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Stanford researchers are closer to understanding how muscles weaken

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Stanford Muscke ageing research

How do muscles weaken and can this decline be slowed? Stanford researchers are seeking an answer.

It’s estimated that sarcopenia, which is characterised by debilitating muscle frailty, affects about 30 per cent of people over 80 and costs the US around $380 billion each year.

But Stanford Medicine researchers are working towards a deeper understanding of how muscles weaken from ageing or disease, and whether it’s possible to combat this decline.

In 2021, the group showed that blocking the activity of 15-PGDH in 24-month-old laboratory mice significantly enhances the animals’ leg strength and endurance when running on a treadmill. (Laboratory mice typically live about 26 to 30 months.) But it wasn’t clear exactly how.

This new research shows that the effect is due to the restoration of lost connections between the nerves and the muscle.

These connections, called neuromuscular junctions, are how the brain signals muscles to contract. As people age, some of these connections are lost, causing muscle contractions to become less powerful and muscles to atrophy. People typically lose muscle mass and strength — as much as 10% per cent per decade — after the age of 50.

The research is the first to show that damaged motor neurons — nerves connecting the spinal cord to muscles — can be induced to regenerate in response to drug treatment and that lost strength and muscle mass can be at least partially regained. It suggests that, if similar results are seen in humans, the drug may one day be used to prevent muscle loss of muscle strength due to aging or disease or to hasten recovery from injury.

The research found that a small molecule previously shown to enhance strength in injured or old laboratory mice does so by restoring lost connections between nerves and muscle fibres, Stanford Medicine researchers have found.

The molecule blocks the activity of an aging-associated enzyme, or gerozyme, called 15-PGDH that naturally increases in muscles as they age. The study showed that levels of the gerozyme increase in muscles after nerve damage and that it is prevalent in muscle fibres of people with neuromuscular diseases.

“There is an urgent, unmet need for drug treatments that can increase muscle strength due to aging, injury or disease,” said Helen Blau, PhD, professor of microbiology and immunology. “This is the first time a drug treatment has been shown to affect both muscle fibers and the motor neurons that stimulate them to contract in order to speed healing and restore strength and muscle mass. It’s unique.”

Blau, the Donald E. and Delia B. Baxter Foundation Professor and director of the Baxter Laboratory for Stem Cell Biology, is the senior author of the study, which was published online this week in Science Translational Medicine.

Blau’s previous research showed that a molecule called PGE2 is critical to the function of stem cells in muscle fibers that repair damage — including the microtears from exercise that lead to an increase in muscle mass and strength. They subsequently showed that levels of 15-PGDH, which breaks down PGE2, increase in the muscles with age and that the loss of strength with aging could be overcome by inhibiting the activity of this PGE2-degrading enzyme.

“PGE2 is part of the body’s natural healing mechanism, and its levels increase in muscle after injury,” Blau said. “We wanted to learn how age triggers an increase in 15-PGDH, and therefore the degradation and loss of PGE2.”

The researchers knew that muscles become less innervated, or infiltrated with nerves, as people and animals age. They wondered if that loss could be what triggers the rising levels of 15-PGDH.

“We found that when you cut the nerve that innervates the leg muscles of mice, the amount of 15-PGDH in the muscle increases rapidly and dramatically,” Blau said.

“This was an exciting new insight. But what surprised us most was that when these mice are treated with a drug that inhibits 15-PGDH activity, the nerve grows back and makes contact with the muscle more quickly than in control animals, and that this leads to a faster recovery of strength and function.”

Additional experiments showed that treatment with the drug restored neuromuscular junctions lost during ageing and increased muscle strength and function in old laboratory mice. The researchers also identified discrete clumps of 15-PGDH in the muscle fibres of people with several types of neuromuscular disorders suggesting that the gerozyme may have a role in causing these human disorders.

Blau and her colleagues plan to investigate at a molecular level how neural growth is stimulated by blocking 15-PGDH activity. Blau has also co-founded a company, Epirium Bio, to develop similar drugs for use in humans. Although her lab is still conducting animal studies, the company hopes to launch a clinical trial within the next year or so.

“Our next steps will be to examine whether blocking 15-PGDH function in people with spinal muscular atrophy can increase lost muscle strength in combination with gene therapy or other treatments,” Blau said. “We are also looking at ALS to see if something like this might help these patients. It’s really exciting that we are able to affect both muscle function and motor neuron growth.”

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Older adults hospitalised for heart failure had high risk of kidney complications, finds study

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In a study of Medicare beneficiaries, researchers from Brigham and Women’s Hospital found that one year after hospitalisation for heart failure, six per cent of patients had progressed to dialysis.

Researchers from Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, have found links between heart failure and kidney disease that support new approaches for integrating the care of these conditions.

In an analysis that included adults ages 65 and older who were hospitalised for heart failure from across 372 sites in the US, researchers found that patients had a substantial risk of kidney complications, with approximately six per cent progressing to dialysis within a year of being hospitalised for heart failure. The new results are published in JAMA Cardiology.

“We know that heart and kidney health are highly interconnected, but management of heart and kidney disease remains relatively siloed, and kidney health often isn’t prioritised in patients with heart disease until advanced stages,” said first author John Ostrominski, MD, a fellow in Cardiovascular Medicine and Obesity Medicine at the Brigham.

“Declining kidney function is often asymptomatic until late in the disease course, but even less advanced stages of kidney impairment can have important implications for cardiovascular health. Hence, there’s a need for analyses that assess kidney outcomes in people with heart failure.”

About two thirds of older adults with heart failure have abnormal kidney function. However, few analyses to date have investigated the occurrence of clinically relevant kidney outcomes, such as hospitalisation for acute kidney injury or dialysis, in patients with heart failure.

Evaluating these more recognisable and patient-centered outcomes, according to Ostrominski, may result in substantial changes to the way that heart and kidney disease are managed together in the clinic.

The study analysed Medicare claims data from 85,298 patients over the age of 65 who were hospitalised with heart failure between 2021 and 2024. The data was sourced from the Get with the Guidelines-Heart-Failure Registry, an initiative supported by the American Heart Association that seeks to connect hospitals with current evidence-based guidelines and accurate measurement tools to improve care quality and industry practices. The registry is also proving a valuable source of information for researchers examining trends in health outcomes for patients with heart failure.

In the present study, 63 percent of patients were discharged with significantly impaired kidney function, as measured by their rate of filtration. The researchers also found that the risk of adverse kidney outcomes increased steeply in patients with lower kidney function. By one year after discharge, six per cent of patients were on dialysis, and seven per cent of patients were either on dialysis or had progressed to end stage kidney disease.

The findings suggest that at the individual provider level, cardiologists should prioritise assessing kidney function – including measuring kidney filtration and looking for evidence of protein in the urine, also known as albuminuria – in all patients with heart failure, and, when indicated, consider heart therapies that are known to improve kidney outcomes.

More broadly, the study emphasises the need for systemic changes that better support the simultaneous management of heart and kidney disease, including establishing clinics focused on integrating these two care areas, incorporating kidney outcomes into health care performance metrics for cardiovascular diseases, and expanding Medicare reimbursement protocols for interdisciplinary chronic care management.

Researchers at Mass General Brigham are actively engaged as sites for clinical trials evaluating newer treatment strategies for individuals with cardiovascular and kidney disease. The Accelerator for Clinical Transformation team is also developing new ways of delivering care—including medications with established kidney benefits—to eligible patients with and without heart failure.

“The trends we’ve observed aren’t especially surprising given what we know about the links between heart and kidney health, but what’s important is that this research emphasises the scope of the problem and gives us information we can act upon to directly improve clinical outcomes in patients with heart failure,” said Ostrominski.

“There are important opportunities for patients and providers, healthcare institutions, and, at the broader state and national levels, in terms of healthcare policy that could make a big difference for patients.”

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Heart healthy behaviours may help reverse rapid cell aging – study

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The benefits gained with higher lifestyle scores may be associated with the positive influence of heart disease risk factors on the aging of the body and its cells, finds a new study.

The benefit of better heart health may be associated with the positive impact of heart healthy lifestyle factors on biological aging (the age of the body and its cells), according to new research published in the Journal of the American Heart Association.

According to the American Heart Association’s 2024 Heart Disease and Stroke Statistics, heart disease and stroke claimed more lives in the US in 2021 than all forms of cancer and chronic lower respiratory disease combined, and also accounted for approximately 19.91 million global deaths.

This study analysed whether a chemical modification process known as DNA methylation, which regulates gene expression, may be one mechanism by which cardiovascular disease health factors affect cell aging and the risk of death.

DNA methylation levels are the most promising biomarker to estimate biological age. To some degree, biological age is determined by your genetic makeup, and it can also be influenced by lifestyle factors and stress.

Researchers examined health data for 5,682 adults (mean age of 56 years; 56% of participants were women) who were enrolled in the Framingham Heart Study, an ongoing, large, multigenerational research project aimed at identifying risk factors for heart disease.

Using interviews, physical exams and laboratory tests, all participants were assessed using the American Heart Association’s Life’s Essential 8 tool. The tool scores cardiovascular health between 0-100 (with 100 being the best) using a composite of four behavioral measures (dietary intake, physical activity, hours slept per night and smoking status) and four clinical measurements (body mass index, cholesterol, blood sugar and blood pressure).

Each participant was also assessed using four tools that estimate biological age based on DNA methylation and a fifth tool that assesses a person’s genetic tendency towards accelerated biological aging. Participants were followed for 11-14 years for new-onset cardiovascular disease, cardiovascular death or death from any cause.

The analysis found:

  • For each 13-point increase in an individual’s Life’s Essential 8 score, the risk of developing cardiovascular disease for the first time was reduced by about 35 per cent death from cardiovascular disease was reduced by 36 per cent and death from any cause was reduced by 29 per cent.
  • In participants with a genetic risk profile making them more likely to have an accelerated biological age, the Life’s Essential 8 score had a larger impact on outcomes potentially via DNA methylation, i.e., DNA methylation accounted for 39 pre cent, 39 per cent, and 78 per cent reduction in the risk of cardiovascular disease , cardiovascular death and all-cause death, respectively.
  • Overall, about 20 per cent of the association between Life’s Essential 8 scores and cardiovascular outcomes was estimated to be due to the impact of cardiovascular health factors on DNA methylation; in contrast, for participants at higher genetic risk, the association was almost 40 per cent.

Jiantao Ma, PhD, senior study author and an assistant professor in the division of nutrition epidemiology and data science at the Friedman School of Nutrition Science and Policy at Tufts University in Boston, said: “While there are a few DNA methylation-based, biological age calculators commercially available, we don’t have a good recommendation regarding whether people need to know their epigenetic age.

“Our message is that everyone should be mindful of the eight heart disease and stroke health factors: eat healthy foods; be more active; quit tobacco; get healthy sleep; manage weight; and maintain healthy cholesterol, blood sugar and blood pressure levels.”

Randi Foraker, Ph.D., M.A., FAHA, co-author of the Life’s Essential 8: Updating and Enhancing the American Heart Association’s Construct of Cardiovascular Health, said the findings are consistent with prior research.

“We know that modifiable risk factors and DNA methylation are independently associated with cardiovascular disease. What this study adds is that DNA methylation may serve as a mediator between risk factors and cardiovascular disease,” said Foraker, who is a professor of medicine at the Institute for Informatics, Data Science and Biostatistics and director of the Center for Population Health Informatics, both at Washington University School of Medicine in St. Louis, Missouri.

“The study highlights how cardiovascular health can impact biological aging and has important implications for healthy aging and prevention of cardiovascular disease and potentially other health conditions.”

As the study is an analysis of previously collected health data, it cannot prove a cause-and-effect relationship between cardiovascular health risk factors and DNA methylation.

In addition, DNA methylation measures were  from a single time point, which limits the validity of the mediation effect. The study’s findings are also limited because the participants were predominantly of European ancestry, so the interactions of Life’s Essential 8 and genetic aging found in this study may not be generalizable to people of other races or ethnicities.

“Currently, we are expanding our research to include people of other racial and ethnic groups to further investigate the relationship of cardiovascular risk factors and DNA methylation,” Ma said.

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€37.5 million for regenerative medicine using smart materials

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A new collaboration has received €37.5 million for regenerative medicine using smart materials to help boost research aiming to cure chronic diseases in an ageing population.

The DRIVE-RM consortium has been awarded the funding under the prestigious NWO SUMMIT programme.

The DRIVE-RM, led by Professor of Experimental Nephrology Marianne Verhaar from UMC Utrecht, collaboration involves UMC Utrecht, Utrecht University, Eindhoven University of Technology, Maastricht University, and the Hubrecht Institute, focusing on smart materials that assist the body in healing.

Regenerative medicine involves repairing or replacing damaged tissues and organs by leveraging the body’s own healing processes. DRIVE-RM specifically focuses on material-driven regeneration, using intelligent, lifelike, or even living materials that can prompt the human body to generate new tissue. This approach could radically change the treatment of chronic diseases such as kidney failure, heart failure, and worn joints in the future.

Verhaar commented: “Over the past 20 years, we have established strong collaborative efforts in regenerative medicine in the Netherlands with several large, innovative, and successful projects like the MDR Gravitation consortium. The SUMMIT grant is a wonderful recognition of this work and underscores the importance of regenerative medicine as a leading field in the Netherlands.”

The involved institutes have been collaborating for some time, resulting in valuable innovations. One example is a synthetic, biodegradable blood vessel that aids the body in regenerating blood vessels.

“With the consortium, we developed a blood vessel made of a degradable material that is gradually replaced by the body’s own tissue,” said Verhaar. “It can function immediately as a blood vessel and does not lose functionality as the body takes over. This innovation beautifully combines biology and technology. Now, we will see if it also works well in patients.”

DRIVE-RM is led by five outstanding scientists, all experienced in leading innovative research projects. In addition to Marianne Verhaar, who focuses on kidney and vascular regeneration, the team contains Carlijn Bouten (TU/e, cardiovascular regeneration and tissue technology), Jos Malda (Utrecht University and UMC Utrecht, biofabrication and bone/cartilage regeneration), Jeroen Bakkers (Hubrecht Institute and UMC Utrecht, regenerative biology and heart regeneration), and Clemens van Blitterswijk (Maastricht University, tissue technology and biomaterials).

The DRIVE-RM project takes a multidisciplinary approach, integrating for example Utrecht innovations such as organoids and 4D bioprinting with the technical and material expertise of TU/e and Maastricht University. This leads to new insights in directing repair processes from the level of individual cells to whole organs. These combinations are essential for customising treatments tailored to individual patients and their specific conditions.

A new approach is needed

The number of people with chronic diseases is increasing significantly, mainly due to aging populations. This leads to human suffering and high healthcare costs.

“Regenerative medicine offers a promising opportunity to effectively treat chronic conditions by encouraging the body to heal itself,” continued Verhaar.

“Our scientists aim to fully understand the repair processes of tissues and organs in the patient and then direct this with implantable smart materials.”

The DRIVE-RM consortium focuses on developing new treatments for heart failure, kidney failure, and disorders of bones, cartilage, and joints.

“Besides advancing scientific research and technological innovation, DRIVE-RM also provides a platform for collaboration with clinicians to make the translation to clinical practice,” added Verhaar, “and with ethicists to address ethical issues surrounding regenerative therapies.”

Together with the involved Health Technology Assessment experts, this provides a framework that ensures these advanced interventions remain affordable and accessible.

Enabling future generations of scientists

The DRIVE-RM consortium places great emphasis on maintaining a healthy, inclusive, and diverse research culture and training the next generation—a key goal of the SUMMIT program. Therefore, the team explicitly includes emerging talents who will continue to strengthen Dutch research in regenerative medicine.

Verhaar concludes, “Ultimately, DRIVE-RM is more than just a research initiative; it is a vision for the future of healthcare. A future in which chronic diseases can truly be cured. By collaborating with leading academic institutions, DRIVE-RM aims to make these visionary treatments a reality.”

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