Category: Ageing

Categories : AgeingTags :

‘Feed-forward’ Loop in Cartilage Cells Worsens Osteoarthritis

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An unfortunate ‘feed-forward’ loop in cartilage cells appears to exacerbate arthritis, according to researchers Duke University and Washington University in Saint Louis.

Cartilage resists compressive forces, enhances bone resilience, and provides support on bony areas where there is a need for flexibility. In osteoarthritis, the most common form of arthritis,  the cartilage breaks down, allowing painful bone-on-bone contact. Osteoarthritis is the and affects millions of people worldwide with joint pain and stiffness. It is most commonly found in the knees, hips and spine.  

Chondrocytes build and maintain cartilage, with force-sensitive ion channels on their surface, which are called Piezo1 and Piezo2. Piezo channels respond to mechanical loads on the joint by sending signals into the cell that can change gene activity.

In osteoarthritis, degeneration and malfunction of chondrocytes, which are unable to repair themselves by division, contributes to the progressive breakdown of cartilage. Osteoarthritis is als marked by chronic, low-grade inflammation, driven by interleukin-1 alpha, a signalling molecule. Taking cartilage cells from pigs and from human joints removed for replacement surgeries, the researchers investigated the way inflammation affects chondrocytes.

The researchers found that interleukin signaling causes the chondrocytes to produce more Piezo channels, in turn increasing their sensitivity to pressure and resulting in what the researchers term a harmful ‘feed-forward’ loop that leads to further cartilage breakdown.

“Interleukin reprograms the chondrocytes so that they’re more sensitive to mechanical trauma,” Liedtke said. “The feed-forward cycle slowly grinds them down and the cell cannot be replaced.”

Liedtke likened healthy chondrocyte to “a tennis ball”, a bouncy sphere which is kept stiff by its internal matrix of actin fibres. But as these cells lose their ability to replace actin fibres, “they get softer, more squishy.”

However, more Piezo channels were created as the chondrocytes became squishier.

“Overexpressed Piezo channels render the inflamed chondrocyte hypersensitive to mechanical microtrauma, thus increasing the risk of mechanically-induced chondrocyte injury and subsequent progression of osteoarthritis,” said  first and co-corresponding author and biomedical engineer, Whasil Lee, who moved from the Liedtke-Lab to open her own laboratory at the University of Rochester

“It’s cartilage reprogramming itself to do more damage,” Liedtke said.

To confirm this relationship, the researchers blocked the activity of the Piezo channels and observed that the ‘squishiness’ of chondrocytes was reverted.

“We have known that mechanical loading of the joint is essential for maintaining cartilage health,” Guilak said. “In this study, we have uncovered a mechanism by which excessive loading under inflammatory conditions can create a situation that can lead to progressive cartilage degeneration.”

“We’re always looking for feed-forward mechanisms as facilitators of chronic disease,” Liedtke said. “Here we found one, which opens the door for us to come up with disease-modifying treatments, currently non-existent for osteoarthritis.”

Source: Duke University

Journal information: “Inflammatory Signaling Sensitizes Piezo1 Mechanotransduction in Articular Chondrocytes as a Pathogenic Feed-Forward Mechanism in Osteoarthritis,” Whasil Lee, et al. PNAS, March 22, 2021, DOI: 10.1073/pnas.2001611118

Categories : AgeingTags :

Telomere Lengthening May Treat Renal Fibrosis

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A new study has shown that it may be possible to treat renal fibrosis, an age-related disease, by lengthening telomeres.

Previous research had shown it was that lengthening telomeres successfully treated pulmonary fibrosis and infarctions in mice.

Renal fibrosis is the leading cause of kidney failure, treatable only with dialysis. Moderate renal fibrosis is present in some 11% of people over 65, and is a predictor of the severity of renal failure. Telomeres are proteins at the end of chromosomes that maintain genetic integrity during cellular division. They shorten over time, eventually to the point where they are too short for cells to divide, becoming senescent. Telomere lengthening, eg through hyperbaric oxygen therapy, has been suggested as a way to reverse many age-related declines.

While short telomeres were by themselves not enough to cause renal fibrosis, the researchers found that mice with short telomeres developed it when they were exposed to small amounts of toxin, mimicking the environmental toxins people are exposed to over their lives. Mice that also lacked a certain protein needed for telomere function, Trf1, developed renal fibrosis, showing that telomeres are indeed involved in proper kidney function.

Since genes involved in epithelial-to-mesenchymal transition are overexpressed in patients with kidney failure, the researchers looked for this in mice with short telomeres. And “we found that short telomeres induce changes in the expression of genes involved in EMT.”

As a final demonstration of the importance of telomeres in kidney fibrosis, the authors cultured kidney cells in which they expressed the gene for the telomerase enzyme, which elongates telomeres. In these cells with restored telomeres, the epithelial-to-mesenchymal transition program returned to normal, and the cells regained their healthy, pre-fibrosis appearance.

“As short telomeres accumulate with ageing in the organism, it is tempting to speculate that pathological EMT programmes associated with ageing, such as cancer and different types of tissue fibrosis, may be originated at least in part by the presence of short telomeres,” the authors conclude.

Source: News-Medical.Net

Categories : Ageing NeurologyTags :

Jump-Starting Neural Stem Cells in Aged Brains

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As we age, neural stem cells lose the ability to divide and create new neurons, resulting in a decline in memory. Now, research led by Sebastian Jessberger, a professor at the Brain Research Institute of the University of Zurich, explains why this happens.

The new neurons are used all over the brain, including the hippocampus which is responsible for memory. Declines here from age and Alzheimer’s mean fewer neurons are produced here, impacting memory functions.

“As we get older, stem cells throughout the body gradually lose their ability to proliferate. Using genetic engineering and cutting-edge microscope technology, we were able to identify a mechanism that is associated with this process,” explained doctoral candidate and first author Khadeesh bin Imtiaz. The results were published in the journal Cell Stem Cell.

The study used a mouse model to show that as organisms age, neurons’ ability to divide becomes impaired. Protein structures ensure that accumulated harmful proteins are laid out unequally among the two daughter neurons, important for the longevity of neurons. As the neurons age, the amount of nucleic proteins changes, resulting in impaired distribution of proteins, reducing the number of newly generated neurons in the brains of older mice.

The researchers identified a nuclear protein called lamin B1, levels of which decrease as people age. When lamin B1 was increased in aged mice, there was an improvement in stem cell division and the number of neurons increased.

The study was part of wider research into ageing and stem cells. “While our study was limited to brain stem cells, similar mechanisms are likely to play a key role when it comes to the ageing process of other stem cells,” said Prof Jessberger.

The latest findings represent an important step in understanding how brain stem cells change with age. “We now know that we can reactivate aging stem cells in the brain. Our hope is that these findings will one day help increase levels of neurogenesis, for example in older people or those suffering from degenerative diseases such as Alzheimer’s. Even if this may still be many years in the future,” concluded Prof Jessberger.

Source: Medical Xpress

Journal information: Cell Stem Cell, DOI: 10.1016/j.stem.2021.01.015

Categories : Ageing GastrointestinalTags :

Gut Microbiome Changes are Linked to Ageing and Longevity

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Ageing in humans is marked by compositional changes in the gut microbiome that become more unique later in life.

Researchers from the Institute for Systems Biology (ISB) analysed gut microbiome, phenotypic and clinical data from over 9000 people across three independent cohorts. Health and survival outcomes were tracked from longitudinal data from a cohort of over 900 community-dwelling older individuals (78-98 years old).

The researchers found that, starting in mid-to-late adulthood, gut microbiomes became increasingly unique as individuals aged, corresponding with a steady decline in the abundance of core bacterial genera common across humans.

Strikingly, while microbiomes became increasingly unique to each individual in healthy aging, the metabolic functions the microbiomes were carrying out shared common traits. Gut microbiome uniqueness was highly correlated with several microbially-derived metabolites in blood plasma. One of them, tryptophan-derived indole, has been shown to extend lifespan in mice. Another metabolite, phenylacetylglutamine, showed the strongest association with uniqueness, and is known to be highly elevated in the blood of people over 100.

“This uniqueness signature can predict patient survival in the latest decades of life,” said study leader Dr Tomasz Wilmanski, who led the study. Healthy individuals aged around 80 showed continued microbial drift toward a uniqueness, but this drift was not seen in less healthy individuals of the same age.

“Interestingly, this uniqueness pattern appears to start in mid-life—40-50 years old—and is associated with a clear blood metabolomic signature, suggesting that these microbiome changes may not simply be diagnostic of healthy aging, but that they may also contribute directly to health as we age,” Wilmanski said. Indoles are known to reduce inflammation in the gut, for example, and chronic inflammation is believed to drive age-related morbidities.

“Prior results in microbiome-aging research appear inconsistent, with some reports showing a decline in core gut genera in centenarian populations, while others show relative stability of the microbiome up until the onset of aging-related declines in health,” said co-corresponding author, microbiome specialist Dr Sean Gibbons. “Our work, which is the first to incorporate a detailed analysis of health and survival, may resolve these inconsistencies. Specifically, we show two distinct aging trajectories: (1) a decline in core microbes and an accompanying rise in uniqueness in healthier individuals, consistent with prior results in community-dwelling centenarians, and (2) the maintenance of core microbes in less healthy individuals.”

This analysis highlights the fact that the adult gut microbiome continues to develop with advanced age in healthy individuals, but not in unhealthy ones, and that microbiome compositions associated with health in early-to-mid adulthood may not be compatible with health in late adulthood.

Source: Medical Xpress

Journal information: Gut microbiome pattern reflects healthy ageing and predicts survival in humans, Nature Metabolism (2021). DOI: 10.1038/s42255-021-00348-0

Categories : Ageing Cardiovascular Disease Substance UseTags :

Recreational Substances Including Cannabis Linked to Heart Disease

On By ModernMedia

Alcohol, tobacco and cannabis are among recreational drugs that contribute to early-onset atherosclerotic cardiovascular disease (ASCVD) in young people, a study has found.

The study drew on data of more than a million people receiving primary care services throughout the VA Healthcare System in 2014 or 2015, of whom there were 135 703 with premature ASCVD.

A number of independent predictors for first-event ASCVD for men (from age 55) and women (from 65) were picked up. Tobacco (adjusted odds ratio [OR] 1.97) and alcohol use (OR 1.50)  conferred significant additional risk, but the greatest risk increase of generally legal substances was cannabis use (OR 2.65). Cocaine use (OR 2.44), amphetamine use (OR 2.74) and other drug use (OR 2.53) all had very high risk increases.

Those using four or more substances had the greatest risk at nearly nine times normal. Women also had much stronger effect sizes for premature ASCVD than men.

In an accompanying editorial Anthony Wayne Orr, PhD, and colleagues at LSU Health Shreveport, wrote: “Substance use disorders have been associated with an acceleration of the ageing process. We are only young once, and we should do everything in our power to maintain that state as long as we can.”

The editorialists suggested a nationwide ASCVD education campaign targeting people with substance use disorders.

“In addition, clinicians and primary care providers should begin screening their adult and young adult patients with a history of a substance use disorder for symptoms of premature or extremely premature ASCVDs at earlier stages in their patients’ lives,” suggested the editorialists.

Limitations included it being an observational study, lack of socioeconomic data and the cohort being mostly white males, as well as not being able to discern between prescription and recreational amphetamine use.
“Retrospective studies are limited by the available data. While this study supports the association between substance use disorder and early-onset ASCVD, the effect of substance use frequency, dose, and duration cannot be reliably ascertained in this patient sample,” the editorialists stated.

The editorialists recommended that specific biomarkers for substance use-associated cardiovascular disease be identified, and therapeutic window characterised to limit these chronic effects of substance use disorder.

Source: MedPage Today

Journal information: Mahtta D, et al “Recreational substance use among patients with premature atherosclerotic cardiovascular disease” Heart 2021; DOI: 10.1136/heartjnl-2020-318119.

Editorial information: Scott ML, et al “Young at heart? Drugs of abuse cause early-onset cardiovascular disease in the young” Heart 2021; DOI: 10.1136/heartjnl-2020-318856.

Categories : Ageing COVID General InterestTags :

Europe’s Oldest Living Person, 116, Survives COVID

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A 116 year old French nun who is Europe’s oldest living person has survived COVID after testing positive.

French nun Sister Andrée had tested positive for COVID in her retirement home in Toulon, but had remained symptom-free. Most of the 88 residents at the home contracted the virus, 10 of whom died. 

Sister Andrée, who is blind and in a wheelchair, said that her main complaint was the solitude necessitated by being confined to her room.
“I didn’t even realise I had it,” she told Var-Matin newspaper:

David Tavella, a spokesperson for the nursing home, told the newspaper that she had no fear of the virus.

“She didn’t ask me about her health but about her routine. She wanted to know for example if the meal and bed times were going to change. She showed no fear of the illness, in fact she was more worried about the other residents,” Mr Tavella said.

When asked by France’s BFM Television if she had been scared of having COVID, she responded: “No, I wasn’t scared because I wasn’t scared to die … I’m happy to be with you, but I would wish to be somewhere else – join my big brother and my grandfather and my grandmother.”

In addition to being Europest oldest living person, she is also the world’s second oldest living person. The oldest living person in the world is Kane Tanaka in Japan, who turned 118 on January 2. Having lived through the First World War as a child, Sister Andrée will turn 117 on Thursday.

Source: The Guardian

Categories : Ageing General Interest Neurodegenerative DiseasesTags :

Legendary Singer Tony Bennett Diagnosed with Alzheimer’s

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Music legend Tony Bennett, 94, revealed in an interview that he was diagnosed with Alzheimer’s disease 4 years ago.

The singer’s career has spanned seven decades, he had continued his initial success in the 1950s across multiple genres, becoming a hit with the MTv generation, and in more recent years collaborating with popular artists like Amy Winehouse and Lady Gaga.

Alzheimer’s disease is an age-related, irreversible neurodegenerative condition. In more than 90% of patients, it begins after age 65, although it can occur as early as in the 30s. It is marked by memory loss and confusion that seem like the normal cognitive decline of older age, but it is more rapid and severe, eventually resulting in death. As people live longer and the risks of developing this disease increase with age, the burden of this disease is expected to increase in the future. In the US, the number of people with Alzheimer’s is expected to nearly triple from 5.5 million to 14 million by 2060.

Mr Bennett has been able to work over the past four years but the toll is perceptible. He still recognises his family members but his short-term and long-term memory have drastically deteriorated. Interviewer John Colapinto noted Mr Bennett gazing at his lavishly illustrated book, “Tony Bennett Onstage and in the Studio” (2018). “He stared into its pages not with the air of warm reminiscence but like a man struggling to recall why these images seemed familiar.” His wife, Susan, added that Mr Bennett is “not always sure where he is or what is happening around him. Mundane objects as familiar as a fork or a set of house keys can be utterly mysterious to him.”

Over the past two years, Mr Bennett recorded a second album of duets with Lady Gaga, a follow-up to the hit album with Gaga in 2014. While he had been known to be a “meticulous and hard-driving perfectionist in the studio,” Mr Bennett was much more subdued. speaking rarely, his words coming haltingly and seeming lost or bewildered. Gaga, who considers Mr Bennett to be “an incredible mentor, and friend, and father figure” is seen breaking down in tears as Tony sings a solo passage of a love song.

The album is due to be released this spring, but Mr Bennett will be unable to do promotional interviews. Mr Bennett, together with his wife and son (who is also his manager) decided to break the news, in the hopes that as many fans as possible know about what will likely be his final record. The neurologist who diagnosed Bennett in 2016,  Gayatri Devi, MD, said: “He is doing so many things, at 94, that many people without dementia cannot do. He really is the symbol of hope for someone with a cognitive disorder.”

Source: MedPage Today

Categories : Ageing Cardiovascular DiseaseTags :

Cannabis can Lower Hypertension in Older Adults

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Adding to a growing body of evidence as to its health benefits, medical cannabis may lower blood pressure in older adults, according to research from Ben-Gurion University of the Negev (BGU) and its affiliated Soroka University Medical Center.

This is the first such study to investigate cannabis’  effect on blood pressure, heart rate and metabolic parameters in hypertensive adults 60 and older.

“Older adults are the fastest growing group of medical cannabis users, yet evidence on cardiovascular safety for this population is scarce. This study is part of our ongoing effort to provide clinical research on the actual physiological effects of cannabis over time,” said Dr Ran Abuhasira, BGU Faculty of Health Sciences and BGU-Soroka Cannabis Clinical Research Institute

Before and three months after beginning medical cannabis therapy, patients in the study were evaluated using 24-hour ambulatory blood pressure monitoring, ECG, blood tests, and body measurements. Patients ingested cannabis either orally in the form of oil extracts or by smoking.

The findings included a significant drop in 24-hour systolic and diastolic blood pressure values, with the lowest point occurring three hours after ingesting cannabis. Both daytime and nighttime reductions in blood pressure were observed, with more greater changes at night. Higher nighttime than daytime blood pressure may also raise the risk of Alzheimer’s disease, so lowering it at night may offer that benefit.

The pain relief from taking cannabis, often a reason for prescriptions, may also have resulted in a reduction of blood pressure, the BGU researchers postulated.

“Cannabis research is in its early stages and BGU is at the forefront of evaluating clinical use based on scientific studies,” said Doug Seserman, chief executive officer of American Associates, BGU. “This new study is one of several that has been published recently by BGU on the medicinal benefits of cannabis.”

Source: News-Medical.Net

Journal information: Abuhasira, R., et al. (2021) Cannabis is associated with blood pressure reduction in older adults – A 24-hours ambulatory blood pressure monitoring study. European Journal of Internal Medicine.doi.org/10.1016/j.ejim.2021.01.005.

Categories : AgeingTags :

APLS1 Inhibitors Eliminate Senescent Cells to Ameliorate Ageing

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A new technique has been developed to eliminate senescent cells that are involved in many age-related diseases, according to a study by researchers at the University of Tokyo.

As ageing progresses, cancers emerge, motor function declines through muscle loss, and metabolic disorders occur due to adipose tissue atrophy. Senescent cells accumulating in organs are behind many of these problems; their telomeres having shortened through divisions as a result of multiple stresses and now at their replication limit, they now no longer function effectively. Previous research using genetic engineering to knock out senescent cells in mice was able to put the onset of age-related diseases such as arteriosclerosis and renal damage, and extended life expectancy. However, the research did not yield a drug which could be given as a treatment.

To tackle this problem, the researchers created a way to produce large numbers of purified senescent. cells to search for genetic targets for drugs. One of the ways they found involved GLS1, a gene involved in glutamine. On testing with GLS1 inhibitors, senescent cells were vulnerable due to damage to the lysosomal membrane and lower intracellular pH. Lysosomes are organelles which produce enzymes to destroy defunct cell parts, bacteria and viruses if needed, and the cell itself if apoptosis is triggered. They also have an essential role in the regulation of intracellular pH, and are very acidic, having to be protected from the rest of the cell by a membrane. Analysing the dynamics of lysosomes, the team found that damage to the lysosomal membranes in senescent cells decreases intracellular pH.

When they administered GLS1 inhibitors to old mice, knocking out senescent cells, their ageing was significantly improved. The symptoms of obese diabetes, arteriosclerosis, and fatty liver disease were ameliorated. GLS1 inhibitors are already being used in trials as cancer treatments.
“We hope that innovative anti-aging therapies and treatments for geriatric diseases will be developed that can remove senescent cells by treatment with GLS1 inhibitors,” said Professor Nakanishi.

Source: News-Medical.Net

Journal information: Johmura, Y., et al. (2021) Senolysis by glutaminolysis inhibition ameliorates various age-associated disorders. Science. doi.org/10.1126/science.abb5916.

Categories : Ageing HIVTags :

Anti-HIV Drugs may Combat Macular Degeneration

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New research has shown that anti-HIV drugs may fight macular degeneration – overturning a preconception about DNA in the process.

Macular degeneration is the leading cause of blindness in developed countries. Even though HIV does not cause dry macular degeneration, the drugs prevented the loss of vision.

“We are extremely excited that the reduced risk was reproduced in all the databases, each with millions of patients,” said Jayakrishna Ambati, MD, a leading macular degeneration researcher at the University of Virginia School of Medicine. “This finding provides real hope in developing the first treatment for this blinding disease.”

A Big Data Archeology review of four health insurance databases showed that Nucleoside Reverse Transcriptase Inhibitors (NRTIs), a commonly used HIV treatment, reduced the incidence of dry macular degeneration by 40%. The records spanned two decades and covered over 100 million patients. The drugs had also previously been shown to possibly prevent diabetes.

The finding also comes with the discovery that DNA can be produced inside the cytoplasm. Alu DNA (found exclusively in primates), which makes up 10% of the human genome, is transposable and can insert itself into other places on the genome. It was long considered “junk” DNA, but are now believed to have important functions, such as allowing for multiple expressions of proteins from a single Alu element. Since it cannot replicate itself, Alu DNA requires a transposon called L1 to accomplish this, which was now reported to allow the production of Alu DNA outside the chromosome. The buildup of Alu DNA in cells contributes to macular degeneration, by killing off cells that support the retina.
The researchers are urging further investigation into NRTIs or safer derivatives known as Kamuvudines, both of which block a key inflammatory pathway, can be useful in preventing vision loss from dry macular degeneration.

“A clinical trial of these inflammasome-inhibiting drugs is now warranted,” said Ambati. “It’s also fascinating how uncovering the intricate biology of genetics and combining it with big data archeology can propel insights into new medicines.”

Source: Medical Xpress

Journal Information: Shinichi Fukuda el al., “Cytoplasmic synthesis of endogenous Alu complementary DNA via reverse transcription and implications in age-related macular degeneration,” PNAS (2021). www.pnas.org/cgi/doi/10.1073/pnas.202275111