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Relax. Stress-induced biological ageing can be reversed

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Conventional wisdom has it that stress turns your hair grey. And there are those who maintain that too much mental and emotional pressure is ageing too.

The jury is still out on whether stress can indeed lead to loss of hair colour. But there is mounting evidence that the diverse pressures and tensions life throws up can lead to biological ageing in humans.

However, new research suggests this damage can be reversed in as little as a few days once the chronic tension is removed.

The study from a multidisciplinary team of scientists published in the journal Cell Metabolism, has shown that stress can both speed up and reverse the biological ageing of humans.

The authors write: “In the most fundamental sense, our data reveals the dynamic nature of biological age; stress can trigger a rapid increase in biological age, which can be reversed.”

The US-led team drawn from the Duke University School of Medicine in Durham, North Carolina, and the Brigham and Women’s Hospital in Boston, Massachusetts, which is a teaching centre of Harvard Medical School, measured changes in biological age in both humans and mice in response to a number of stressful situations.

Repeatedly they found that biological ageing increased during stressful situations such as major surgery, pregnancy, and severe Covid-19, but that once the anxiety-ridden event was over, ageing was partly or completely restored to baseline in a matter of months, if not days.

The authors write: “A clear pattern that emerged over the course of our studies is that exposure to stress increased biological age. When the stress was relieved, biological age could be fully or partially restored.”

The premise of the research carried out on both humans and mice is that chronological and biological age aren’t necessarily the same. Increasing evidence in animal models and humans indicates that biological age can be influenced by disease, drug treatment, lifestyle changes, and environmental exposures, among other factors.

For example, just because your birth certificate says you’re 58 doesn’t mean your biological age tallies. If you have led a healthy life and aren’t suffering from any illnesses, then your biological age could be that of someone five or even 10 years younger.

However, the reverse would be true of someone who hasn’t led a healthy life.

The question the researchers wanted to answer is whether a recovery period following a stressful event could reverse biological ageing.

Co-senior study author James White of Duke University School of Medicine, said: “Previous reports have hinted at the possibility of short-term fluctuations in biological age, but the question of whether such changes are reversible has, until now, remained unexplored. Critically, the triggers of such changes were also unknown.”

Fellow co-senior study author Vadim Gladyshev of Brigham and Women’s Hospital added: “Despite the widespread acknowledgment that biological age is at least somewhat malleable, the extent to which biological age undergoes reversible changes throughout life and the events that trigger such changes remain unknown.” 

To find out the team harnessed the power of DNA methylation clocks, which use biomarkers of growing old which can predict chronological age with remarkable accuracy and infer health status as an indicator of biological age.

They measured changes in biological age in humans and mice in response to various stressful stimuli. In one set of experiments, the researchers surgically attached pairs of mice that were 12-weeks-old and 20 months old in a procedure known as heterochronic parabiosis.

The results revealed that biological age may increase over relatively short time periods in response to tension, but this rise is transient and trends back toward baseline following recovery from stress.

At epigenetic, transcriptomic, and metabolomic levels, the biological age of young mice was increased by heterochronic parabiosis and restored following surgical detachment.

First author Jesse Poganik of Brigham and Women’s Hospital, said:  “An increase in biological age upon exposure to aged blood is consistent with previous reports of detrimental age-related changes upon heterochronic blood-exchange procedures. However, reversibility of such changes, as we observed, has not yet been reported.

“From this initial insight, we hypothesized that other naturally occurring situations might also trigger reversible changes in biological age.”

One interesting find was that people recovering from severe covid-19 using an immunosuppressive drug called tocilizumab had a faster recovery time. This, along with the other findings, led the report authors to hint at the idea of therapeutic interventions such as an anti-ageing drug.

Since ageing can be reversed, the authors write: “This implies both the existence of intrinsic mechanisms to reverse increased biological age and the opportunity to reverse transient increases in biological age therapeutically.”

They further added that their findings suggest that severe stress increases mortality “at least in part, by increasing biological age.  This notion immediately suggests that mortality may be decreased by reducing biological age and that the ability to recover from stress may be an important determinant of successful aging and longevity.”

The team admits there are limitations to the study, however. They relied mainly on DNA methylation clocks to infer biological age in the human studies because these tools are the most powerful aging biomarkers currently available.

And additionally it’s not clear how short-term fluctuations in biological ageing and recovery may affect long-term ageing.

But Dr White said: “Our study uncovers a new layer of aging dynamics that should be considered in future studies.”

There have been other recent studies looking at slowing biological ageing. One conducted by scientists at Duke-NUS Medical School, National Heart Centre Singapore (NHCS) in collaboration with colleagues in China and the US, looked at a novel method of rapidly and precisely measuring the length of a single telomere – the caps at the ends of chromosomes that protect our genetic materials from the brunt of cellular wear and tear – to determine the key markers of biological ageing.

Another study conducted in the US indicated it may be possible to reverse the body’s biological clock in as little as two months with diet and lifestyle changes. Five women following a tailored ‘longevity’ diet and lifestyle programme saw their biological age reduced by up to 11 years in the small study looking at whether time can be turned back.

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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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