Connect with us

News

Short-lived fish could hold key to reversing muscle ageing

Published

on

The vibrantly coloured and short-lived African killfish may hold secrets to reversing muscle ageing, say researchers.

As we age, our muscles start to waste. Called sarcopenia, it happens to everyone, but no-one has ever understood how and why it occurs.

Now new research from the Australian Regenerative Medicine Institute (ARMI) at Monash University in Melbourne, has used a surprising animal model – the African killfish – to reveal that towards the end of life, our muscles actually reverse to an ‘early-life’ state, slowing mortality.

This finding could provide a clue to slowing, halting or even reversing age-related loss of muscle mass and strength.

The research, published in the monthly peer-reviewed Aging Cell and led by Professor Peter Currie and Dr Avnika Ruparelia, who are from ARMI and the University of Melbourne, is important because of the expected dramatic increase in the prevalence and severity of sarcopenia with those aged over 60 expected to rise from one billion to 1.4 billion by 2030.

By 2050 the World Health Organisation predicts the global population of people aged 60 and over will have doubled to 2.1 billion.

According to Professor Currie, “…there is a pressing need to understand the mechanisms that drive sarcopenia, so that we can identify and implement suitable medical interventions to promote healthy muscle ageing.”

The African turquoise killifish, scientifically known as Nothobranchius furzeri, has recently emerged as a new model for the study of ageing.

Killifish have the shortest known life span of any vertebrate species that can be bred in captivity. Life for a killifish begins with the African rains. The drought-resistant eggs and embyros enter a state of suspended animation, entombed in hard mud until the next rainfall creates water pools – which can be months or even years.

The arrival of the rain then triggers the eggs into hatching, They grow, mature, reach sexual maturity and mate in just 14 days, reproducing daily until the rain pool dries. In all, the killfish will only live for around nine or ten weeks. Even those bred in captivity will only survive for between four and six months.

Importantly for scientists, their short life span is accompanied with symptoms of ageing seen in humans. These include the appearance of cancerous lesions in the liver and gonads, reduced regenerative capacity of the limbs, in this case the fin, and genetic characteristics that are the hallmark of getting old such as a reduction in mitochondrial DNA copy number and function and shortening of telomeres – the protective caps on the ends of chromosomes that affect how quickly cells age.

A just-hatched killifish larvae. Image: Dr Avnika Ruparelia

According to Dr Ruparelia, this study is the first to use the killifish to examine sarcopenia, which can affect not only muscle mass, but also impact on gait, balance and people’s ability to go about daily tasks and physical activities, exacerbating the problem.

She explained: “In this study, we performed a thorough cellular and molecular characterisation of skeletal muscle from early life, aged and extremely old late-life stages, revealing many similarities to sarcopenia in humans and other mammals.”

Surprisingly the researchers also found these same metabolic hallmarks of ageing are reversed during the late-life stage, “suggesting that in extremely old animals, there may be mechanisms in place that prevent further deterioration of skeletal muscle health, which may ultimately contribute to an extension of their life span,” Dr Ruparelia added.

“Importantly, the late-life stage during which we observed improved muscle health perfectly coincides with a stage when mortality rates decline. We therefore postulate that the improvement in muscle health may be a critical factor contributing to the extension of life span in extremely old individuals.”

To better understand the mechanisms behind this, the research team surveyed the metabolism of fish at different stages of the ageing process.

This experiment surprisingly revealed that certain features of the metabolism of the very oldest fish actually were rejuvenated to resemble those of young fish.

It highlighted the critical role of lipid metabolism in this process of rejuvenation.  By using drugs that regulate the formation of certain lipids a similar rejuvenation of ageing muscle could be achieved.

Senior author, Prof Currie., said: “During extreme old age, there is a striking depletion of lipids, which are the main energy reserves in our cells. We believe that this mimics a state of calorie restriction, a process known to extend life span in other organsims, which results in activation of downstream mechanisms ultimately enabling the animal to maintain nutrient balance and live longer.

“A similar process is seen in the muscle of highly trained athletes.”

Dr Ruparelia went on to say: “The idea that muscle ageing may be reversible, and potentially treatable by drugs that can manipulate a cell’s metabolism, is an exciting prospect especially given the social, economic and healthcare costs associated with the ever-growing aged population around the world.

“We are excited by the potential of the killifish model, and very grateful to the Winston Churchill Trust for funding, and to Hon Dr Kay Patterson for her assistance with establishing the import regulations to establish the first and only killifish facility in Australia.

“We now have a unique opportunity to study biological processes regulating ageing and age-related diseases, and to investigate strategies to promote heathy ageing.”

News

Gut microbes from aged mice induce inflammation in young mice

Published

on

Findings from a new study suggest that changes to the gut microbiome play a role in the systemwide inflammation that often occurs with ageing.

When scientists transplanted the gut microbes of aged mice into young “germ-free” mice — raised to have no gut microbes of their own — the recipient mice experienced an increase in inflammation that parallels inflammatory processes associated with ageing in humans. Young germ-free mice transplanted with microbes from other young mice had no such increase.

Published in Aging Cell, the study also found that antibiotics caused longer-lasting disruptions in the gut microbiomes of aged mice than in young mice.

“There’s been a growing consensus that ageing is associated with a progressive increase in chronic low-grade inflammation,” said Jacob Allen, a professor of kinesiology and community health at the University of Illinois Urbana-Champaign who led the new research with Thomas Buford, a professor of medicine at the University of Alabama at Birmingham.

“And there’s a kind of debate as to what drives this, what is the major cause of the ageing-induced inflammatory state. We wanted to understand if the functional capacity of the microbiome was changing in a way that might contribute to some of the inflammation that we see with ageing.”

Previous studies have found associations between age-related changes in the microbial composition of the gut and chronic inflammatory diseases such as Parkinson’s disease and Alzheimer’s disease. Some studies have linked microbial metabolism to an individual’s susceptibility to other health conditions, including obesity, irritable bowel syndrome and heart disease. Age-related changes in the gut microbiome also may contribute to the so-called leaky gut problem, the researchers said.

“Microbiome patterns in aged mice are strongly associated with signs of bacterial-induced barrier disruption and immune infiltration,” they wrote.

“The things that are in our gut are supposed to be kept separate from the rest of our system,” Buford said. “If they leak out, our immune system is going to recognize them. And so then the question was: ‘Is that a source of inflammation?’”

Many studies have compared the relative abundance and diversity of species of microbes in the gut, offering insight into some of the major groups that contribute to health or disease. But sequencing even a portion of the microbes in the gut is expensive and the results can be difficult to interpret, Allen said. That is why he and his colleagues focused on microbial function — specifically, how the gut microbiomes of ageing mice might spur an immune response.

The team focused on toll-like receptors, molecules that mediate inflammatory processes throughout the body. TLRs sit in cellular membranes and sample the extracellular environment for signs of tissue damage or infection. If a TLR encounters a molecule associated with a potential pathogen — for example, a lipopolysaccharide component of a gram-negative bacterium — it activates an innate immune response, calling in pro-inflammatory agents and other molecules to fight the infection.

The researchers first evaluated whether the colonic contents of young and aged mice were likely to promote TLR signalling. They found that microbes from aged mice were more likely than those from young mice to activate TLR4, which can sense lipopolysaccharide components of bacterial cell walls. A different receptor, TLR5, was not affected differently in aged or young mice. TLR5 senses a different bacterial component, known as flagellin.

Young germ-free mice transplanted with the microbes of aged mice also experienced higher inflammatory signalling and increased levels of lipopolysaccharides in the blood after the transplants, the team found.

This finding provides “a direct link between ageing-induced shifts in microbiota immunogenicity and host inflammation,” the researchers wrote.

In other experiments, the team treated mice with broad-spectrum antibiotics and tracked changes in the microbiomes during treatment and for seven days afterward.

“One of the most interesting questions for me was what microbes come back immediately after the treatment with antibiotics ends,” Buford said. And in the mice with aged microbiota in their guts, “these opportunistic pathogens were the most quick to come back.”

“It appears that as we age our microbiome might be less resilient to antibiotic challenges,” Allen said. “This is important because we know that in the U.S. and other Western societies, we’re increasingly exposed to more antibiotics as we age.”

The study is an important step toward understanding how age-related microbial changes in the gut may affect long-term health and inflammation, the researchers said.

Co-authors of the study also included Illinois postdoctoral researcher Elisa Caetano-Silva; U. of I. Ph.D. student Akriti Shrestha; National Children’s Hospital research scientist Michael Bailey; and Jeffrey Woods, the director of the Center on Health, Aging and Disability at Illinois.

Allen also is a professor of nutritional sciences at Illinois and an affiliate of the Carl R. Woese Institute for Genomic Biology at the U. of I.

Continue Reading

News

Evening exercise benefits elderly hypertensives

Published

on

Evening exercise benefits elderly hypertensives

A study conducted at the University of São Paulo with 23 volunteers found that aerobic exercise performed in the evening benefits elderly hypertensives more than morning exercise.

Aerobic training is known to regulate blood pressure more effectively when practiced in the evening than in the morning.

Researchers who conducted a study of elderly patients at the University of São Paulo’s School of Physical Education and Sports (EEFE-USP) in Brazil concluded that evening exercise is better for blood pressure regulation thanks to improved cardiovascular control by the autonomic nervous system via a mechanism known as baroreflex sensitivity.

Leandro Campos de Brito, first author of the article, commented: “There are multiple mechanisms to regulate blood pressure, and although morning training was beneficial, only evening training improved short-term control of blood pressure by enhancing baroreflex sensitivity.

“This is important because baroreflex control has a positive effect on blood pressure regulation, and there aren’t any medications to modulate the mechanism.”

In the study, 23 elderly patients diagnosed and treated for hypertension were randomly allocated into two groups: morning training and evening training. Both groups trained for ten weeks on a stationary bicycle at moderate intensity, with three 45-minute sessions per week.

Key cardiovascular parameters were analysed, such as systolic and diastolic blood pressure, and heart rate after ten minutes’ rest. The data was collected before and at least three days after the volunteers completed the ten weeks of training.

The researchers also monitored mechanisms pertaining to the autonomic nervous system, which controls breathing, heart rate, blood pressure, digestion, and other involuntary bodily functions, such as muscle sympathetic nerve activity, which regulates peripheral blood flow via contraction and relaxation of blood vessels in muscle tissue, and sympathetic baroreflex sensitivity, assessing control of blood pressure via alterations to muscle sympathetic nerve activity.

In the evening training group, all four parameters analysed were found to improve: systolic and diastolic blood pressure, sympathetic baroreflex sensitivity, and muscle sympathetic nerve activity. In the morning training group, no improvements were detected in muscle sympathetic nerve activity, systolic blood pressure or sympathetic baroreflex sensitivity.

“Evening training was more effective in terms of improving cardiovascular autonomic regulation and lowering blood pressure. This can be partly explained as due to an improvement in baroreflex sensitivity and a reduction of muscle sympathetic nerve activity, which increased in the evening. For now, all we know is that baroreflex control is the decisive factor, from the cardiovascular standpoint at least, to make evening training more beneficial than morning training, since it induces the other benefits analysed. However, much remains to be done in this regard in order to obtain a better understanding of the mechanisms involved,” said Brito, who is currently a professor at Oregon Health & Science University’s Oregon Institute of Occupational Health Sciences in the United States, and continues to investigate the topic via circadian rhythm studies.

Baroreflex sensitivity regulates each heartbeat interval and controls autonomic activity throughout the organism.

“It’s a mechanism that involves sensitive fibres and deformations in the walls of arteries in specific places, such as the aortic arch and carotid body. When blood pressure falls, this region warns the brain region that controls the autonomic nervous system, which in turn signals the heart to beat faster and tells the arteries to contract more strongly. If blood pressure rises, it warns the heart to beat more slowly and tells the arteries to contract less. In other words, it modulates arterial pressure beat by beat,” Brito explained.

In previous studies, the EEFE-USP research group showed that evening aerobic training reduced blood pressure more effectively than morning training in hypertensive men (read more at: agencia.fapesp.br/34194), and that the more effective response to evening training in terms of blood pressure control was accompanied by a greater reduction in systemic vascular resistance and systolic pressure variability (read more at: agencia.fapesp.br/37432).

“Replication of the results obtained in previous studies and in different groups of hypertensive patients, associated with the use of more precise techniques to evaluate the main outcomes, has strengthened our conclusion that aerobic exercise performed in the evening is more beneficial to the autonomic nervous system in patients with hypertension. This can be especially important for those with resistance to treatment with medication,” Brito said.

Continue Reading

News

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

Published

on

Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

A new hybrid nanotube stamp system has been developed which revolutionises precision medicine with high efficiency and cell viability rates for cancer treatment.

Precision medicine and targeted therapies are gaining traction for their ability to tailor treatments to individual patients while minimising adverse effects. Conventional methods, such as gene transfer techniques, show promise in delivering therapeutic genes directly to cells to address various diseases.

However, these methods face significant drawbacks, hindering their efficacy and safety. Intracellular protein delivery offers a promising approach for developing safer, more targeted, and effective therapies. By directly transferring proteins into target cells, this method circumvents issues such as silencing during transcription and translation and the risk of undesirable mutations from DNA insertion. Additionally, intracellular protein delivery allows for precise distribution of therapeutic proteins within target cells without causing toxicity.

A group of researchers led by Professor Takeo Miyake at Waseda University, Japan in collaboration with the Mikawa Group at the RIKEN Institute have now developed a hybrid nanotube stamp system for intracellular delivery of proteins. This innovative technique enables the simultaneous delivery of diverse cargoes, including calcein dye, lactate oxidase (LOx) enzyme, and ubiquitin (UQ) protein, directly into adhesive cells for cancer treatment.

The researchers explored the therapeutic potential of delivering LOx enzyme for cancer treatment. “Through our innovative stamp system, we successfully delivered LOx into both healthy mesenchymal stem cells (MSC) and cancerous HeLa cells. While MSC cells remained unaffected, we observed significant cell death in HeLa cancer cells following LOx treatment with viabilities decreasing over time. Our findings highlight the promising efficacy of intracellularly delivered LOx in selectively targeting and killing cancer cells, while sparing healthy cells, offering a targeted therapeutic strategy for cancer treatment,” explains Miyake.

Finally, the team successfully delivered 15N isotope-labeled UQ proteins into HeLa cells using the HyNT stamp system. This delivery allowed for the analysis of complex protein structures and interactions within the cells. In addition, optical and fluorescence imaging confirmed the presence of delivered UQ in HeLa cells, and nuclear magnetic resonance spectroscopy matched the intracellular UQ protein concentration with that of a solution containing 15N-labeled UQ. These results demonstrate the effectiveness of the stamp system in delivering target proteins for subsequent analysis.

The results demonstrate the remarkable capability of the HyNT stamp system in delivering LOx and UQ into a substantial number of adhesive cells, as required for regenerative medicine applications. The system achieved a notably high delivery efficiency of 89.9%, indicating its effectiveness in transporting therapeutic proteins into the target cells with precision. Moreover, the cell viability rate of 97.1% highlights the system’s ability to maintain the health and integrity of the treated cells throughout the delivery process.

The HyNT stamp system offers transformative potential in intracellular protein delivery, with applications spanning from cancer treatment to molecular analysis. Beyond medicine, its versatility extends to agriculture and food industries, promising advancements in crop production and food product development. With precise cell manipulation and efficient delivery, the HyNT stamp system is poised to revolutionize biomedical research, clinical practice, and diverse industries, paving the way for personalized interventions and shaping the future of modern medicine.

Continue Reading

Trending