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Mutations across animal kingdom shed light on ageing

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The study analysed genomes from 16 species of mammal, from mice to giraffe

The first study to compare the accumulation of mutations across many animal species has shed new light on decades-old questions about the role of these genetic changes in ageing and cancer.

Researchers from the UK’s Wellcome Sanger Institute found that despite huge variation in lifespan and size, different animal species end their natural life with similar numbers of genetic changes.

The study, published today in Nature, analysed genomes from 16 species of mammal, from mice to giraffes.

The authors confirmed that the longer the lifespan of a species, the slower the rate at which mutations occur, lending support to the long-standing theory that somatic mutations play a role in ageing.

Genetic changes, known as somatic mutations, occur in all cells throughout the life of an organism. This is a natural process, with cells acquiring around 20 to 50 mutations per year in humans.

Most of these mutations will be harmless, but some of them can start a cell on the path to cancer or impair the normal functioning of the cell.

Since the 1950s, some scientists have speculated that these mutations may play a role in ageing. But the difficulty of observing somatic mutations has made it challenging to study this possibility.

In the last few years, technological advances have finally allowed genetic changes to be observed in normal tissues, raising hopes of answering this question.

Peto’s paradox

Another long-standing question is Peto’s paradox. Since cancers develop from single cells, species with larger bodies (and therefore more cells) should theoretically have a much higher risk of cancer.

Yet cancer incidence across animals is independent of body size. Animal species with large bodies are believed to have evolved superior mechanisms to prevent cancer.

Whether one such mechanism is a reduction in the accumulation of genetic changes in their tissues has remained untested.

In this study, researchers at the Wellcome Sanger Institute set out to test these theories by using new methods to measure somatic mutation in 16 mammalian species, covering a wide range of lifespans and body masses.

This included species such as human, mouse, lion, giraffe, tiger, and the long-lived, highly cancer-resistant naked mole-rat, with samples provided by a number of organisations including the Zoological Society of London.

Whole-genome sequences were generated from 208 intestinal crypts taken from 48 individuals, to measure mutation rates in single intestinal stem cells.

Analysis of the patterns of mutations (or mutational signatures) provided information on the processes at work.

The researchers found that somatic mutations accumulated linearly over time and that they were caused by similar mechanisms across all species, including humans, despite their very different diets and life histories.

Evidence of a possible role of somatic mutations in ageing was provided by the researchers’ discovery that the rate of somatic mutation decreased as the lifespan of each species increased.

“To find a similar pattern of genetic changes in animals as different from one another as a mouse and a tiger was surprising,” said Dr Alex Cagan of Wellcome Sanger Institute.

“But the most exciting aspect of the study has to be finding that lifespan is inversely proportional to the somatic mutation rate. This suggests that somatic mutations may play a role in ageing, although alternative explanations may be possible.

“Over the next few years, it will be fascinating to extend these studies into even more diverse species, such as insects or plants.”

The search for an answer to Peto’s paradox goes on, however.

After accounting for lifespan, the authors found no significant association between somatic mutation rate and body mass, indicating that other factors must be involved in larger animals’ ability to reduce their cancer risk relative to their size.

“The fact that differences in somatic mutation rate seem to be explained by differences in lifespan, rather than body size, suggests that although adjusting the mutation rate sounds like an elegant way of controlling the incidence of cancer across species, evolution has not actually chosen this path,” said Dr Adrian Baez-Ortega of Wellcome Sanger Institute.

“It is quite possible that every time a species evolves a larger size than its ancestors – as in giraffes, elephants and whales – evolution might come up with a different solution to this problem. We will need to study these species in greater detail to find out.”

Despite vast differences in lifespan and body mass between the 16 species studied, the quantity of somatic mutations acquired over each animal’s lifetime was relatively similar.

On average a giraffe is 40,000 times bigger than a mouse, and a human lives 30 times longer, but the difference in the number of somatic mutations per cell at the end of lifespan between the three species only varied by around a factor of three.

Understanding the exact causes of ageing remains an unsolved question and an area of active investigation.

Ageing is likely to be caused by the accumulation of multiple types of damage to our cells and tissues throughout life, including somatic mutations, protein aggregation and epigenetic changes, among others.

Comparing the rates of these processes across species with very different lifespans can shed light on their role in ageing.

“Ageing is a complex process, the result of multiple forms of molecular damage in our cells and tissues,” said Inigo Martincorena of Wellcome Sanger Institute.

“Somatic mutations have been speculated to contribute to ageing since the 1950s, but studying them had remained difficult.

“With the recent advances in DNA sequencing technologies, we can finally investigate the roles that somatic mutations play in ageing and in multiple diseases.

“That this diverse range of mammals end their lives with a similar number of mutations in their cells is an exciting and intriguing discovery.”

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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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Heat waves damage humans’ vital organs, shows new study

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Researchers from the University of California, Irvine have found evidence of the molecular causes of the damaging impact heat stress causes on the gut, liver and brain in the elderly.

The researchers suggest these findings point to the potential of developing precise prognostic and therapeutic interventions.

These organs have a complex and multidirectional communication system that touches everything from our gastrointestinal tract to the nervous system. Whether it is our brain affecting hunger or the liver influencing mental health, understanding the gut-liver-brain communication or “axis” is crucial to protecting human health.

Their study, which was conducted on mouse models, is published in the journal Scientific Reports, a Nature Portfolio journal. It is one of the first to fill the knowledge gap on the effects of heat stress on a molecular level of this crucial biological conversation.

“Inflammation in the brain and spine contributes to cognitive decline, compromises the ability to form new neurons and exacerbates age-related diseases,” said corresponding author, Saurabh Chatterjee, a professor of environmental & occupational health at the UC Irvine Program in Public Health. “By investigating the effects of heat stress on the gut-liver-brain crosstalk, we can better protect our increasingly vulnerable aging population.”

Using RNA analysis and bioinformatics to analyse elderly, heat-stressed mice, Chatterjee and his team found evidence of heat stress-affected genes in the brain and liver. A significant increase in the production of ORM2, a liver-produced protein, was observed in the heat-stressed mice. The control group of unstressed mice did not show a change, providing proof of organ dysfunction in the heat-stressed mice.

Researchers believe that increased secretion of ORM2 is a coping mechanism that may be due to gut inflammation and imbalance. In addition, ORM2 may impact the brain through a leaky blood-brain barrier, emphasizing intricate multi-organ crosstalk.

Additionally, the study shows the potential to use ORM2 for targeted biomarker interventions to prevent liver disease in heat exposure. This observation advances molecular insights into the pathophysiology of adverse heat events and will serve as a foundation for future research.

“Our findings have the potential to be used for the development of prognostic and therapeutic markers for precise interventions,” said Chatterjee. “In a dynamically changing global landscape, the imminent threat of climate change is evident in rising temperatures, raising concerns about intermittent heat waves. Our heating planet is undoubtedly leading to acute and chronic heat stress that harms the health of our aging population.”

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