Tag: ageing

A ‘Fountain of Youth’ for Bone Marrow Stem Cells

Source: National Cancer Institute on Unsplash

Scientists have shown that reduced bone marrow stem cell function with ageing is due to changes in their epigenome, and they were able to reverse these changes in isolated stem cells by adding acetate. This ‘fountain of youth’ for the epigenome could become important for the treatment of diseases such as osteoporosis.

One responsible mechanism for age-related osteoporosis and fracture risk involves the impaired function of the bone-marrow stem cells, which are required for the maintenance of bone integrity. 

For a long time, researchers have looked at epigenetics as a cause of ageing. Epigenetics looks at changes that affect the activity of genes. One of these is changes in proteins called histones, which package and thus control access to DNA. In this study, the researchers investigated the epigenome of mesenchymal stem cells, which are found in bone marrow and can give rise to different types of cells such as cartilage, bone and fat cells.

“We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice,” explained Andromachi Pouikli, first author of the study. “We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected.”

The researchers then sought to find out if it was possible to rejuvenate the epigenome of stem cells. To do this, they treated isolated stem cells from mouse bone marrow with a nutrient solution which contained sodium acetate. The cell converts the acetate into a building block that enzymes can attach to histones to increase access to genes, thereby boosting their activity. “This treatment impressively caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells,” Pouikli said.

To see if this change could also be responsible for increased fracture risk and osteoporosis with age, the researchers studied human mesenchymal stem cells from hip surgery patients. In elderly patients with osteoporosis, the same epigenetic changes seen with mice were also seen in these human cells.

“Sodium acetate is also available as a food additive, however, it is not advisable to use it in this form against osteoporosis, as our observed effect is very specific to certain cells,” cautioned study leader Peter Tessarz. “However, there are already first experiences with stem cell therapies for osteoporosis. Such a treatment with acetate could also work in such a case. However, we still need to investigate in more detail the effects on the whole organism in order to exclude possible risks and side effects.”

The results were published in the journal Nature Aging.

Source: Max Planck Society

Traitorous Immune Cells Explain Why the Elderly Feel the Cold

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In a new study, Yale researchers found that the immune cells within fat that are designed to burn calories to protect us from cold temperatures start to turn against us as we age, making the elderly more vulnerable to the cold.

The study, published in Cell Metabolism, found that the fat tissue of older mice loses the immune cell group 2 innate lymphoid cells (ILC2) which restore body heat in cold temperatures. However, trying to stimulate production of new ILC2 cells in aging mice actually makes them more prone to cold-induced death, showing how difficult it is to solve aging-related problems.

“What is good for you when you are young, can become detrimental to you as you age,” said Vishwa Deep Dixit, the Waldemar Von Zedtwitz Professor of Comparative Medicine and of Immunobiology and co-corresponding author of the study.

Prof Dixit and former colleague Emily Goldberg, now an assistant professor at UCSF, were curious about why there are immune cells in fat tissue, as they are usually concentrated in pathogen-exposed areas like nasal passages, lungs, and skin. When they sequenced genes from cells of old and young mice they found that older animals lacked ILC2 cells, a deficit which limited their ability to burn fat in cold conditions.

When they introduced a molecule that boosts the production of ILC2 in aging mice, the immune system cells were restored but the mice were surprisingly even less tolerant of cold temperatures.

“The simple assumption is that if we restore something that is lost, then we are also going to restore life back to normal,” Dixit said. “But that is not what happened. Instead of expanding healthy cells of youth, the growth factor ended up multiplying the bad ILC2 cells that remained in fat of old mice.”

However, when ILC2 cells were taken from younger mice and transplanted into older mice, the older animals’ cold tolerance was restored.

“Immune cells play a role beyond just pathogen defense and help maintain normal metabolic functions of life,” Dixit said. “With age, the immune system has already changed and we need to be careful how we manipulate it to restore the health of the elderly.”

Source: SciTech Daily

Some Cognitive Abilities Improve With Age

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While it has long been held that all cognitive abilities decline with age, new research shows that some of these abilities can actually improve over a lifetime.

The findings, published in Nature Human Behavior, show that two key brain functions, focusing and attending to new information, can in fact improve in older individuals. These functions underlie key aspects of cognition including memory, decision making, and self-control, and even navigation, math, language and reading.

“These results are amazing, and have important consequences for how we should view aging,” said senior investigator, Michael T Ullman, PhD, a professor in the Department of Neuroscience and director of Georgetown’s Brain and Language Lab.

“People have widely assumed that attention and executive functions decline with age, despite intriguing hints from some smaller-scale studies that raised questions about these assumptions,” he said. “But the results from our large study indicate that critical elements of these abilities actually improve during aging, likely because we simply practice these skills throughout our life.”

“This is all the more important because of the rapidly aging population, both in the U.S. and around the world,” Ullman said, adding that with further research, it may be possible to deliberately improve these skills to protect against cognitive decline.

The research team explored three separate components of attention and executive function in a group of 702 participants aged 58 to 98. This age range was chosen since this is when cognition often changes the most during aging.

The components they studied are the brain networks involved in alerting, orienting and executive inhibition. Each has different characteristics and relies on different brain areas and different neurochemicals and genes. Therefore, Ullman and Veríssimo reasoned, the networks may also show different aging patterns.

Alerting is characterised by a state of enhanced vigilance and preparedness, while orienting involves shifting brain resources to a particular location in space. The executive network inhibits distracting or conflicting information, allowing us to focus on what’s important.

“We use all three processes constantly,” Veríssimo explains. “For example, when you are driving a car, alerting is your increased preparedness when you approach an intersection. Orienting occurs when you shift your attention to an unexpected movement, such as a pedestrian. And executive function allows you to inhibit distractions such as birds or billboards so you can stay focused on driving.”

Surprisingly, only alerting abilities declined with age while both orienting and executive inhibition actually improved.

The researchers hypothesis is that because orienting and inhibition are simply skills that allow selective attention, these skills can improve with lifelong practice. Ullman and Veríssimo suggest that these gains can be large enough to outweigh the underlying neural declines. Alerting declines, they believe, because this basic state of vigilance and preparedness cannot improve with practice.  
“Because of the relatively large number of participants, and because we ruled out numerous alternative explanations, the findings should be reliable and so may apply quite broadly,” Veríssimo said, adding that “because orienting and inhibitory skills underlie numerous behaviors, the results have wide-ranging implications.”

“The findings not only change our view of how aging affects the mind, but may also lead to clinical improvements, including for patients with aging disorders such as Alzheimer’s disease,” said Ullman. 

Source: Georgetown University Medical Center

Metabolism Through Life Varies in Unexpected Ways

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A new study published in Science suggests that falls in metabolism occur much later in life, with a peak at a much younger age than anticipated.

“There are lots of physiological changes that come with growing up and getting older,” said study co-author Herman Pontzer, associate professor of evolutionary anthropology at Duke University. “Think puberty, menopause, other phases of life. What’s weird is that the timing of our ‘metabolic life stages’ doesn’t seem to match those typical milestones.”

Together with an international team of scientists, Prof Pontzer analysed the average energy expenditure of more than 6,600 people ranging from one week old to age 95 as they went about their daily lives in 29 countries.

Previously, most large-scale studies measured how much energy the body uses to perform basic vital functions. But that amounts to only 50% to 70% of the calories we burn each day. It doesn’t take into account the energy we spend doing everything else.

To come up with a number for total daily energy expenditure, the researchers relied on the “doubly labeled water” method, a urine test that involves having a person drink water with isotopes of hydrogen and oxygen and measuring how quickly these were flushed. This gold standard technique for measuring energy expenditure in humans outside the lab since the 1980s, but studies have been limited in size and scope due to cost. To overcome this, multiple labs pooled their data.

The research into energy expenditures revealed some surprises: compared to body weight, infants had the highest metabolic rates of all, rather than people in their teens or 20s as might be expected.

Energy needs shoot up during the first 12 months of life, and by their first birthday, a one-year-old burns calories 50% faster for their body size than an adult.

This comes from more than just tripling their birth weight in the first year. “Of course they’re growing, but even once you control for that, their energy expenditures are rocketing up higher than you’d expect for their body size and composition,” said Pontzer, author of the book, “Burn,” on the science of metabolism. “Something is happening inside a baby’s cells to make them more active, and we don’t know what those processes are yet,” Pontzer said.

After this initial surge in infancy, the data show that metabolism slows by about 3% each year until we reach our 20s, when it stabilises.

Teenagers, despite their growth spurt, did not result in an uptick in energy intake once weight was accounted for. “We really thought puberty would be different and it’s not,” Pontzer said.

Midlife was another surprise, with a thickening waistline from the 30s often ascribed to a changing metabolism, but the results show other factors are responsible.

In fact, the researchers discovered that energy expenditures from the 20s to 50s were the most stable. Even during pregnancy, a woman’s calorie needs were no more or less than expected given her added bulk as the baby grows. Metabolism only declines after age 60, and only by 0.7% a year. A person in their 90s needs 26% fewer calories than one in midlife.

Lost muscle mass explains part but not all of the picture. “We controlled for muscle mass,” Pontzer said. “It’s because their cells are slowing down.”

The patterns held even when differing activity levels were taken into account.

Energy expenditure changes have been difficult to analyse because so much else is going on, Prof Pontzer said. But the research supports the idea that it’s more than age-related changes in lifestyle or body composition.

“All of this points to the conclusion that tissue metabolism, the work that the cells are doing, is changing over the course of the lifespan in ways we haven’t fully appreciated before,” Prof Pontzer said. “You really need a big data set like this to get at those questions.”

Source: Duke University

A Cognitive Rejuvenating Effect with Gut Microbe Transplant

Source: Pixabay

A novel approach to reverse aspects of ageing-related deterioration in the brain and cognitive function via the microbes in the gut was revealed in research published in Nature Aging.

With ageing populations increasing worldwide, a key challenge is the development of strategies to maintain healthy brain function. This ground-breaking research with gut microbes lays open new possibilities such as microbial-based interventions to slow down brain ageing and cognitive problems associated with it.

The work was carried out by researchers at Microbiome Ireland (APC) at University College Cork (UCC).

There is a growing appreciation of the importance of the microbes in the gut on all aspects of physiology and medicine. In this most recent study, the authors demonstrated that by transplanting gastrointestinal microbes from young into old mice, they were able to rejuvenate aspects of brain and immune function.

Study leader Professor John F Cryan said: “Previous research published by the APC and other groups internationally has shown that the gut microbiome plays a key role in aging and the ageing process. This new research is a potential game changer, as we have established that the microbiome can be harnessed to reverse age-related brain deterioration. We also see evidence of improved learning ability and cognitive function”.

Despite the promising results, Prof Cryan cautioned that “it is still early days and much more work is needed to see how these findings could be translated in humans”.

APC Director Prof Paul Ross stated that “This research of Prof Cryan and colleagues further demonstrates the importance of the gut microbiome in many aspects of health, and particularly across the brain/gut axis where brain functioning can be positively influenced. The study opens up possibilities in the future to modulate gut microbiota as a therapeutic target to influence brain health”.

Source: University College Cork

Cancer Survivors Experience Accelerated Ageing

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A new study published in Journal of the American Geriatrics Society indicates that cancer survivors, especially older ones, are more likely to experience faster functional decline as they age, compared with those without a history of cancer.

For the study, 1728 men and women (aged 22 to 100 years) were evaluated from 2006 to 2019, with 359 of these adults reporting a history of cancer. Among all participants, a history of cancer was associated with a 1.42 greater odds of weak grip strength. Those with a history of cancer and over 65 had a 1.61 greater odds of slow gait speed than those with no cancer history, and also had lower physical performance scores. Additionally, compared with those with no history of cancer, older individuals with a history of cancer experienced steeper declines in grip strength and gait speed. Reduced prefrontal cortex area is one of the factors thought to contribute to slow gait.

“Findings from our study add to the evidence that cancer and its treatment may have adverse effects on aging-related processes, putting cancer survivors at risk for accelerated functional decline,” said senior author Lisa Gallicchio, PhD, of the National Cancer Institute. “Understanding which cancer survivors are at highest risk, and when the accelerated decline in physical functioning is most likely to begin, is important in developing interventions to prevent, mitigate, or reverse the adverse aging-related effects of cancer and its treatment.”

Source: EurekAlert!

Study Uncovers Assortment of New Biomarkers for Dementia

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An international study identified 15 novel biomarkers that are linked to late-onset dementias. These protein biomarkers predict cognitive decline and subsequent increased risk of dementia 20 years before the disease onset. 

The proteins identified by the study are involved with immune system dysfunction, blood-brain-barrier dysfunction, vascular pathologies, and central insulin resistance. Six of these proteins can be modified with currently available medications.  

“These findings provide novel avenues for further studies to examine whether drugs targeting these proteins could prevent or delay the development of dementia,” explained lead author Joni Lindbohm MD, PhD from the University College London and University of Helsinki.

The study findings have been published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association.

Pathophysiological research on dementia aetiology has focused on amyloid beta and tau proteins, but thus far prevention and treatment trials targeting these biomarkers have been unsuccessful. This has spurred the search for other potential mechanisms that could predispose to dementia. Recent development of scalable platforms has made it possible to analyse a wide range of circulating proteins, which may reveal novel dementia-linked biological processes.

In this study, the researchers analysed proteins with a novel large-scale protein panel from stored blood samples of the British Whitehall II and US Atherosclerosis Risk in Communities (ARIC) study collected 20 years ago. Using a panel of 5000 proteins, the researchers identified proteins in plasma that predicted cognitive decline in 5-yearly screenings and subsequent onset of clinical dementia. The 15 proteins that were identified were predictive of dementia in both the British and US cohorts.

“This new study is the first step in our 5-year Wellcome Trust funded research programme. We will next examine whether the identified proteins have a causal association with dementia, and whether they are likely to be modifiable, and druggable”, said study author Professor Mika Kivimäki, Director of the Whitehall II study at University College London.

The research programme ultimately aims to identify novel drug targets for dementia prevention.

Source: EurekAlert!

Centenarians’ Unique Microbiomes Protect Against Bacterial Infections

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A new study has discovered that people who live to be 100 or older have a unique microbiome that may protect against certain bacterial infections  including those caused by multidrug-resistant bacteria. The findings, published in Nature, could point to new ways to treat chronic inflammation and bacterial disease.

A team of researchers studied microbes from  faecal samples of 160 Japanese centenarians who had an average age of 107. They found that centenarians, compared to people aged 85 to 89 and those between 21 and 55, had higher levels of several bacterial species that produce molecules called secondary bile acids. Secondary bile acids are generated by microbes in the colon and are thought to help protect the intestines from pathogens and regulate the body’s immune responses.

Next, the researchers treated common infection-causing bacteria in the lab with the secondary bile acids that were elevated in the centenarians. One molecule, called isoalloLCA, was found to strongly inhibit the growth of the  antibiotic-resistant bacterium Clostridioides difficile. Feeding mice infected with C. difficile diets supplemented with isoalloLCA similarly suppressed levels of the bacteria. The team also found that isoalloLCA potently inhibited or killed many other gram positive pathogens, suggesting that isoalloLCA may play a role in keeping the delicate equilibrium of microbial communities in a healthy gut.

“The ecological interaction between the host and different processes in bacteria really suggests the potential of these gut bugs for health maintenance,” said Plichta, a computational scientist at the Broad.

Additional studies from different regions around the world with more participants and longer duration could help find a causal link between longevity and bile acids. The bacteria identified in this study could help researchers in the meantime discover how to treat infections caused by antibiotic-resistant bacteria by manipulating bile acid.

“A unique cohort, international collaboration, computational analysis, and experimental microbiology all enabled this discovery that the gut microbiome holds the keys to healthy aging,” said co-first author Xavier, core institute member at the Broad. “Our collaborative work shows that future studies focusing on microbial enzymes and metabolites can potentially help us identify starting points for therapeutics.”

Source: Broad Institute of MIT and Harvard

Journal information: Sato Y, Atarashi K, et al. Unique bile acid-metabolizing bacteria in centenarians’ microbiome. Nature. Online July 29, 2021. DOI:10.1038/s41586-021-03832-5

AI Model Identifies Compounds That Could Extend Life

Photo by Tara Winstead from Pexels
Photo by Tara Winstead from Pexels

The University of Surrey has developed an artificial intelligence (AI) model that identifies chemical compounds that promote healthy ageing, which could help the development of pharmaceuticals for human lifespan extension.

In a paper published in Scientific Reports, a team of chemists from Surrey built a machine learning model based on the information from the DrugAge database to predict whether a compound can extend the life of Caenorhabditis elegans, a translucent worm whose metabolism is similar to humans. Because the worm has such a short lifespan, the researchers were able to test the effectiveness of the compounds.

The AI model identified three compounds that have an 80 percent chance of increasing the lifespan of elegans:

  • flavonoids (anti-oxidant pigments found in plants that promote cardiovascular health, examples include certain spices and herbs),
  • fatty acids (such as omega 3), and
  • organooxygens (compounds that contain carbon to oxygen bonds, such as alcohol).

Co-author Sofia Kapsiani, final year undergraduate student at the University of Surrey, said: “Ageing is increasingly being recognized as a set of diseases in modern medicine, and we can apply the tools of the digital world, such as AI, to help slow down or protect against ageing and age-related diseases. Our study demonstrates the revolutionary ability of AI to aid the identification of compounds with anti-aging properties.”

Commenting on the research, lead author Dr Brendan Howlin, Senior Lecturer in Computational Chemistry at the University of Surrey, said: “This research shows the power and potential of AI, which is a specialty of the University of Surrey, to drive significant benefits in human health.”

Source: SciTech Daily

Journal information: “Random forest classification for predicting lifespan-extending chemical compounds” by Sofia Kapsiani and Brendan J. Howlin, 5 July 2021, Scientific Reports.
DOI: 10.1038/s41598-021-93070-6

Junk DNA Yields Insights into Ageing and Cancer

Findings from a new study into ‘junk DNA’ have brought scientists one step closer to solving the mysteries of ageing and cancer.

Jiyue Zhu, a professor in the College of Pharmacy and Pharmaceutical Sciences, led a team which recently identified a DNA region known as VNTR2-1 which seems to drive activity of the telomerase gene, which has been shown to prevent ageing in certain types of cells. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS).

The telomerase gene controls the activity of the telomerase enzyme, which helps produce telomeres, the caps at the end of each strand of DNA that protect the chromosomes within our cells and which shorten over time until cells are no longer able to divide.

However, in certain cell types, such as reproductive cells and cancer cells, the telomerase gene’s activity ensures that telomeres are reset to the same length when DNA is copied. This is essentially what restarts the aging clock in new offspring but is also the reason why cancer cells can continue to multiply and form tumors.

Understanding how the telomerase gene is regulated and activated and why it is only active in certain types of cells could someday be the key to understanding how humans age, as well as how to stop the spread of cancer. That is why Prof Zhu has focused the past 20 years of his career as a scientist solely on the study of this gene.

Zhu said that VNTR2-1’s discovery is especially noteworthy due to the type of DNA sequence it represents.

“Almost 50% of our genome consists of repetitive DNA that does not code for protein,” noted Prof Zhu. “These DNA sequences tend to be considered as ‘junk DNA’ or dark matter in our genome, and they are difficult to study. Our study describes that one of those units actually has a function in that it enhances the activity of the telomerase gene.”

In previous work, deleting the DNA sequence from human and mouse cancer cells caused telomeres to shorten, cells to age, and tumours to stop growing. They conducted a subsequent study measuring the length of the sequence in DNA samples taken from Caucasian and African American centenarians and control participants in the Georgia Centenarian Study, a study that followed a group of people aged 100 or above between 1988 and 2008. The researchers found that the length of the sequence ranged from as short as 53 repeats of the DNA to as long as 160 repeats.

“It varies a lot, and our study actually shows that the telomerase gene is more active in people with a longer sequence,” Prof Zhu said.

Since very short sequences were found only in African American participants, they looked more closely at that group and found that there were relatively few centenarians with a short VNTR2-1 sequence as compared to control participants. However, Prof Zhu said that a shorter sequence does not necessarily translate to a shorter lifespan, since the telomerase gene is less active with possibly a shorter telomere length which could reduce cancer risk.

“Our findings are telling us that this VNTR2-1 sequence contributes to the genetic diversity of how we age and how we get cancer,” Prof Zhu said. “We know that oncogenes–or cancer genes–and tumor suppressor genes don’t account for all the reasons why we get cancer. Our research shows that the picture is a lot more complicated than a mutation of an oncogene and makes a strong case for expanding our research to look more closely at this so-called junk DNA.”

Prof Zhu observed that many African Americans in the United States for generations have Caucasian ancestry, which could have added this sequence. So he and his team hope to next be able to study the sequence in an African population.

Source: Washington State University

Journal information: Xu, T., et al. (2021) Polymorphic tandem DNA repeats activate the human telomerase reverse transcriptase gene. PNAS. doi.org/10.1073/pnas.2019043118.