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Have scientists finally found the cure for ageing?

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Cleopatra is said to have favoured asses’ milk, the ancient Greeks olive oil and yoghurt, Elizabethan women slices of raw meat, the Georgians mature wine, and the Victorians honey, oatmeal and egg yolks.

The above may read like a catalogue of fashionable foods from an historical grocery list or the latest fad diet. But in their day these mixed bag of ingredients were considered to be cutting-edge anti-ageing cures.

The fight against wrinkles and lines has been preoccupying humans if not quite from the dawn of time, from at least 2500BC when the people of the Indus Valley Civilisation are known to have developed powders and herbal remedies to improve not just their complexion but prevent thinning tresses and the appearance of grey hair.

The desire to turn back the human biological clock and stay forever young has become the  modern day Holy Grail. According to industry research company IMARC Group, the global anti-ageing market was worth US $67.2bn in 2022. That figure is predicted to swell to a staggering US $98.6bn by 2028 on the back of a rising awareness of the plethora of anti-ageing products now on the market, the increased consciousness among individuals about their physical appearance, and the growing popularity of non-surgical procedures and treatments designed to counter the process of becoming old.

Reversing or slowing down the effects of ageing isn’t just pre-occupying the beauty industry and the billions around the world slavishly buying into medical procedures and over-the-counter remedies promising to restore a youthful body and complexion.

Research scientists too are captivated with finding an answer to the centuries old question of how the brakes can be applied to ageing.

And not necessarily for the sake of our vanity. Ageing is the most debilitating problem humans face. Sadly, getting old can open a Pandora’s box of unpleasant health issues, from cancer to dementia, mobility problems, hearing loss, diabetes, pulmonary disease and depression.

According to the latest figures from the EU, 84.9% of all deaths in 2020 across European Union countries occurred in people over the age of 65. Of those, just over a third (35%) of deaths were caused by diseases of the circulatory system. Nearly one in three of these (11%) were as a result of ischaemic heart disease.

The second most common cause of death among elderly people was cancer at 20.5%.

But a growing number of scientists claim it doesn’t have to be like this and are seeking ways of rebooting the body.

According to João Pedro de Magalhães, a professor of Molecular Biogerontology in the Institute of Inflammation and Ageing at the University of Birmingham in the UK, most mechanistic explanations of ageing put forward that it’s caused by the accumulation of one or more forms of molecular damage.

But Professor Magalhães thinks otherwise. He believes ageing could be seen as an error in the software that guides how our bodies regulate themselves. In other words, ageing is a software design flaw, and to understand the process scientists need to decode human genetic software.

Professor Magalhães has been exploring the question of why ageing happens uniformly, when current models work on the assumption that we accumulate ‘damage’ randomly, and has recently had a review published on the subject in the open access scientific journal, Genome Biology.

“If we imagine that the human body is a bit like a computer, the paper suggests that ageing is not an accumulation of damage to the hardware, but a process driven by design flaws in the software, a radical departure from damage-based theories that until now have prevailed in ageing research,” he explained.

“Ageing is inherent to all human beings. It is widely thought that ageing occurs due to the accumulation of various forms of molecular damage. What if, however, ageing changes are not primarily a result of a build-up of stochastic, random damage but are rather a product of regulated processes?

“In other words, what if we age not because of inevitable damage to the hardware but rather because of the software, defined as the DNA code that orchestrates how a single cell develops into an adult organism? As a result, we could see ageing is an information problem.”

He suggests that medical interventions to combat ageing could be based on a faulty premise and needs to be reconsidered in light of the uniform, DNA-encoded nature of ageing.

Professor Magalhães compares the challenge of understanding ageing to how a computer system functions, likening cells and their components to computer hardware, and genetic information to software.

He argues that interventions akin to a computer restart, such as cell reprogramming, which is also known as epigenetic rejuvenation, could hold clues for future interventions to promote healthy ageing.

In addition, Professor Magalhães warns that existing treatments which work on the basis that ageing is an accumulation of cell damage over time, are unlikely to lead to broad positive impacts.

He said: “Seeing ageing as the outcome of ‘flaws’ in our software has important implications for studying and developing interventions for ageing. Traditional anti-ageing interventions targeting damage, like oxidative damage and telomere shortening, will have limited success.

“By contrast, ageing therapies will only be effective if targeting the software rather than the hardware. Seeing ageing as a programmed process would transform our perception of the ageing process with multiple and profound implications.”

Professor Magalhães believes understanding the biology of ageing would shed important light on the cause of age-related diseases. He said: “I suggest that design flaws in the developmental software program contribute to the development of many age-related diseases. Even cancer, which is largely due to molecular damage, is influenced by ageing processes.”

Professor Magalhães is not alone in his thinking. A 13-year study by researchers at Harvard University has also shown that the modification of gene expression can lead to cell ageing.

The study, published in the journal Cell, suggests it is the way DNA is governed that drives ageing.

Put simply. the Harvard study is suggesting that ageing doesn’t mean that cells are damaged and incapable of behaving like young cells, but that something has got lost in translation in their genetic make-up.

The researchers say that in theory, if epigenetic (the study of stable changes in cell function that do not involve alterations in the DNA sequence) interventions are used to get cells back on the right track, they can ‘remember’ how to be young and fully functioning again, effectively reversing the ageing process.

In the main experiment using mice, the scientists at Harvard mimicked breaks in chromosomes that cells experience every day in response to things such as breathing, exposure to sunlight and contact with certain chemicals.

They ensured these breaks did not occur in the coding regions of the DNA so mutations were prevented from occurring over time. The team noticed that the epigenome grew disorganised leading to more aged looks and behaviour.

Next, they delivered gene therapy to reverse the changes and found the organs and tissues had resumed their youthful state.

The paper’s senior author, David Sinclair, a professor of genetics in the Blavatnik Institute at Harvard Medical School and co-director of the Paul F Glenn Center for Biology of Aging Research, said: “It’s like rebooting a malfunctioning computer,” explaining that the therapy “set in motion an epigenetic programme that led cells to restore the epigenetic information they had when they were young. It’s a permanent reset.”

Dr Sinclair hopes the work inspires other scientists to study how to control ageing to prevent and eliminate age-related diseases and conditions in humans, such as cardiovascular disease, type 2 diabetes, neurodegeneration, and frailty.

“These are all manifestations of ageing that we’ve been trying to treat with medicines when they arise, which is almost too late,” he said.

Co-first author Jae-Hyun Yang, a research fellow in genetics in the Sinclair lab. added: “We expect the findings will transform the way we view the process of ageing and the way we approach the treatment of diseases associated with ageing,”

The ultimate goal, Dr Sinclair  concluded, would be to address the root causes of ageing to extend human health span: the number of years that a person remains not just alive, but well.

Medical applications are a long way off and will take extensive experiments in multiple cell and animal models. But, Dr Sinclair said, scientists should think big and keep trying to achieve such dreams.

“We hope these results are seen as a turning point in our ability to control aging,” said Dr Sinclair. “This is the first study showing that we can have precise control of the biological age of a complex animal; that we can drive it forwards and backwards at will.

“We’re talking about taking someone who’s old or sick and making their whole body or a specific organ young again, so the disease goes away. It’s a big idea.”

 

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Gut microbes from aged mice induce inflammation in young mice

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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.

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Evening exercise benefits elderly hypertensives

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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.

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Revolutionising cancer treatment: intracellular protein delivery using hybrid nanotubes

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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.

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