And Maintains Muscle Regeneration (Biology)

Researchers at UPF, the National Centre for Cardiovascular Research, ICREA and Ciberned have identified a physiological mechanism that maintains the regenerative capacity of muscle stem cells, and surprisingly resists the passage of time far more than expected, until geriatric age. This study presents the results of more than seven years of research and collaborations with several laboratories in Europe and the US.

A subgroup of muscle stem cells (above) retain high regenerative capacity until geriatric age. ©UPF and CNIC.

Skeletal muscle regeneration depends on a muscle stem cell population (satellite cells) in a dormant or quiescent state, a situation that can be triggered by damage or stress to form new muscle fibres and expand in new stem cells.

The regenerative functions of these stem cells are known to decline with ageing. Dr. Pura Muñoz-Cánoves, the ICREA professor who leads the Cell Biology research group of the Department of Experimental and Health Sciences (DCEXS) at Pompeu Fabra University (UPF) in Barcelona, and head of the Tissue Regeneration Group of the National Centre for Cardiovascular Research (CNIC) in Madrid, and of Ciberned, and colleagues, have found in experiments with mice that all muscle stem cells, despite being quiescent, are not equal, and have identified a subgroup that maintains its regenerative capacity over time, declining only at geriatric age.

The researchers have shown that this subgroup of quiescent stem cells has a greater regenerative capacity through the activation of the FoxO signalling pathway (previously associated with longevity), which maintains the expression of a youthful gene programme throughout life; however, at geriatric age, FoxO activation in this subgroup of cells is lost, causing their loss of functionality.

According to the results presented in Nature Cell Biology, compounds that activate FoxO may have a rejuvenating effect on aged muscle stem cells, opening the way to improve the health of elderly people who are debilitated by the loss of muscle mass. It may also be useful for persons who have lost muscle mass as a result of neuromuscular diseases or effects associated with cancer or infectious or inflammatory diseases.

References: García-Prat, L., Perdiguero, E., Alonso-Martín, S. et al. FoxO maintains a genuine muscle stem-cell quiescent state until geriatric age. Nat Cell Biol (2020). https://doi.org/10.1038/s41556-020-00593-7 link: https://www.nature.com/articles/s41556-020-00593-7

Provided by Universitat Pompeu Fabra